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David Tarin

Understanding
Cancer
The Molecular Mechanisms, Biology, Pathology and
Clinical Implications of Malignant Neoplasia
Understanding Cancer
David Tarin

Understanding Cancer
The Molecular Mechanisms, Biology,
Pathology and Clinical Implications
of Malignant Neoplasia

123
David Tarin
University of California, San Diego
San Diego, CA, USA

ISBN 978-3-030-97392-6 ISBN 978-3-030-97393-3 (eBook)

https://doi.org/10.1007/978-3-030-97393-3

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or
part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and
retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter
developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed
to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty,
expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been
made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional
affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
I dedicate this book to my wife Dawn, my constant colleague, friend,
supporter and my muse.
And my family for their love and patience, now and in bygone years.
Preface

The Molecular Mechanisms, Biology, Pathology and Clinical Implications

of Malignant Neoplasia

The purpose of this book is to provide a broad overview of the phenomenon of cancer as seen
in many different multicellular living creatures in the natural world, including plants. From the
assembled information, it also aims to derive detailed generally applicable concepts, valid for
all types of cancers, which are useful for understanding the origin and behaviour of the disease
process and for developing methods to control it.
This is not a conventional book. It is based upon knowledge and experience acquired over a
lifetime studying the cancer problem, but it has a contrarian outlook that questions many
assumptions which are currently taken for granted. It does so in order to resolve some common
misunderstandings which are hampering progress towards deeper knowledge of major prop-
erties of neoplasms, and to present conclusions that may be pragmatically useful.
The book is written for a wide audience of physicians, veterinarians, biologists and
investigators in other basic sciences. Accordingly, some information may already be known to
specialists in one discipline, but unknown to those specialising in another. The aim is to
provide a thought provoking source of reference for all interested in this topic.
An important step in gaining understanding of the mechanisms of any biological aberration
is to define how the abnormal phenomenon differs from the “normal” healthy state. Cancers
differ in many ways from the normal organs in which they originate, but the most fundamental
of these deviations is described by a single word: miscommunication. Malfunctions of genes,
excess cellular proliferation, invasion and metastasis are all properties or manifestations of
cancers but the most fundamental causal process resulting in neoplasia is a disorder of
communications within a normally self-organising multicellular society. This book assembles
and evaluates evidence relevant to this perspective. It does not attempt to review the most
recent findings and interpretations in the field, because many of them have not yet been
corroborated by several laboratories. Instead, it focuses on information that has been repeat-
edly tested and found to be correct by many investigators in different locations. It also
incorporates personal observations and experience in the field, acquired over 60 years of
clinical and scientific work. The aim of the author is to record a body of knowledge for
subsequent physicians and scientists that will stand the test of time and remain true and
correct, permanently.

San Diego, California, USA David Tarin

July 2022

vii
Acknowledgements

It is a pleasure to acknowledge, with gratitude, the help that I have received in writing this
book and in conducting the work that it contains.
First, I wish to record and appreciate the loyal help, support and commitment, both sci-
entific and personal, that my wife Dawn has given me over so many years. She has also been
an active participant in some of the research that is described herein. Without her contribution
in many areas of professional and home life, the creation of this work would not have been
possible.
Dr Esther Peters, Associate Professor at George Mason University generously provided
unpublished illustrations of the macroscopic and microscopic features of tumours of corals
(Figs. 5.4, 5.5 and 5.6) and checked my draft manuscript of Chap. 5 for accuracy generally and
especially relating to cancers in invertebrate animals. Dr Roni Aloni, Emeritus Professor at Tel
Aviv University kindly provided pictures of plant tumours shown in Figs. 5.12 and 5.13 and
checked my draft manuscript of Chap. 5 for accuracy generally and especially relating to cancers
in plants. I am very grateful to both of these experts for their input. I also thank Dr A. Molinolo for
providing the image shown in Fig. 3.2e and Dr P. Saran for those shown in Fig. 5.11a–d.
In a career that has lasted nearly 6 decades and involved participation in clinical medicine,
diagnostic pathology and scientific research in various disciplines, I have worked with and
learned from many people. All of them, regardless of level of skill or experience, have made
contributions in different ways to the development of my thinking and, directly or indirectly, to
the content of this book. It would be impossible to mention each of them individually and, I
feel, unfair to recognise some and not others. Therefore, I would like to pay tribute to all who
have worked with me and thank them for the interest, insights and pleasure that they have
brought into my professional life. Recognising them collectively does not in any way dilute
my gratitude and appreciation; rather it includes them all in my “professional family”. I have
always felt most invigorated and stimulated when working with my mentors, colleagues and
students. Sharing the fascination of medical and scientific findings with them has, for me,
always increased the pleasure of the work.
The team of editors and production managers at Springer deserve thanks for their patience,
cooperation and good will during the several years that it has taken to complete this project.
I wish to express my sincere appreciation to them and especially to Dr Melania Ruiz and Dr
Ina Stoeck for their support and conscientious help.

ix
Guide for Readers

This guide is provided to help the reader plan how to use this treatise on cancer and how to
navigate its contents.

• This book is a reference work incorporating a large amount of information on cancer from
many sources, including the authors own diagnostic and research work.
• It is composed of several Chapters which are extensively cross-referenced to minimise
repetition of information and of illustrations and to facilitate comprehension.
• The Chapters are arranged so that they first describe the fundamental structural details and
pathological physiology of a new cancer, relative to normal healthy tissue (Chaps. 1–4),
before describing the abnormal behaviour of malignant tumours (Chaps. 7 and 8).
• Chapters on the occurrence of cancer in many other species (Chap. 5) and on the history of
study of the disease (Chap. 6) are placed after the Chapters explaining the defining features
of a cancer (Chaps. 1–4), so that the new information is easily assimilated.
• The Chapters on experimental analysis of cancer behaviour (Chaps. 7 and 8) and on
mechanisms of cancer formation (Chap. 9) occur later in the narrative, because the
information in earlier Chapters facilitates understanding of the data presented.
• Chapters 10–12 describe the impact of malignant neoplasia on the whole organism and its
implications for humans and other species on the planet.
• All chapters are designed to be useful independently, but their value is increased when the
cross-referenced information in other Chapters is readily available.
• Although this is a reference work it also has a narrative thread to help students and others
unfamiliar with the field to orientate themselves and learn sequentially.
• Even so, advanced scholars and experts will be able to use this book as a reference work, in
which the individual chapters are independently comprehensible, in any order.
• Readers of the electronic version of this book may find it helpful to know that, after using a
hyperlink, they can return to the page they were originally reading by pressing the
Command** key (Apple Mac) and the back arrow key on the computer simultaneously.
(**Alt key for a Microsoft Windows PC)

xi
Introduction

Cancer: A Remarkable Entity That Thrives on Progressive Disorder

Cancer is a disease as well as a biological process. In addition to its enigmatic origin and
behaviour, it has major deleterious effects upon the life and well-being of individuals in whom
it arises. It affects a wide range of the living world including humans and most known species
of multicellular (metazoan) animals and plants so far examined. Moreover, paleological
findings demonstrate that cancerous growths have been afflicting living organisms, including
the dinosaurs, since the dawn of time. In order, therefore, to understand and manage its
behaviour and impact, it is necessary to apply knowledge gained from the medical as well as
the biological and other basic sciences. In addition, many cancers exert influences upon
surrounding tissues and distant organs and thereby cause systemic disturbances and gener-
alised illnesses in the host, among which those known as the paraneoplastic syndromes, are the
most striking and mysterious. First recognised in humans, these syndromes have now been
documented in many domestic and wild animal species and are, therefore, an intrinsic part
of the spectrum of cancer. Accordingly, these secondary consequences of the primary dis-
turbance, also merit joint medical and basic scientific analysis.
Cancer is also a family of diverse disorders, the manifestations of which depend upon the
organ, the species and the individual in which it develops. These different clinical forms of the
disease, however, share many important characteristics and behaviours (see Chaps. 1, 3, 7 and 8),
which identify them as a mechanistically-related group of conditions, rather than completely
separate disease entities. This great variability in types of cancer results from the huge diversity
of cells and tissues composing the bodies of animals and plants. As it affects such a wide variety
of organisms and is recognisable by a signature disorganisation of local cellular and tissue
arrangement, it is likely that cancer results from failure of core mechanisms creating and
maintaining the body structure of metazoan life forms.
Terminology is also highly variable in this field and, for clarity, needs to be defined early in
this narrative. Although the term tumour has been in use for centuries (see historical section
below), to signify a cancer, it is non-specific and simply denotes a lump or nodule, which can
be caused by many processes including inflammation, infection, wound-healing callus,
developmental malformation or aneurysmal dilation. Over time, the word tumour has come to
signify a tissue overgrowth rather than a temporary swelling and will be used in the same sense
in this book. Cancer denotes a life-threatening growth capable of outward expansion and
colonisation of distant body regions. Cancers comprise a large sub-section of the group of
lesions classified as tumours. Thus, all cancers are tumours, but tumours are not all cancers.
The most accurate specific umbrella term for this whole category of pathological lesions is
neoplasm and the causative process as neoplasia. Cancer and tumour are more colloquial
commonly used terms, but all the terms defined above will be used in the following text.
Malignant and benign are loose clinical terms indicating life-threatening potential or
probable indolent or docile behaviour, respectively. They should be used with caution because
nothing in medicine, biology or life can be predicted with certainty and, over time, some

xiii
xiv Introduction

malignant tumours (cancers) can regress spontaneously while occasional benign ones can
unexpectedly become invasive and metastatic.
In recognition of the diffuse distribution of cancerous lesions in various species in nature
and their protean manifestations in different individuals, this book is structured to provide a
unified account of the field assembled from many scattered sources. It adopts a combined
approach, integrating basic science with medical experience to derive conclusions, some of
which are substantially different from prevailing beliefs about the nature, causation and pro-
gression of cancer. It also draws conclusions that are practically useful in efforts to design new
approaches to its diagnosis, treatment and prevention. In particular, insights from observations
upon the pathogenesis and behaviour of cancers are interpreted with the aid of principles
derived from experimental embryology, pathology and molecular biology to provide a
coherent new explanation of cancerous life history, which fits better with clinical and bio-
logical observations.
Contrary to current prevailing opinion, cancerous growths are not simply collections of
disorderly cells manifesting genetic abnormalities. They are maladjusted living entities that
incorporate large populations of non-neoplastic cells, which support their growth and
expansion, and parasitise their hosts, with which they share near complete genetic identity.
This book provides a multidisciplinary description of the nature, origin, life history and
behaviour of such strange new life forms, which die with the hosts from which they take
origin. Many of these growths achieve such dominance over the terrain in which they grow
that they eventually overwhelm the resources of the host, from which they take origin and
cause its death. However, modern research is revealing that many others fail to sustain their
continuing encroachment and control upon the vital supplies and services rendered by the host
and, therefore, either stall and become dormant, or completely regress.
The aim of this work is to provide the reader with a comprehensive overview of the process
of cancer formation and how it impacts upon the affected individual to produce illness and
disease. It provides information on the nature of cancer in humans, other animals and even
plants. Also included is a brief historical account of the gradual recognition of the nature of
cancer since antiquity. Most of this contextual information, which modern scholars take for
granted, has accrued over centuries, from observations on humans by their physicians and
surgeons. Advances in understanding were necessarily gradual because sufficient examples
of the disease in other animal species and in plants were not easily available until recent times
and observations on humans take substantial time to accumulate. However, we now recognise
that there are many similarities between cancers in humans and those in other organisms, but it
is important to warn that significant differences also exist and that direct extrapolation of
conclusions from experiments on other species to humans can lead to serious misconceptions.
The large amount of data to be found within this volume constitutes a reference work
documenting findings relating to the origin and behaviour of cancer in a wide variety of
multicellular organisms. The dominant focus is upon histopathological features of surgically
excised cancer biopsies and macroscopic findings of autopsies upon human cancer, which are
now becoming difficult to access because of the fast-declining frequency of autopsies on
deceased humans with the disease. A significant proportion of this information has come from
the author’s own clinical work and laboratory research over half a century and it is integrated
with well-established knowledge from the work of many other investigators, described later, to
produce a working explanation of the cancer process. It has become routine to rely upon scans
using magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) to assess
extent of cancer dissemination in patients. However, these methods cannot reliably substitute
for the ability to move and feel the organs and tissues in an autopsy and take samples for
histological confirmation. Accordingly, it is appropriate and helpful for future generations, for
the author to record observations made in this rapidly disappearing field of study. The nar-
rative provided in the following chapters describes information derived from the simplest
observations with the unaided eye and hand and collates them with those made with the most
advanced and complicated modern instruments. The melding of these observations, made
Introduction xv

using simple ancient methods, with those obtained with the most advanced current equipment
and reagents, provides a novel perspective on this disease which has affected billions of
individuals over millions of years.
The data provided here are also assembled into a coordinated new vision of the cancer
process. It is derived by integrating advances in understanding of how tissues and organs are
formed in developing embryos with pathological observations upon the progressive histolog-
ical disorganisation which characterises advancing neoplasia. From this it emerges that the
ultimate, underlying nature of this disorder goes to the very heart of how the human body is
organised and explains why cancer is such a powerful, constantly changing, threat to survival.
This vision opens new prospects for diagnosis and treatment of cancer that differ radically from
current concepts, but would complement and strengthen them. It is a work in progress, not a
polished product, which is provided as a reference source for future investigators of this
extremely ancient and widely distributed phenomenon in nature. Deeper investigation of this
progressively disorganised life-form phenomenon will counter-intuitively lead to more pro-
found understanding of how healthy, complicated, well coordinated, independently functioning
organisms emerged over aeons from simple multicellular aggregates. When we truly grasp the
significance of what cancer is showing us about the organisation of the bodies of diverse
animals and plant species, we stand in awe of the immensity of the task to control its impact on
the human body, but that increases the interest and challenge of the task which faces us.
Currently, cancer is often claimed to be a collection of several different diseases, but the
commonalities in characteristics (progressive growth, cellular multiplication, disorganised
tissue architecture, transplantability) and behaviours (invasion, infiltration, dissemination,
metastasis) exceed the differences in clinical effects and responses to treatments. So, in this
book, this disease entity will be regarded as a single type of illness with many manifestations.
Terminology

The following brief lexicon of common pathological and clinical terms is provided for clarity
of description and to aid understanding:
Connective tissue/Stroma: These terms are used interchangeably to refer to non-epithelial
tissue containing sparse cells and much extra-cellular material consisting of collagen, elastin
and reticulin fibres embedded in a featureless ground substance or matrix traversed by blood
vessels, nerves and lymphatics. It provides the structural framework of organs and tissues.
Epithelium: This describes tightly packed squamous, transitional, cuboidal or columnar
shaped cells with virtually no extra-cellular material which covers external surfaces or lines
internal spaces. It exercises protective, secretory and absorptive functions.
Tumour/Neoplasm: These terms are used interchangeably to denote a disorganised growth
of tissue. The term cancer denotes a tumour that has become invasive into adjacent tissues and
may have metastasised to other organs. Cancers are therefore a sub-category of tumours.
Malignant/benign: These are imprecise clinical terms which denote the likely impact of the
disease on the patient’s survival. Malignant implies that the tumour is invasive and/or
metastatic.
Parenchyma: The cells which perform the specific functions of an organ (eg the kidney or
liver epithelium), as distinct from the supporting stromal cells and the fibrous tissues of the
capsule, septae and blood vessels of the organ.

xvii
Contents

Part I Defining Cancer: Comparisons of Normal Development and Cancer

Formation
1 Understanding the Nature of Cancer–General Principles . . . . . . . . . . . . . . .. 3
1.1 Cancer Pathology—Analysis of Structural and Functional Disorder . . . .. 3
1.2 Normal Tissue and Organ Composition: The Social Life of Cells,
the Origins of Superorganisms and Emergent Behaviour . . . . . . . . . . . .. 7
1.3 Mechanisms of Self-assembly of Complex Organisms: Embryological
Organ Formation and Its Relevance to Cancer . . . . . . . . . . . . . . . . . . . . 12
1.4 Hierarchical Organisation of Multicellular Organisms . . . . . . . . . . . . . . . 14
1.4.1 The Molecular Dimension . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
1.4.2 The Cellular Dimension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.4.3 Tissue, Organ and Whole Organism Dimensions . . . . . . . . . . . . 21
1.5 Order and Disorder in Multicellular Systems: Cancerous
and Non-cancerous Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 24
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 24
2 The Phenomenon of Inappropriate Gene Expression and Its Biological
and Clinical Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.1 A Fundamental Characteristic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.2 Defining Inappropriate Gene Expression and Its Potential Effects . . . . . . 27
2.3 Inappropriate Gene Expression in Neoplasia . . . . . . . . . . . . . . . . . . . . . . 28
2.3.1 Tumour Invasion and Metastasis: A Striking Example
of Semi-coordinate Inappropriate Gene Expression . . . . . . . . . .. 29
2.3.2 Inappropriate Gene Expression and Cancer Metastasis
Demonstrated by Experiments with Two Isogenic Cancer
Cell Lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 36
2.3.3 Identity of Misdirected Gene Expression Programme
Causing Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 37
2.4 Clinical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 43
2.4.1 Inappropriate Gene Expression and Cancer Diagnosis . . . . . . .. 43
2.5 Inappropriate Gene Expression and Paraneoplastic Syndromes:
Tumour—Host Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 47
2.6 Mechanisms of Inappropriate Gene Expression and Silencing . . . . . . . .. 47
2.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49
2.8 Summary: Implications of Inappropriate Gene Expression for Clinical
and Research Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 50
2.9 Appendix: Refutation of the Claim That Epithelial Mesenchymal
Transition (EMT) is Needed for Metastasis . . . . . . . . . . . . . . . . . . . . .. 50
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 54

xix
xx Contents

Part II The Tumour “System”—Pathology and Pathophysiology

of the Tumour Microenvironment
3 The Tumour System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... 61
3.1 A Self-Propagating Heterogeneous Parasitic Entity . . . . . . . . . . . . . . ... 61
3.2 Differences Between Cancers and Healthy Counterpart Organs
and Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... 62
3.2.1 Some Basic Concepts About the Organisation of Cells
and Intercellular Materials in Multicellular Organisms . . . . . . . . 62
3.3 Types of Tumours—Macroscopic and Microscopic Cancer Diagnosis . . . 69
3.3.1 Macroscopic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3.3.2 Microscopic Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3.4 Histopathological Cancer Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
3.4.1 Practical Aspects of Clinical Diagnostic Work . . . . . . . . . . . . . . 73
3.4.2 Microscopic Features of Main Tumour Types . . . . . . . . . . . . . . 75
3.5 Why People Die of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
3.5.1 Pathophysiological Effects of the Cancer on the Host . . . . . . . . . 85
3.6 The Tumour as a Parasitic Organism . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4 The Host Stroma and the Tumour Microenvironment . . . . . . . . . . . . . . . . . . 93
4.1 Interactions Between Components of the Tumour System . . . . . . . . . . . . 93
4.2 The Role of the Host Stroma in Health and in Neoplasia . . . . . . . . . . . . 95
4.3 The Tumour Microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
4.4 Cancer Pathogenesis and Progression . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4.4.1 Embryological Organ Formation . . . . . . . . . . . . . . . . . . . . . . . . 99
4.4.2 Cancer Formation: Sequence of Microscopic Events
in the Boundary Zone Between Neoplastic and Non-neoplastic
Cell Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 99
4.4.3 Differences Between Stromal Events in Wound Healing
and in Early Neoplasia; Comparison of Healthy and Disorderly
Reactions to Injurious Agents . . . . . . . . . . . . . . . . . . . . . . . . . . 100
4.4.4 Specificity of Microscopic Changes in Neoplasia . . . . . . . . . . . . 101
4.4.5 Implications of Stromal and Microenvironmental Changes
for the Mechanisms of Carcinogenesis . . . . . . . . . . . . . . . . . . . 101
4.4.6 Invasion of Adjacent Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . 102
4.4.7 Matricellular Molecules, miRNA and Other Signalling
Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
4.5 Specific Examples of Clinical Conditions Showing Disturbed
Microenvironmental Conditions: Dysplasia Versus Neoplasia . . . . . . . . . 103
4.6 Why is the Histopathological Tissue Context Important? . . . . . . . . . . . . 104
4.7 Small Cancers Can Regress. Cancer Screening Follow up Studies
and Death Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
4.8 Diagnostic, Prognostic and Therapeutic Implications of Understanding
the Cancer Microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
4.9 Synthesis and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.10 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Contents xxi

Part III Prevalence of Cancer in Nature and History of Study of the Disease
5 The Biology and Natural History of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.1 An Ancient Disease Ubiquitous Among Multicellular Species . . . . . . . . . 113
5.2 Cancer in Human Populations; Geographic, Racial and Organotypic
Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
5.3 Cancer in Domestic and Farm Animals . . . . . . . . . . . . . . . . . . . . . . . . . 115
5.4 Cancer in Captive Laboratory Animals . . . . . . . . . . . . . . . . . . . . . . . . . 116
5.5 Cancer in Wild Animals and Plants: Cancer in the Wild . . . . . . . . . . . . . 116
5.5.1 Mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
5.5.2 Registry of Tumours in Other Species . . . . . . . . . . . . . . . . . . . . 118
5.5.3 Fish, Amphibians, Riverine and Lake Dwelling Species . . . . . . . 118
5.5.4 Birds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
5.5.5 Invertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
5.5.6 Neoplasms in Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
5.6 Tumours and Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
5.7 Cancer and Embryonic Development . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
5.8.1 A Cosmic Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
6 Major Events in the History of Medical Understanding of Cancer . . . . . . . . 141
6.1 Earliest Records—Egyptian and Greek Periods to 15th Century . . . . . . . 141
6.2 Sixteenth to 19th Centuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
6.3 Nineteenth Century . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
6.4 Twentieth and 21st Centuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

Part IV Causes and Mechanisms of Cancer Formation, Invasion, Metastasis

and Associated Symptoms: Clinical and Experimental Studies
7 The Behaviour of Cancers: Invasion and Metastasis I. Clinico-Pathological
Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
7.1 Hyperplasia, Atypia and the Pathological Significance of Carcinoma
in Situ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
7.1.1 Diagnostic Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
7.2 Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
7.2.1 Prognostic Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
7.3 Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
7.3.1 The Major Pathways of Metastasis . . . . . . . . . . . . . . . . . . . . . . 160
7.3.2 Circulating Cancer Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
7.3.3 The Timing of Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
7.3.4 Kinetic Sequence of Events in Metastasis . . . . . . . . . . . . . . . . . 163
7.3.5 Patterns of Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
7.3.6 The Histological Structure of Metastases Reflects Their Tissue
of Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
7.3.7 Instability of the Metastatic Process . . . . . . . . . . . . . . . . . . . . . 170
7.3.8 Is Metastasis Restricted to Tumours? . . . . . . . . . . . . . . . . . . . . 171
7.3.9 The Clinical Effects of Metastasis . . . . . . . . . . . . . . . . . . . . . . . 171
7.3.10 Summary of the Current State of Clinical and Pathological
Knowledge about of Human Cancer Metastasis . . . . . . . . . . . . . 171
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
xxii Contents

8 The Behaviour of Cancers: Invasion and Metastasis II. Experimental

Analysis of Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
8.1 Paradoxical Aspects of the Phenomenon of Cancer Metastasis . . . . . . . . 175
8.2 Methodological and Statistical Considerations . . . . . . . . . . . . . . . . . . . . 176
8.3 The Metastatic Drive of Tumour Cells—Cell Biological Aspects . . . . . . . 177
8.3.1 Clonogenicity and Clonal Evolution . . . . . . . . . . . . . . . . . . . . . 178
8.3.2 Cell Surface Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
8.3.3 Cell Surface Receptors and Cognate Ligands . . . . . . . . . . . . . . . 182
8.3.4 Proteases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
8.4 Interactions Between Cancer Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
8.5 Interactions Between Tumour Cells and Non-neoplastic Host Cells . . . . . 196
8.5.1 Further Experimental Analysis of Mechanisms Determining
Organ Distribution of Metastatic Deposits and of the Dormancy
of Disseminated Tumour Cells . . . . . . . . . . . . . . . . . . . . . . . . . 199
8.5.2 Interactions Between Tumour Cells and the Structural
Constituents of the Extra-Cellular Matrix . . . . . . . . . . . . . . . . . . 205
8.6 Genetic Basis of the Intrinsic Metastatic Drive . . . . . . . . . . . . . . . . . . . . 207
8.6.1 Modulation of Gene Expression Can Affect Metastatic
Behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
8.6.2 Transfer of Metastatic Properties with Genomic DNA . . . . . . . . 209
8.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Appendix: Original data relating to Metastasis Associated Gene or Nucleic Acid
(MAGNA) Sequence Isolated from Human Metastatic Cells . . . . . . . . . . . . . . . . 220
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

9 Causes of Cancer and Mechanisms of Carcinogenesis . . . . . . . . . . . . . . . . . . 229

9.1 Types of Carcinogenic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
9.2 Chemical Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
9.2.1 Activation and Deactivation . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
9.2.2 Tobacco Smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
9.2.3 The Roles of the International Agency for Research on Cancer
(IARC) and the World Health Organisation (WHO) . . . . . . . . . . 232
9.3 Solid State Carcinogenesis: Physical (Foreign Body) Agents: Asbestos,
Plastics and Other Foreign Body Implants . . . . . . . . . . . . . . . . . . . . . . . 232
9.3.1 Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
9.3.2 Foreign Body Carcinogenesis—Plastic Sheets . . . . . . . . . . . . . . 249
9.4 Carcinogenesis by Infective Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
9.4.1 Types of Agents: Prevalence of Viruses, Bacteria
and Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
9.4.2 Infectivity and Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
9.4.3 Mechanisms of Tumour Induction . . . . . . . . . . . . . . . . . . . . . . . 255
9.4.4 Factors Influencing Implementation or Abeyance of Viral
Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
9.5 Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
9.6 Further Mechanistic Considerations Relevant to Carcinogens
of All Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
9.6.1 Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
9.6.2 Initiation, Promotion and Progression . . . . . . . . . . . . . . . . . . . . 262
9.6.3 Timing of Action—Relationship to Cell Division . . . . . . . . . . . . 263
9.6.4 Complete Carcinogens, Co-Carcinogens and Incomplete
Carcinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
9.6.5 Relationships Between Cancer, Inflammation and Immunity . . . . 264
9.6.6 Mutations, Penetrance and Gene Networks . . . . . . . . . . . . . . . . 267
Contents xxiii

9.6.7 Carcinoma In Situ and the “Field Effect” . . . . . . . . . . . . . . . . . . 267

9.6.8 Latency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
9.6.9 Progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
9.6.10 Regression and Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
9.6.11 The Target of Action of Carcinogenic Agents: “Stem” Cells
Versus Progenitor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
10 Paraneoplastic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
10.1 Diversity of Systemic Effects of Malignancy . . . . . . . . . . . . . . . . . . . . . 281
10.2 Haematological and Vascular Syndromes . . . . . . . . . . . . . . . . . . . . . . . . 282
10.2.1 Thrombophlebitis Migrans and Other Coagulopathies . . . . . . . . . 284
10.2.2 Polycythaemia and Thrombocytosis . . . . . . . . . . . . . . . . . . . . . . 285
10.3 Cutaneous Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
10.3.1 Erythema Gyratum Repens . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
10.3.2 Acanthosis Nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
10.3.3 Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
10.4 Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
10.4.1 Cushing’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
10.4.2 Hypercalcaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
10.4.3 Hypoglycaemia and Hyperglycaemia . . . . . . . . . . . . . . . . . . . . . 289
10.4.4 Inappropriate Anti-Diuretic Hormone (IADH) Secretion . . . . . . . 289
10.5 Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
10.5.1 General Considerations Applicable to Central and Peripheral
Nervous Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
10.5.2 Syndromes Affecting the Central Nervous System . . . . . . . . . . . 291
10.5.3 Peripheral Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
10.6 Renal Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
10.6.1 Nephrotic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
10.6.2 Haematological and Hepatic Syndromes Caused by Renal
Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
10.7 Musculo-Skeletal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
10.7.1 Myaesthenia Gravis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
10.7.2 Arthritis, Polymyositis, Myopathies, Hypertrophic Pulmonary
Osteodystrophy and Finger Clubbing . . . . . . . . . . . . . . . . . . . . 295
10.8 Cachexia and Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
10.8.1 Cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
10.8.2 Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
10.9 Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
10.10 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
10.11 Unifying Concepts and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

Part V Synthesis and Significance of a New Perspective on Malignancy

11 Clinical Implications of Multi-level (Scalar) Disorganisation in Cancer . . . . . 303
11.1 The Concepts of Scale and Dimension in Body Organisation
and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
11.2 Diagnostic Implications of Multi-scale Dysfunction in Tumour Cells . . . . 304
11.2.1 At the Molecular Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
11.2.2 At the Cellular Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
11.2.3 At the Tissue, Organ and Whole Organism Scale . . . . . . . . . . . . 305
11.2.4 Prospects for Non-Invasive Diagnosis . . . . . . . . . . . . . . . . . . . . 305
xxiv Contents

11.3 Treatment and Palliation Implications of Molecular, Cellular, and Tissue

Incoordination in Tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
11.3.1 Clonal Dynamics and Choices of Therapeutic Strategies . . . . . . . 308
11.3.2 Therapeutic Implications of Disturbances at the Molecular
Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
11.3.3 Manipulating the Pathophysiology of the Tumour
Microenvironment to Enhance Cytotoxic Chemotherapy . . . . . . . 309
11.3.4 Contributions of Combined Therapeutic Modalities . . . . . . . . . . 309
11.3.5 Intrinsic Body Defence Mechanisms . . . . . . . . . . . . . . . . . . . . . 310
11.3.6 Treatment of Systemic Effects and the Value of Palliative
Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
11.4 Public Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
11.4.1 Aspects Related to Chemical Carcinogenesis . . . . . . . . . . . . . . . 311
11.4.2 Infectious Transmission of Cancer . . . . . . . . . . . . . . . . . . . . . . 312
11.4.3 Cancer from Ionising Radiation . . . . . . . . . . . . . . . . . . . . . . . . 312
11.4.4 Screening for Early Detection and Treatment of Cancer . . . . . . . 312
11.5 Wider Social Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
12 Understanding the Significance of Cancer in the Overall Spectrum
of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
12.1 Disease and Destiny—Biological Considerations . . . . . . . . . . . . . . . . . . 315
12.2 Clinical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
12.3 Research Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
12.4 A Parting Comment—Gazing into Infinity . . . . . . . . . . . . . . . . . . . . . . . 318
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
About the Author

David Tarin DM (Oxon), FRCPath is an internationally

recognised physician, pathologist and scientist who has
specialised in clinical diagnostic pathology and research on
carcinogenesis, cancer metastasis and developmental biology.
Over 6 decades he has held positions as Director of the
Comprehensive Cancer Centre at the University of California,
San Diego; Professor of Pathology at Oxford University
School of Medicine and Professor of Pathology at the Royal
Postgraduate School of Medicine, London, as well as faculty
positions at other Universities. He has also worked briefly at
the Department of Pathology and the Department of Zoology in
the University of Helsinki, Finland and at the Austrian Cancer
Institute in Vienna, Austria. In addition to the current volume,
he has published 2 other books on cancer, cited below and
multiple research and clinical articles and book chapters. He
has acted as an advisor to the US National Cancer Institute and
to the Cancer Research Campaign of the United Kingdom. He
is also widely regarded as an expert medical witness in
occupational and environmental carcinogenesis and in patho-
logical diagnosis, based on his research and clinical experience
and has testified in many jurisdictions internationally. Cur-
rently, he is Emeritus Professor of Pathology at the University
of Oxford, England, Emeritus Fellow of Green Templeton
College, Oxford and Emeritus Professor of Pathology at the
University of California San Diego.

• Tissue Interactions in Carcinogenesis; Academic Press

London 1972.
• Drug Delivery Systems Based upon the Tumour Microen-
vironment; Springer Japan 2020.

xxv
 Part I
Defining Cancer: Comparisons of Normal
Development and Cancer Formation
 Understanding the Nature
of Cancer–General Principles 1

Abstract 1.1 Cancer Pathology—Analysis

Malignant neoplasms are usually first recognised as hard of Structural and Functional Disorder
or firm solid lumps growing within, or expanding out of,
otherwise apparently healthy, organs or tissues of the Cancer is fundamentally a disorder of social organisation and
body. Closer inspection at the microscopic and communications among a cellular population, accompanied by
sub-microscopic level reveals their disorderly structure overgrowth of cells and tissues in a localised region of the
and function, compared to corresponding healthy tissues. body. It is manifested most obviously by disruption of the
This disorder results from unregulated growth patterns that microscopical structure of an organ and invasion of the cells
differ fundamentally from normal patterns seen during the composing the cancer into adjacent healthy tissues. The
embryonic development of organisms, when the body plan resulting severe structural disorganisation interferes with the
and orderly arrangements of tissues and organs are orderly spatial arrangement of cells and intercellular materials
established. This Chapter describes the differences necessary for their coordinated function. These defining char-
between normal development and cancer formation and acteristics of cancerous lesions are not easily comprehended
provides an introduction to how developing cancers can be unless one first has some visual familiarity with the orderly
recognised. The Chapter also describes how events at architecture and reproducibility of the specialised patterns of
vastly different levels or scales of organisation (whole arrangement of cells within organs of higher organisms.
body, organ, tissue, cell, molecular and sub-molecular) all Microscopical analysis of the cellular composition and
shape the emergence of a self-organising, self-sustaining arrangement within the affected area is essential for definitive
organism, composed of trillions of cells, from a single classification of a lesion as a cancer. It is the gold-standard of
fertilised egg cell. It explains how this vast cellular cancer diagnosis in clinical practice and is also vital for accu-
community is a superorganism whose identity and rate research on cancer, because many lesions which look like
behaviour constitutes an emergent phenomenon resulting neoplastic lesions to the naked eye (e.g. Fig. 1.1a–k) are
from interactions between its component cells. The actually due to infective, inflammatory or other non-cancerous
wholeness, self-regulation and adaptability of the system, disease processes. Therefore, investigators cannot perform
although obviously dependent upon events at an elemental meaningful research investigations on cancer without famil-
level, can only be properly understood at the supra-cellular iarity with the microscopical features of tumours.
level, because dissociation of the component parts for To orientate the reader, some examples of the histological
study eliminates the emergent phenomenon. In the same structure of normal, healthy organs are shown in Figs. 1.2
way as quantum mechanics does not accurately explain and 1.3, juxtaposed with the microscopical changes which
the laws of classical physics, events at the sub-microscopic are characteristic of cancerous changes in them. These are
biological level do not accurately predict the future photomicrographs of cancers of the lungs, kidneys and
behaviour of the whole living system, because many of prostate and of corresponding normal tissues, for compari-
the processes are stochastic and interactive. The informa- son. They demonstrate clearly that the regular, orderly
tion presented in this Chapter lays the foundation for later arrangement of cells and tissues composing a healthy organ
Chapters in which the breakdown of multicellular organ- is severely disrupted within a growing cancer. Many other
isation in cancers and its pathological and medical examples of this fundamental defining feature of neoplasia
consequences are described and explained. are shown in later chapters.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 3

D. Tarin, Understanding Cancer,
https://doi.org/10.1007/978-3-030-97393-3_1
4 1 Understanding the Nature of Cancer–General Principles

a
b

*
*
*
c
d

Fig. 1.1 Macroscopic and microscopic appearances of metastases and nodular lesions mimicking metastatic lesions in murine and human organs.
1.1 Cancer Pathology—Analysis of Structural and Functional Disorder 5

e f

g
h

Fig. 1.1 (continued)

6 1 Understanding the Nature of Cancer–General Principles

j k
 1.2 Normal Tissue and Organ Composition: The Social Life of Cells, the Origins of Superorganisms and Emergent Behaviour 7

b Fig. 1.1 a Normal mouse lungs. Macroscopic view. Upper and lower located in the right upper lobe (arrow). f Histology of the nodule
lobes of the left lung on the left of the picture. Upper, middle and lower showing that it is a metastasis from an adenocarcinoma. It originated
lobes of the right lung on the right. (15). b Microscopic histology of from a carcinoma in a mammary gland of the animal. g Macroscopic
the lung showing two transversely sliced bronchi surrounded by aerated view of multiple metastases in the lungs of a mouse with mammary
pulmonary alveoli and blood vessels containing red blood cells adenocarcinoma. h Histopathological confirmation that the lesions in
(H&E 40). c Lungs containing multiple nodular lesions (15). These panel g) were metastases. i Slice of human liver showing nodular
were histopathologically confirmed as pulmonary metastases. The scale cirrhosis (inset: magnified view of nodules resembling confluent
below is graduated in millimetres. d Histopathology of macroscopically metastases. Histologically these were regenerative nodules of hepatic
similar nodules (arrows) in the spleen of the same mouse. This image parenchymal cells). j Survey view of histopathology of a nodule with
shows that these nodules are pyocentric granulomata (white asterisks) necrotic centre in human lung (H&E 40). k Higher magnification of
characteristic of yersinia pseudotuberculosis infection lying in splenic the same nodule showing fungal hyphae (arrows) and mycelium at the
red pulp (black asterisk), not metastases (H&E 40). From Tarin [1] periphery of the lesion confirming that it is an aspergilloma, not a
e Lungs of a mouse with a single solid nodule resembling a metastasis metastasis (Giemsa  400)

The organisational structure of the liver, breast, bone and

other organs is extremely similar in all mammals, whether 1.2 Normal Tissue and Organ Composition:
the individual is a human sitting reading this book, a whale The Social Life of Cells, the Origins
swimming around the polar ice cap or a bat sleeping in a of Superorganisms and Emergent
cave in the Sierra Madre mountains. In all these creatures Behaviour
and in all other multicellular organisms including plants, this
highly systematic and characteristic arrangement of different The body of a multicellular organism comprises a vast cel-
cell types composing an organ of a multicellular being lular society with shared characteristics but different spe-
becomes progressively disturbed in cancerous lesions. This cialisations (cell lineages). By living as an aggregated
results in a haphazard distribution of cells compared to the community in which sub-groups of cells perform different
pattern seen in the normal counterpart, associated with specialised functions for the organism, greater efficiency,
invasion of adjacent tissues. Disproportionate and persistent security and adaptability to varying habitats is achieved by
proliferation of cells in the field of the developing tumour, division of labour among the participants. The lives of indi-
compared to healthy tissue is another important feature of vidual cells are governed by social interactions that specify
neoplasia. This proliferation has dominated the attention of their positional addresses [3–5] within the organism, as well
investigators seeking to understand the neoplastic process as their functions. Thus, for example, cells of the skin, brain,
but, in fact, the disruption of cell and tissue organisation is liver etc. are assigned specific locations which are fixed for
mechanistically, functionally and clinically more important life and only cells of the white cell series remain free to patrol
and the information assembled in this book explains why the whole body via different specific routes, which they do for
this wider perspective, which includes attention to prolifer- defence and other purposes (see Tarin [6] and Chaps. 2 and 8
ation, is appropriate. To appreciate how such disorder of this book, for further discussion of the implications of such
among cell populations can originate, propagate and spread patrolling behaviour for cancer metastasis).
within the diseased area and exert disruptive effects threat- The composite entity includes eukaryotic as well as
ening the survival of the host, it is first necessary to consider prokaryotic cells and still more ancient, assimilated entities
how normal order is created among the trillions of cellular (e.g. retro-viruses and obligate intracellular alphaproteobac-
descendants of the original fertilised egg and then main- teria). In a healthy human, all of these partners contribute
tained throughout life. significantly to the harmonious functioning of the whole.
This Chapter, therefore, describes the processes and Additionally, the retroviruses, DNA viruses and viral rem-
mechanisms involved in forming and maintaining tissues nants in the genome play important roles in regulating the life
and organs from these primordial cells and sustaining them and evolution of multicellular organisms (see Villarreal and
in the state of balanced equilibrium seen in the healthy adult Witzany [7]). This is not the place to discuss each of these
host. Subsequent Chapters present and discuss the sequence co-symbionts at length, but a couple of examples will suffice
of events occurring in the descent into cellular anarchy and to explain the concept: (a) Many different species of bacteria
progression to death, which characterises malignant neo- inhabiting the intestines of adults, complement the activities
plasia. The narrative presented throughout this book will not of host enzymes in digesting carbohydrates, lipids and pro-
attempt to include the most recent data on the topics dis- teins in the diet, synthesising vitamins especially of the B and
cussed, because these, by their very nature, still await the K groups and recycling of bile acids [8]. Germ free animals
confirmation provided by reproducibility. It will instead and human newborn infants that do not receive vitamin K
provide a verifiable record of facts that have stood the test of supplements have low prothrombin activity and can develop
time and serve as a source of reference. life threatening haemorrhages. Similarly, adult humans with
8 1 Understanding the Nature of Cancer–General Principles

a b

c d
Fig. 1.2 Examples of human lung and kidney cancers and comparable Healthy glomeruli (arrows) lie among numerous profiles of transverse
normal tissues to show histological disorganisation in cancers. a Normal slices across proximal and distal tubules in orderly arrangement. Note
human lung showing several air-containing alveoli (A) and a small that the glomeruli and tubules are embedded in a modest amount of
bronchus (B) b Adenocarcinoma of the human lung. The irregularly moderately cellular stroma. d Clear cell renal carcinoma showing
shaped glands (arrow) are lined with pleomorphic columnar cells and irregularly arranged, pale staining malignant tubules invading com-
are infiltrating dense collagenous stroma. c Normal human kidney. pressed adjacent tumour and stroma. (All H&E x250)
1.2 Normal Tissue and Organ Composition: The Social Life of Cells, the Origins of Superorganisms and Emergent Behaviour 9

a b c

d e f g

Fig. 1.3 Examples of histopathology of human prostate cancer, benign continue to contain non-neoplastic, mixed, basal and luminal cell
prostatic hyperplasias and normal prostate. a Micrograph of the populations. The other glands are frankly malignant. f Prostatic
histology of normal human prostate containing a small cyst (asterisk). adenocarcinoma composed of numerous irregularly disposed malignant
Several normal glands (G), lined by normal epithelium composed of two glands lined by a single layer of cells. The glands surround a residual
cell layers are seen separated by fibromuscular stroma (S) (H&E 100). non-neoplastic draining duct lined by a double cell layer. The outer layer
b A section showing benign prostatic hyperplasia a condition charac- of myoepithelial cells of this gland is stained brown with a peroxidase
terised by the formation of numerous nodular aggregates of benign labelled antibody to CD44v6 and the inner luminal layer of epithelial
hypertrophied glands similar to the one in this image (H&E 100). cells is highlighted only by the counter-stain. (250) From Tarin [2].
c Three areas of prostatic adenocarcinoma (bounded by dashed lines) in g Prostatic adenocarcinoma reacted with a peroxidase-labelled antibody
a background of benign prostatic hyperplasia (H&E 40). In the to prostate specific antigen (PSA). Note that some of these malignant
cancerous foci the glands are much more numerous and disorganised glands are stained brown and others are not. This is an example of
than in the benign area. d Prostatic adenocarcinoma composed of tightly tumour heterogeneity, discussed in the text (250). h Normal prostatic
packed irregular small glands (H&E, 100). e Immunohistochemical stroma consisting of smooth muscle bundles (bottom right) and fibrous
stain (brown) to demonstrate residual non-malignant glands within a connective tissue containing blood vessels (top left). (H&E 250).
sheet of malignant glands counter-stained light blue. The detection of i Nodule of benign fibromuscular (i.e. not glandular) hyperplasia
basal myoepithelial cells by the stain for high molecular weight (H&E 100). j Magnified view of the edge of a benign fibromuscular
cytokeratin (HMWCK) (100) in a few glands indicates that these nodule composed of monomorphic cells (H&E 250)

dietary vitamin K deficiency can develop haemorrhagic constitute our mitochondria, which perform essential oxida-
events when treated with broad spectrum antibiotics. These tive reactions for cellular energy generation and replicate in
phenomena demonstrate the difficult to quantitate, but coordination with the host cell. Thus, prokaryotic and
important, contributions made by intestinal microrganisms to eukaryotic organisms have, over millennia, evolved cooper-
human health. (b) The descendants of ancient Rickettsial ative relationships for mutual benefit and these consortia have
prokaryotes (alphaproteobacteria), incorporated into the developed into beings that are so sophisticated in their
eukaryotic cytoplasm by endocytosis millennia ago, now functions and capabilities that the individual components and
10 1 Understanding the Nature of Cancer–General Principles

h i j

Fig. 1.3 (continued)

the whole organisms can live their entire intertwined lives During embryonic development of multicellular organ-
without even being aware of each other’s existence. See also isms, regional specialisation of subgroups of eukaryotic cells
Chaps. 2 and 10, Sect. 9.4 for examples of the roles played results in the emergence of cell lineages dedicated to specific
by retroviral elements, incorporated aeons ago, in normal and tasks/functions, which are tightly coordinated with related
abnormal human gene regulation. tasks performed by neighbouring cell lineages to create a
The inventory of non-human organisms co-existing structurally and functionally integrated tissue, organ or body
within and upon the surfaces of the healthy human host component. In health, each lineage replicates to maintain a
includes not only a large variety of bacterial species (esti- balanced equilibrium in its population size and functional
mated at *10,000 by the Human Microbiome Project activities, in harmony with those of neighbouring lineages
[HMP]) but also fungi, small arthropods (e.g. demodex fol- within the tissue or organ. For example, in the skin the
licularis) and other minute organisms. The proportion of external surface is covered with a sheet of tightly apposed
bacteria to human cells in a human male/female has been cells bonded to each other by special junctions. This is a
estimated by various sources [9] and their results range specialised cell lineage, assembling to form a tissue called an
between 1:1 and 10:1 but are in the range of 1013 organisms. epithelium and it functions to form a protective barrier over
Hence, prokaryotic organisms constitute a significant pro- the whole organism. This layer is firmly adherent to under-
portion of the total cell population in a human being; i.e. at lying fibrous material called the connective tissue or the
least as numerous as human cells, if not much greater. This dermis, which is mainly composed of intercellular material
estimate excludes the even greater and essentially immea- secreted by different cell lineages including fibroblasts.
surable numbers of intracellular microbes (mitochondria) Among its many functions, it provides a firm substratum for
and viruses that inhabit us. attachment of the epithelium and fixes it to deeper tissues
1.2 Normal Tissue and Organ Composition: The Social Life of Cells, the Origins of Superorganisms and Emergent Behaviour 11

like muscle and adipose tissue. Within the epithelial layer, dis-assembled. Naturally, human beings and all other mul-
small groups of cells specialise further to become ticellular organisms can clearly be seen to satisfy this defi-
sub-lineages that interact with adjacent different lineages in nition. Hence, anyone now reading this article will be
the dermis to form sweat glands and hair follicles. Collec- becoming aware of the complexity of interactions among the
tively, the epithelial and connective tissues form an organ trillions of units composing themselves, that enables them to
called the skin that has protective, secretory and temperature read and understand the ideas conveyed in these pages.
control functions. This brief description serves to explain the While they read, the cells composing their lungs continue to
concept of cell lineages and how they self-assemble into exchange gases, cardiac cells continue to pump blood, the
larger units like tissues and organs which will be discussed cells of their kidneys continue to purify the blood and con-
in more detail below and in subsequent chapters. trol fluid balance, while cells of the liver and other organs
In turn these hierarchically more advanced entities com- continue their function, all without instructions from any
posed of heterogeneous specialised cell lineages (i.e. organs) obvious leader.
interact with each other, to perform more complicated spe- Superorganism is a term applied to large colonies of
cialised and coordinated functions necessary for the survival social organisms such as bees, ants, termites, certain crus-
and propagation of the whole organism. Additionally, over taceans, hydrozoans, arthropods and eusocial mammals,
immense evolutionary periods, such complex creatures such as the naked mole rat and the Damaraland mole rat, in
including humans have, as mentioned above, gradually been which individuals perform specific tasks, closely coordinated
colonised by many other species of unicellular and multi- with those of others, for the common good. It is particularly
cellular organisms, most of which interact symbiotically important to note that, in these examples the individual
with the larger host and in some cases are essential for its living elements that cooperate are multicellular organisms
survival. The numbers and relative proportions of different segregated into different specialised lineages (e.g. nurse
bacterial species in humans are now known to vary among bees, guard bees, forager bees and a queen bee) performing
different individuals of the same species and even between different functions, all co-existing in a single colony, in a
different parts of the same individual at different stages of comparable manner to cells in a multicellular animal or
life in health and disease [10]. Gradually this leads to greater plant. In some species (e.g. honey bees), a single individual
and greater complexity of the whole organism. The degree of can cycle sequentially through many of these lineages/
multi-hierarchical coordination required to maintain order functions [12], while in others (e.g. colonial hydrozoans
among colossal numbers of different living units, eukaryotic called siphonophores) [13], their identities and functions are
and prokaryotic, each capable of independent survival under fixed for life. Coordination between individual units within a
suitable circumstances, but living together harmoniously, is lineage and between different lineages is achieved by short
difficult to contemplate. The task of understanding the and long range signals carried by chemicals, sounds, elab-
interleaved and dynamically interweaving regulatory com- orate dances, electrical currents and even vibrations, but
mands between the coexisting cells increases, as one con- there is no hierarchical governing leadership. In effect, these
siders the adaptability of the composite organism to super-large collections of coordinated individuals behave as
unpredictable circumstances in the environment. single composite organisms, sometimes to the extent of
This leads us into a deeper consideration of the social life of going to war with nearby colonies/composite individuals of
cells composing an organism. Recent work on the coordina- the same species.
tion of activities of large groups of biological organisms has The parallels between the social organisation of super-
led to the recognition of an aspect of life called emergent organism type life forms described above and the internal
behaviour and of entities termed superorganisms [11]. Any- organisational processes occurring within composite multi-
one who has seen schools of thousands of fish or flocks of birds cellular organisms that we refer to as humans are obvious
execute complicated manoeuvres as a single entity without a and have been recognised by biological scholars at least
leader, will have been struck with wonder about how such since Herbert Spencer wrote about the “Principles of Soci-
coordination is achieved. The coordination of the activities of ology” in 1876. Decades of subsequent research have shown
the immense numbers of organisms composing the human that in humans the coordination of at least the eukaryotic
body is at least on the same level of complexity and, again, is components depends on short range signalling molecules
achieved without the presence of a coordinating leader. (receptors and ligands), long range chemical signals (hor-
A system is said to be emergent if its dynamic activity is mones) and electrical impulses (neural circuits). These
more than the sum of the properties of its individual parts. It messengers regulate and coordinate the behaviour of indi-
is the interaction between the components which creates new vidual cell lineages and tissues such as the epidermis or the
properties that then supervene upon and re-order the whole bone marrow or of internal organs (liver, kidneys, lungs) and
system. The superimposed properties which create the of the whole human superorganism. It is of course possible
emergent system cannot be seen when the system is that other coordination mechanisms, which are yet to be
12 1 Understanding the Nature of Cancer–General Principles

discovered, exist in our bodies. Superimposed on this level whole new individual [15]. Soon afterwards, an organising
of organisation is another hierarchy of inter-cellular inter- centre emerges in this collection of cells and directs the
actions between stationary cells and migratory or patrolling developmental fate of different regions of the cell mass. It
cells (eg lymphocytes, monocytes etc.) trafficking through achieves this by a process known as primary embryonic
tissues and organs monitoring the environment for intruders induction [15], which specifies the rostro-caudal (sagittal)
and for internal irregularities. The trafficking cells convey and dorso-ventral (coronal) axes of the future body and the
and receive information relevant to the protection of the position of the brain and spinal cord (Fig. 1.4). Subse-
internal environment. quently, the developing nervous system triggers the forma-
The significance of discussing the highly complex and tion of other organs (e.g. the eyes, ears, limbs and kidneys)
integrated regulatory systems involved in coordinating in their correct body locations, by a series of secondary
superorganisms and the components of human bodies is that inductions.
these mechanisms must necessarily persist throughout life. In the 1950s and ‘60s it was found that a series of further
They create and maintain [14] not only the structural and hierarchical inductive interactions between epithelial and
architectural integrity of our histological and macroscopic mesenchymal cell lineages specify the formation of even the
anatomy but also the dynamic equilibrium between the rel- detailed micro-anatomical structure of each individual organ
ative numbers of cells of different cell types as well as including the salivary glands, teeth, lungs, breasts, skin
physiological, biochemical and immunological processes. appendages and pancreas, among others. It also emerged that
They are also essential for rebuilding tissues and organs these interactions continue into and throughout adult life to
damaged by trauma, infection or toxic environmental agents maintain and repair organ structure [14]. The detailed evi-
such as chemicals or ionising radiation. dence for these conclusions is too extensive to provide here
The information assembled above demonstrates that the and can be accessed in excellent articles published previ-
human body displays all the qualities of a large multicellular ously by other investigators [16]. These data demonstrate
community that functions as a superorganism with emergent that the formation and maintenance of multicellular organ-
properties. Order and stability are created and maintained by isms depends upon reciprocal interactions between different
intricate webs of intercellular communications mediated by cell lineages composing each organ. For example, various
combinations of signalling molecules, which transduce their specialised resident and transiting cell types participate in the
messages to the cell-interiors via specific receptors to acti- formation, function and repair of the skin including epithe-
vate context-appropriate responses. These mechanisms lium (epidermis), endothelium, pericytes, smooth muscle
operate at multiple hierarchical levels of organisation (see (arrectores pilorae), adipocytes, haematological precursor
below). They extend from the level of individual cells cells, lymphocytes, macrophages, mast cells and at least two
responding to molecular signals in their immediate envi- distinguishably different types of fibroblasts [17]. The
ronment, to the supra-cellular level, where the behaviour of interactions coordinating the formation, maintenance and
large populations of different interacting cell types (eg ep- repair of such an organ are therefore numerous and com-
ithelium, stroma, nerves, vessels, muscle, etc.) is coordinated plicated. Subsequent research has shown that these interac-
to create the activities of tissues, which in turn coordinate tions are mediated by context-dependent signalling
with other tissues to form organs. Examples of the orderly mechanisms that are spatially and temporally precise and
spatial arrangement of different cell types at the micro- specific [18]. Expression of a particular mediator in a slightly
scopical level to form tissues and organs, as seen in histo- inaccurate location or time can result in biochemical or
logical sections, are shown in Figs. 1.2a and c and 1.3a. In structural defects and this applies to many different organ
turn, organs interact with other organs to create a dynamic systems [19]. Conversely, some molecules, such as osteo-
equilibrium, which enables the whole organism (animal or pontin and CD44 (a cell surface transmembrane glycopro-
plant) to respond appropriately to local stimuli and adapt to tein), can mediate completely different interactions among
changing environmental situations. separate cell lineages in different tissues and organs via
alternatively spliced or glycosylated isoforms. Thus, osteo-
pontin plays a role in lactation [20, 21], bone morphogen-
1.3 Mechanisms of Self-assembly esis, wound healing [22], signalling between gonadotrophs
of Complex Organisms: Embryological and other cell populations in the pituitary [23] and other
Organ Formation and Its Relevance processes, while CD44 is involved in lymphocyte homing to
to Cancer lymph nodes, epithelial cell adhesion to the substratum,
haemopoiesis and macrophage activation among many other
Initially, all of the cells in the inner cell mass created by the roles (reviewed in [24]). Hence, the structure and behaviour
early cleavage divisions of the fertilised egg, the zygote, are of tissues composing normal organs depends upon integrated
totipotent and, if separated from the others, can each create a parallel and serial communications between differing cell
1.3 Mechanisms of Self-assembly of Complex Organisms: Embryological Organ Formation and Its Relevance to Cancer 13

S
a

HB

HB

b c

Fig. 1.4 Macroscopic views of successive stages in the development of the widened folds comprising the primordial brain (below asterisk) and
an embryo of Xenopus laevis, the South African clawed toad. This the anterior neuropore (P) of the neural tube. c Still later neurula (30),
species has large eggs and embryos very suitable for experimental showing elongation of the body, developing spinal cord (S), posterior
embryology research. a Image of an early neurula stage embryo viewed edge of the thickening representing the caudal region of the rudimentary
through a dissecting microscope (40). The neural folds (arrows) hind-brain (HB) and the bumps corresponding to the eyecups (E) on the
delimiting the neural plate are closing to enclose the future neural tube. lateral aspects of the forebrain. Signalling and coordination among the
b Scanning electron micrograph of a slightly later stage neurula showing expanding cell population is necessary to achieve this orderly process

populations in an organ and the messengers and receptors external coverings and the CNS (from ectoderm), the internal
involved in these signals can vary, depending upon the lining of the gut and its derivatives (from endoderm) and the
identities of the living players in a specific context at a given internal organs and interstitial tissues (from mesoderm). Later
time. sub-specialisations produce more differentiated cell lineages,
Embryonic development involves the sculpting of a body which form the skin, nervous system, gut, muscles, heart, etc.
plan, with regional specialisations, in which clusters of and the mesenchymal stroma supporting the parenchyma of
organs, appropriate for each body region, are gradually all organs throughout the body. These segregating lineages
formed in stepwise manner, as first demonstrated by Spe- coordinate their activities and movements during organo-
mann [15]. The process starts with divisions of a single celled genesis by inductive [19, 25], and inhibitory [26] signals to
zygote to form an amorphous group of cells within which organise themselves into complicated patterns of functioning
specialised sub-categories emerge. This process re-arranges organ components (organogenesis). Voluminous evidence in
the small community into 3 main groups, ectoderm, endo- the embryonic literature shows that the regional stroma plays
derm and mesoderm. These will, respectively, produce the a major role in such coordination. The complexity and
14 1 Understanding the Nature of Cancer–General Principles

magnitude of the task of integrating these diversifying ele- 1.4 Hierarchical Organisation
ments into an orderly functioning entity is appreciated when of Multicellular Organisms
it is understood that, in the development of the human lung
alone, over 40 different cell types [27, 28] work together [18, All multicellular organisms with stable anatomic structure,
27, 29, 30] to produce the functioning organ. The interplay of from corals, sponges and plants to humans are hierarchically
molecular signals between different cell types displays baf- organised, meaning that order and function at the gross
fling intricacy, with the same factor sometimes acting on both anatomical level of body regions, depends upon orderly
sides of the interaction at different times [26], sometimes as placement of functioning components, such as organs and
an inducer and other times as an inhibitor. Hence, context, conduits for nutrients, waste disposal and gas exchange.
timing and coordination are all critical in determining the These structures, in turn, require orderly arrangements of
outcome. tissues, supporting materials and scaffolding such as colla-
Ingenious embryological experiments conducted by gen and/or calcium salts, composing them. The constituent
Grobstein [25, 31, 32] and others [16, 19] established cells of the organism are also arranged in specific patterns to
decisively that successive hierarchical interactions between maximise their efficiency of function. The patterns are
the stroma and other tissues then create locally appropriate characteristic of each organ of the animal or plant and are
specialised anatomical structures. Examples include hair consistent across wide ranges of each species making them
follicles and/or feathers in the skin, induced by the dermis distinctive and easily recognisable in microscopical prepa-
[33], bile canaliculi in the liver [34], exocrine and endocrine rations. Within the cells themselves, molecules, atoms and
elements in the pancreas [35] and specific mesenchymal ions align and/or flow according to physical and chemical
structures such as the bones, cartilages [4], tendons and conditions and the interactions between different metabolic
muscles. The result is a self-organised, adaptable live processes within the living cell. The dynamic interplay
organism, which cannot be created by any of the cell lin- within and between these different hierarchical levels pro-
eages individually and therefore represents a classic example duces a balanced self-regulating equilibrium working to
of an emergent phenomenon [11, 36, 37], in which the optimise the adaptive responses of the cellular society
whole has new properties not detectable in any individual composing the organism to environmental circumstances.
component. Accordingly, the emergent process is as diffi- Thus, the flow of chemical and physiological processes in a
cult, if not impossible, to analyse by separating cells from multicellular organism are multidimensional in time and
their neighbours and studying them separately, as it would space, and life propagating events are measured on different
be to explain the activities of a flock of birds or a shoal of scales, depending upon the dimension (molecular, cellular,
fish, by studying the behaviour of a single separated indi- tissue or organ) in which they occur. Such reference to scale
vidual. This is because the novel, superimposed dynamic (sometimes referred to as “scaling”) is important because,
properties disappear when the special population mix dis- for example, simple diffusion can be relied upon for removal
aggregates. Cancer is also an emergent phenomenon in being of waste products from a single cell, whereas for removal of
a living entity that progressively develops novel unpre- waste from a whole organism such as an animal or a plant,
dictable properties not shown by its components [6]. To vascular and filtration systems are needed to deal with large
study these processes in vivo, new non-reductionist methods quantities.
must be used to study group activities of cell populations and The life history and behaviour of tumours is likewise
suggested approaches are proposed later in this book. determined by interplay between events and processes in
Discussion of the interactions between healthy eukaryotic many dimensions and meaningful investigation requires
cells, algae, bacteria and viruses, constituting various com- analysis at many levels, from studies on cancer cells in vitro
plex organisms including humans and the mechanisms to observations on the growth and spread of cancers in living
involved therein forms a major theme of this book. The hosts. It also requires incorporation of data on changes in the
following sections of this chapter begin this process by overall health, well-being and demeanour of the host indi-
considering organisational aspects of coordination between vidual. Despite its difficulty and complexity, it is essential to
heterogeneous body components across many different use this integrated approach to obtain a realistic and useful
scales of size, diversity and complexity in both health and understanding of the neoplastic process and how it might be
disease. The extent of this coordination, once recognised, is controlled.
daunting to contemplate, but the healthy body accomplishes The next section reviews activities in molecular, cellular,
it faultlessly over many decades and the methods by which it tissue and organ dimensions of a normal multicellular being
does so command attention and intense analysis for their in greater detail, as preparation for discussion of how they
relevance to the cancer problem. The theme will be explored become deranged during the formation and progression of a
from different perspectives in subsequent chapters. neoplasm. The purpose is to show how disturbances in
1.4 Hierarchical Organisation of Multicellular Organisms 15

coordination of processes occurring at different levels in the become evident in multicellular life forms, but they can be
organisation of multicellular life, can gradually escalate to induced by unicellular or acellular (viral) organisms.
produce a malfunctioning but self-sustaining and parasitic The fertilised ovum contains abundant transcription fac-
entity within the host organism. This will explain how a tors, polymerases and other enzymes and possesses all the
self-propagating disturbance in organisational interactions resources necessary for producing all the structural and
can produce branching sets of downstream consequences, functional components of the whole new individual. Each of
which progressively amplify disorder at successively greater the first 8 blastomeres produced by the first 3 cleavage
scales of magnitude. If compatible with life, ramifying divisions also possesses all of these resources, and can each
process can culminate in an independent cancerous growth form a complete new individual, as demonstrated by Spe-
within the host, derived from its own component parts. If mann [15]. Following this stage, the developmental capa-
disturbances at any level become incompatible with life, bility of each blastomere and its progeny becomes restricted
within any part of the emerging tumour, that part, or the by limitation of supply of specific transcription factors and
whole new growth will abort and disappear. enzymes and other resources. Epigenetic influences exerted
by differential methylation and histone acetylation in specific
cell groups now begin to introduce progressively irreversible
1.4.1 The Molecular Dimension changes, by silencing or activating genes respectively [39],
leading to the emergence of specific germ layers, body
Living organisms, like all other physical matter, are com- regions, tissues and organs. As Spemann [15] and others
posed of molecules, which are in turn composed of atoms have demonstrated, there are “windows of competence”
and ultimately elementary particles that are themselves during which tissues have the resources to respond to
inanimate, although they form the structural basis of life and inductive signals from adjacent groups of cells, by showing
mediate its activities. The physics and chemistry of associ- new properties, but these periods of responsiveness fade
ations and dissociations of these constituent elements within away and do not return. This gradual, programmed differ-
living cells affect the kinetics and directions of atomic and entiation of specialised cell groups and tissues ensures the
molecular reactions. Normal cells within tissues and organs correct three dimensional placement of different tissues in
of all living creatures (life forms) are composed of these various organs for the different components to function
basic inanimate materials and utilise chemical properties to effectively. For instance, during early development, the
perform routine metabolic and catabolic activities in invagination of the mesoderm triggers the formation of the
response to diverse environmental stimuli. However, the cephalo-caudal axis of the embryo as well as the induction of
coordinated life and behaviour of cell populations is deter- the formation of the brain and spinal cord by the overlying
mined and regulated at higher levels than atoms and ele- ectoderm. The early invaginating mesoderm induces the
mentary particles. Tissue, organ and whole organismal formation of the brain at the terminus of its migration and the
coordination and control require even higher levels of late invaginating mesoderm induces the spinal cord at the
feedback, information processing and tuned response. As other end of the embryo. Sequential analysis demonstrates
complexity increases, regulatory processes become more that the transcriptomes of the tissues in each of these regions
specific and sophisticated and processes which are appro- change radically as these morphological changes occur [40].
priate for one level of organisation are not suitable at a Concomitantly changes occur in chromatin modifying
different level. For example, the mechanisms for transport enzymes and in the length of S phase of the cell cycle
and localisation of proteins within the cell [38] differ radi- allowing time for epigenetic chromatin changes to stabilise
cally from the multi-layered mechanisms required for release the new differentiated status of the cell populations as local
and vascular transport of hormones secreted by endocrine development proceeds. Delays in these embryonic move-
glands, such as the pituitary and targeting of their effects ments cause malformations of the nervous system because
upon distant organs in the body, such as the adrenal glands the status of the molecular components assembled in the
and kidneys. It is evident that disturbances at any level in ectoderm to enable it to respond to the signal from the
complicated hierarchical networks of controls with feed- mesoderm has decayed [15, 31, 41–43]. Likewise, the optic
backs, can result in ramifying, far reaching, consequences. cup growing out of the side of the forebrain induces the
The smallest organisational unit capable of independent overlying ectoderm to thicken, invaginate and begin crys-
life is the cell. Smaller elements such as viruses and prions tallin protein production to form a lens in exactly the correct
are considered to be alive, but they are obligate intracellular positional relationship to the developing retina, but delay in
passengers, which harness the machinery of the host cell in arrival of the cup results in failure of lens induction [15].
order to perform their activities and to propagate. Unicellular These are general statements and the precise details can vary
organisms do not display the characteristic features of cancer from species to species, but the overall concept, that
described and discussed in this book. These features only inductive capability of the inducer emerges much earlier and
16 1 Understanding the Nature of Cancer–General Principles

lasts much longer in development than the competence of this can be achieved by overproducing them and then bal-
the target tissue to respond to the signal, is consistently ancing the quantities of activators, inhibitors and ligands to
correct. regulate the biological outcome appropriate for the situation.
In the early stages of development of the embryo or of a In this way, for example, a receptor can be flooded with a
body region there is an abundance of the necessary tran- ligand making it unavailable for a different ligand which
scription factors, RNA transcripts, enzymes and other would induce the opposite effect. Data from RNA
components to accomplish a task, so control does not need to sequencing studies on over 30 human tissues from 54 body
be extremely precise, but as time passes, the availability of sites indicates that global transcriptional activity is indeed
these operationally important agents diminishes and very high in human cells [49] providing evidence for this
methylation then creates irreversible constraints on gene mechanism of cell function. Some of the transcriptional
expression. Consequently, differentiation of cell types activity appears to have no known function leading to the
becomes more channelled and tissue-restricted. interpretation that the cell transcribes much more DNA into
An additional important aspect to take into consideration, RNA than it needs, simply to ensure that enough is available
in the orderly progress of differentiation of cells and tissues, to achieve the required effect and the surplus may just be
is the role of alternative splicing of genes. Approximately regarded as transcriptional noise.
90–95% of genes are now known to produce alternatively The genocentric view of protein expression, where genes
spliced products [44–46] and the functions of these are dictate the types and quantities of proteins expressed at a
highly varied. The basic structure of genes consists of exons given time and where many diseases (particularly cancer) are
(coding regions) interspersed with non-coding introns thought to primarily be the result of aberrations in the
aligned along the DNA strand. Promoters and enhancers lie sequence of some key gene, is now outmoded and simplistic.
upstream (ie 5’) of the start codon, at which transcription There are, however, some single gene disorders in which a
begins with the binding of RNA polymerase ll. Promoters point mutation or deletion of a portion of the sequence can
are the attachment site for transcription factors and two types cause a specific clinical syndrome. Examples include cystic
are needed: a core promoter incorporating a TATA box, that fibrosis, sickle cell disease, Fragile X syndrome, muscular
is similar for all genes and an upstream form, that is dystrophy, haemochromatosis and Huntington’s disease.
gene-specific. Enhancers usually lie further upstream and These conditions are rare and can be inherited either domi-
increase transcription of RNA from the gene. Downstream nantly or recessively, but can manifest fully or partially in
(i.e. 3’) lies an untranslated region (UTR) that can influence different individuals due to the modifying influence of other
translation efficiency and stability of the transcript and the genes. For multigenic disorders, including cancer, the situ-
attachment of a poly A tail which aids nuclear export. Splice ation is much more complicated and results in a wide variety
variants result from the RNA corresponding to peptide- of different presentations.
encoding exons of the gene being assembled in different Data from diverse sources indicate that the genetic
combinations after excision of intervening introns from the sequence of an individual organism is, actually, mostly a
precursor mRNA initially transcribed from the gene. This is massive repository or library of information that is inert, but is
achieved by multiple splicing factors, enzymes and poly- utilised by regulatory elements to respond to environmental
merases acting in combination. Variations occur when the signals. Thus, the overall dynamic pattern of protein expres-
transcripts from one or more exons are omitted from the sion by cells is the result of a flux of information in the form of
messenger RNA or when transcripts from the complemen- molecular signals through regulatory networks within com-
tary strand of DNA in the gene are included. Some proteins munities of cells. The networks may exert both inhibitory and
encoded by the same gene perform entirely different func- stimulatory effects upon other network elements and the
tions and others even act antagonistically to each other [47, equilibrium determines the result. The outcome of this flux is
48]. It is evident therefore that, as cell differentiation and also highly dependent upon the inherited constitution of the
tissue organisation proceed, controls need to become individual and the precise environmental context. Aberrations
increasingly precise, in order to produce and maintain the in the balance between these interacting components can
well-ordered and stable patterns of cell organisation seen cause inappropriate expression of a gene or genes (see
histologically in the organs of mature multicellular organ- Chap. 2) without any obvious defect in the nucleotide
isms (see Chap. 3). These controls can be exerted by the sequence of the genome. Post-translational modifications
relative abundance or avidity of activated factors or their including glycosylation and sialylation add further possibili-
receptors, or by differential breakdown of regulatory mole- ties for fine-tuning. It should also be mentioned at this stage in
cules in different molecular reactions. It is not necessary for the narrative that a regulatory effect can sometimes be caused
the number of transcription factor molecules to be closely by massive overproduction of a molecule that displaces all
matched to the number of target receptors or ligands because other molecules from a target ligand. The result may seem to
1.4 Hierarchical Organisation of Multicellular Organisms 17

look like fine-tuning, but is actually a highly effective upon tumour cell populations, providing one pathway for
“shot-gun” mechanism for ensuring a specific outcome. tumour recurrence after therapy.
The dynamic flux described above is driven by energy Over many millennia, retroviruses, transposons and par-
generated by respiration and stored via oxidative phospho- asitic naked RNA elements have invaded eukaryotic cells
rylation in energy-rich bonds of molecules such as ATP and and their remnants are still detectable in human genomes [7,
GTP from which it is transferred to biochemical reactions by 52–54]. Their impact on the emergence of new species has
protein phosphorylation. Phosphorylation of specific proteins been enormous and defensive responses to their incursions
at specific amino-acid residues, catalysed by enzymes called have shaped genomic control mechanisms. The blocking of
kinases, causes them to undergo reversible conformational gene transcription by methylation and the control of gene
changes, termed activation, enabling them to bind or release expression by small interference RNA (siRNA) and long
ligands according to the local concentrations of ions and non-coding RNA (lnRNA) are examples of defences against
other factors. Chains of such reactions can result in bio- potential genetic havoc threatened by invading retroviruses
chemical “pathways” which, in turn participate in regulatory and transposons. Sequences such as long terminal repeats
networks to achieve cellular activities such as movement, (LTRs), Alu repeats and multiple copy genes are the signs of
secretion or ingestion. Control of such processes depends previous invasions, which have been mitigated by the inte-
upon intra- and intercellular signalling mediated by binding gration and utilisation of operationally effective genetic
of specific protein ligands to conformationally-matched “re- sequences accidentally generated by the viral activities. It is
ceptors”. Such binding causes down-stream signalling, via estimated that inserted elements from viruses comprise
further protein activations or by translocation of receptor- approximately 50% of the human genome [52, 53]. From
ligand complexes to nuclear regulatory locations, where they these findings it can plausibly be postulated that advanced
interact with genetic elements. These interactions, initiated multicellular life on the planet could be an incidental
and sustained by continuous incoming streams of signals byproduct of viral survival and self-propagation strategies
from the cell periphery, involve transportation, binding and (see Villareal and Witzany [7] for further discussion). In a
release of scores of molecular species including enzymes masterly article, these authors provide compelling evidence
(polymerases, ligases, methylases etc.) transcription factors that, over the millennia, swarms of different RNA virus
and binding proteins to and from specific DNA and RNA species have played a prominent role in evolution and con-
sequences. The outcomes of such interactions are determined tinue to interact with each other and with the human genome
by the concentrations of the relevant molecules and the in the process of regulating both normal and abnormal gene
timing of their assembly into active complexes. Ultimately, expression in living humans. Direct evidence that an “arms
these chemical reactions lead to the transcription of coding race” between viral elements and vertebrate (including
and non-coding RNA species, which organise protein syn- human) genomes is in progress is available [55, 56]. This
thesis and thus deliver the responses of the living cell to indicates that these invasions and host defensive responses
incoming stimuli via networks of inhibitory and facilitatory continue to shape the form and function of complex organ-
protein networks. Additionally, post-translational control of isms and may also generate new diseases, as yet unimagined,
the amount, type, glycosylation and rate of production of as well as new defensive strategies.
these proteins can be exerted by another class of small RNA Evidence of the pathological effects of de-methylated
molecules called micro RNAs (miRNAs). These are now viral LTRs causing neoplastic disease is provided and dis-
known to be involved in gene regulatory mechanisms cussed in Chap. 2. From such data, it is clear that
involving inhibition or stimulation of gene expression by de-stabilisation of these complicated gene regulation mech-
hybridising with specific DNA sequences [50]. anisms, which maintain order at the molecular level in a
Two further processes, termed redundancy and degener- given cell population, can cause major disorder and mal-
acy play significant roles in stability of gene expression and function in the cellular, tissue and organ dimensions of the
cellular function in eukaryotes. For the purposes of this whole organism. Cancerous behaviour is just one of the
discussion we will use the definitions proposed by Edelman many classes of disease that can result from such perturba-
and Gally [51], that degeneracy is the ability of elements that tions. Disturbance of gene regulation within the cancerous
are structurally different to perform the same function, cell colony can also cause gene expression that is inappro-
whereas redundancy is the performance of the same function priate for its tissue of origin [2] and consequent secretion of
by identical (ie duplicated) elements. Scattered throughout proteins, such as hormones, which can have deleterious
the genome are several examples of duplicated genes and clinical effects on distant organs and the whole body [57]
sequences whose products can substitute functionally for (see section on inappropriate gene expression (Chap. 2) and
one another and this allows some degree of compensatory on paraneoplastic syndromes (Chap. 10) for further details).
regulation for DNA damage. It also confers evolutionary Cells, given their self-sustaining processes discussed
adaptability upon organisms and drug resistance capabilities above, can in suitable environmental conditions survive and
18 1 Understanding the Nature of Cancer–General Principles

propagate, either as independent solitary entities, or as social the organism and cannot be readily re-assembled. Partial
organisms that subdivide tasks among themselves and de-differentiation, or reversion to a less specialised and
coordinate with each other by signalling mechanisms. While organised histological state, does occur in randomly dis-
the lives and activities of solitary cells are informative for tributed regions of many cancers and is a sign of increasing
understanding basic cell biology, the rules and regulations malignancy and poor prognosis.
which govern interactions between cells that have evolved to As discussed above, in the section on embryological
form multicellular organisms are more relevant to cancer development (Sect. 1.3), the progressive differentiation of
development. Disorganised, uncooperative cell behaviour cell types and their spatial assignment to specific anatomic
can only be recognised relative to other cells and, although it locations, based upon expression of cell surface adhesion
originates and depends upon actions in the molecular molecules, results in the formation of germ layers, tissues
dimension, it is manifest in the cellular dimension, whose and ultimately organs and body regions. During this process,
actions are superimposed upon and coordinated with activities in the cellular dimension organise the progressive
molecular events. And so, this narrative now considers differentiation and eventual developmental destiny of each
processes occurring in the cellular dimension of multicellular cell type and its neighbours. Thus, initially, epithelial cells
eukaryotic organisms. assemble into sheets with minimal intercellular material
between them, covering exterior surfaces or lining body
cavities. Later, some groups of cells invaginate into deeper
1.4.2 The Cellular Dimension tissues and fold to form tubes which elongate and branch to
form ducts and glands (Fig. 1.5). Cells participating in the
Omnis cellula e cellula. e cellula. All cells are derived from formation of mesenchymal structures begin to secrete col-
other cells. This fact was only recognised as late as the lagen, glycosaminoglycans and other intercellular materials
middle of the 19th Century, as a consequence of the appropriate for cartilage, bone or loose connective tissue.
microscopic studies of Francois-Vincent Raspail (1794– Neural tissue elements differentiate into neurons and glia and
1878), Theodore Schwann (1810–1882), Matthias Schleiden extend processes to make contacts with other specialised
(1804–1881), Robert Remak (1815–1865), who used the cells. In plants, cellular interactions in the meristem regions
latin phrase above to describe his observations, and others in result in the formation of roots and vascular (xylem and
the late 1830s and early 1840s. Unicellular organisms living phloem) conducting systems. All these activities are coor-
in the wild possess all of the requirements for survival and dinated in space and time by complicated intercellular sig-
for continuity of their species, but cells of multicellular nalling networks and lead to the establishment of mature
organisms specialise to perform differing functions. This organ systems and/or body regions appropriate for the spe-
enables them to participate in a cellular society and allows cies of animal or plant.
the individual cells to share in the greater adaptability and The activities of life require cells to sustain a dynamic
survival advantages in wider range of habitats, displayed by equilibrium of interactions in order to respond to changes in
such organisms. A pre-requisite for the formation of stable the environment and in the internal milieu, as well as to
cell groupings, the antecedents for multicellular organisms, injury and disease. Such interactions, mediated by short and
was the evolution of cell surface adhesion molecules [58], long-range signals by local mediators and by hormones are
sub-specialisations of which enabled the co-location of cells essential for the ongoing maintenance and integrity of nor-
with similar properties. Such specialisation, however, carries mal tissue and organ structure and for integration with
the penalty of the constituent cells becoming dependent intracellular molecular processes. The flux and direction of
upon the community in which they live and of sacrificing this traffic of signals depends upon vascular flow, electrical
freedom to reproduce at will. It is clear that submission to potentials and the flow of streams of ions, which can be
rules coordinating proliferation rates among various cell visualised with charge sensitive dyes [59].
types is necessary in order to maintain structural integrity Living organisms are highly adaptable to changing envi-
and functional efficiency of the whole organism. Also, only ronmental circumstances and this quality enables hardy
the gametes within the cellular community retain the capa- species to survive and eventually thrive in seriously adverse
bility to generate whole new individuals of that species. This conditions by switching to alternate metabolic pathways,
process of differentiation of specialised lineages within a cell habitats and/or behaviour patterns. In part, this is accom-
population derived from a totipotent parent cell involves plished by degenerate mechanisms, pathways or patterns of
sequestration and partitioning of molecular resources. Con- gene expression within individuals explained above and
sequently, differentiation in free-living multicellular organ- genetic heterogeneity in a population can also contribute.
isms in the wild is only partially reversible, as the necessary Alternative splicing mechanisms and, very occasionally, new
ingredients for cellular toti- and multi-potency have already gene combinations produced by invasive viral elements can
been distributed among the growing population composing lend further flexibility of response. However, adaptability has
1.4 Hierarchical Organisation of Multicellular Organisms 19

Fig. 1.5 Sequential phases in the embryonic development of exocrine to the surface. e–g Branching morphogenesis and formation of terminal
secretory glands and other tubular structures formed by epithelia. secretory acini. h Clusters of acini at the terminus of each branch form
a Invagination of epithelial bud induced by adjacent specialised lobules. i and j Transverse and longitudinal slices across ducts
mesenchyme. b Lateral budding from initial invagination. c Differenti- conducting secretions (or air). k Coronal slice through human breast
ation of specialised secretory cell types in the epithelial rudiment and showing mature branching duct system and collections of acinar lobules
focally in the duct. d Longitudinal section along the axis of a budding (gold colour). l En-face view of the breast duct system carrying milk to
stem of a primordial gland. The hollow lumen is lined by two cell layers, the nipple from the lobules of secretory acini. (Arteries, red; veins blue )
which specialise. The inner layer performs secretory and channelling Created with BioRender.com
functions and the outer lay is contractile to aid propulsion of secretions

its limits and if the selection pressure is sufficiently extreme it however, it can be briefly stated that structural changes
can eliminate individual organisms or result in seriously associated with neoplasia and invasion of adjacent tissues
sociopathic behaviour in a population. It is this boundary would be expected to be seen first at the boundary between
which is crossed when formerly healthy, adaptable cells neoplastic and healthy tissue.
composing multicellular organisms become unresponsive to In fact, this is clearly visible in optical and electron
signals regulating their proliferation and their orderly microscopic studies (see Chap. 2 and Figs. 2.1 and 2.2) of
arrangement. The result is a continuously replicating disor- the boundary areas between tissues in developing cancers
ganised cell population, which begins to take resources from [60–63] and in biopsies of pre-cancerous, dysplastic or
orderly neighbours, invade their territory and compromise in situ cancerous lesions (Fig. 3.5), but not in healing
their abilities to perform their functions for the host. wounds [64] or inflamed tissues [65], (Fig. 2.3). In early
From this background information, it is evident that dis- pre-cancerous lesions, the cells undergoing neoplastic
turbances in these interactions between cells and their sur- change show marked variation in nuclear and cytoplasmic
roundings can be caused by, and can contribute to, the size, shape and staining characteristics, termed dysplasia.
morphological disorganisation characteristically seen in sites Soon after this, the cells in the affected population become
of cancerous development in complicated multicellular hyperplastic and display disturbances in arrangement, ter-
organisms. Later sections of this book will describe this med carcinoma in situ. This anarchic cell population is not
process and its biomedical consequences in detail. For now, yet fully autonomous from the forces regulating orderly
20 1 Understanding the Nature of Cancer–General Principles

reciprocal cooperative behaviour among the different cell As discussed above, the molecular mechanisms by which
lineages composing the cellular community in the vicinity such transformations can be achieved include epigenetic
and has not yet begun invasion into adjacent tissues. From alterations of the methylome, or mutations induced by
histopathological studies associated with cancer screening reactive oxygen species, as well as direct insults to the cel-
programmes (see Chap. 4) and from follow-up studies on lular DNA caused by carcinogenic agents, which form
individual patients, it is known that many such lesions stall, adducts with the nucleotides (see also further details in
or regress in their growth and/or disappear. Due to the Chap. 9). Ultimately, with increasing errors, the process
physical factors limiting the diffusion of oxygen in tissues, becomes autonomous and can propagate the tumour indefi-
solid cell aggregates cannot increase in size beyond about nitely. It is interesting to note that histopathological obser-
1 mm diameter without vascularisation. However, if any of vations show that the non-neoplastic cells intermingled with
these local disorderly cell groups then, by chance, inappro- the tumour cells frequently display mitotic protein markers
priately triggers mechanisms which attract, recruit and (e.g. Ki 67] as prevalently as the tumour cells themselves
incorporate adjacent non-neoplastic cell lineages and small (Fig. 1.6a). This reveals that, if the tumour cells are to
blood vessels into their midst, to support their growth, the remain viable, the proliferation rate of the supporting cells
local disturbance transforms into a cancer. must keep pace with or exceed that of the tumour cells in

a
Fig. 1.6 Examples of histopathological features of pancreatic adeno- cells (white arrows), termed desmoplasia, surrounding the hyperplastic
carcinomas compared with normal pancreas. a Section of a pancreatic disorganised ductal (red arrows) and acinar (encircled) epithelial
carcinoma stained with antibody Ki 67 to mitotic protein. Note that the structures (H&E 100). The disorder results from the failure of
frequency of mitotic cells (brown nuclei) in non-neoplastic stroma (thick coordination and communication between the cells constituting the
arrow) at least equals that in the carcinomatous epithelium [thin arrows) organ. c Histological section of normal human pancreas showing acini
of malignant glands (200). b Histological section of a human pancreatic (dashed white arrow), a pancreatic islet (solid white arrow) and a duct
carcinoma showing the marked proliferation of spindle-shaped stromal (black arrow) (H&E 100), for comparison with 1.6b
1.4 Hierarchical Organisation of Multicellular Organisms 21

b
Fig. 1.6 (continued)

order to provide support. We see clear examples of such supplied by networks of vascular channels which circulate
excess proliferation of non-neoplastic cells in biopsies of nutrients, ions and signalling molecules and remove
histopathologically desmoplastic tumours (Fig. 1.6b), in metabolites and waste products. The need for maintenance
which the abundance of spindle shaped stromal cells is of orderly arrangement of cells of various different types and
particularly prominent. of intercellular scaffolding materials to support them is
These considerations highlight the significance of events demonstrated by histological examination. For example,
occurring at the supra-cellular level in determining the fate of organs providing secretions for digestive purposes (e.g.
cells that have developed neoplastic tendencies. They also pancreas and liver) need ducts to conduct the secretions to
explain the effects of advancing malignancy upon vital the appropriate locations and the micro-architecture of these
functions of local tissues and organs and on whole body and the secretory organs which they drain is perfectly
coordination, discussed in the next section and Chaps. 2, 7, 8, positioned and aligned (see Fig. 1.6c, and 3.4a and b).
9 and 10. Airways (Fig. 1.2a) and urinary passages need open unob-
structed channels for conducting gases and fluids from and
to the exterior. Milk, saliva and sweat can only reach the
1.4.3 Tissue, Organ and Whole Organism surface by flowing along anatomically accessible ducts (e.g.
Dimensions Figs. 1.7 and 2.8a). Hence it immediately becomes obvious
that failure to maintain a correct, stable balance between cell
At these levels of organisation, healthy cells act as large, proliferation and cell death as well as a fixed and exact
coordinated groups, supported by intercellular materials and anatomical location for specific cell types can result in organ
22 1 Understanding the Nature of Cancer–General Principles

c
Fig. 1.6 (continued)

failure leading to disease or even death of the host. The in the thyroid, (iii) vitamin D, absorbed via the
mechanisms by which such complicated order is created and epithelial lining of the gut, acting upon osteoblasts and
maintained in large multicellular organisms operate at mul- osteoclasts in bone and renal tubular epithelium. Within
tidimensional levels from the molecular to the macroscopic the cells of each of these organs, surface receptors
and work in synchrony with biochemical processes imple- sensitive to levels of hormones, vitamins and elec-
menting specific functions of each organ and cell type. The trolytes in the blood, bind their cognate ligands and
coordination between processes at all these levels becomes activate intracellular messengers. These mediate signals
progressively more complex with increasing size and to the cell nucleus and cytoplasmic organelles (e.g.
requires reliable, self-regulating control systems with parathormone granules) thereby stimulating or inhibit-
fail-safe signalling mechanisms, operating in highly com- ing actions on calcium and phosphorus metabolism.
plicated feed-back networks. Superimposed upon this short-range signalling within
Reliable coordination is necessary not only for the preser- and between the cells composing each organ are
vation of anatomical organisation discussed above, but also for long-range hormonal signals, carried via the blood,
the integration and regulation of many physiological func- between cells in the different organs (thyroid, parathy-
tions. Examples of such interconnected, overlapping mecha- roids, intestines, bones and kidneys) participating in this
nisms controlling physiological body functions include: regulatory axis.
(b) The regulation of salt and water balance in the body by
(a) The regulation of calcium and phosphate balance via (i) the cells in the hypothalamus and anterior pitu-
(i) para-thyroid hormone, secreted by the parathyroid itary secreting anti-diuretic hormone (ADH) and or
gland, (ii) calcitonin released by the interfollicular cells adreno-cortico-trophic hormone (ACTH) in response to
1.4 Hierarchical Organisation of Multicellular Organisms 23

Fig. 1.7 The microanatomy of the duct drainage system of the normal breast ducts converge on the sinuses to deliver milk generated by the
human breast. (Compare with Fig. 1.5 h). Histological section through mammary lobules (L) scattered in the adipose tissue of the breast.
a normal human breast nipple (40). The surface is covered with a Unless this organisation is maintained throughout life, the product
thickened epithelium below which lactiferous sinuses (S) ascend made by the mammary gland cannot exit from the organ, when
through the sub-epithelial collagenous connective tissue. Below these, necessary

changes in osmolality, sensed via their osmoreceptors, transmission of signals relaying the status of metabolic
(ii) the adrenals producing mineralo- and gluco- activities in progress. This is especially important when the
corticoids and (iii) kidney tubules which transport physiological functions to be achieved require cooperation
sodium and water either along their lumina or through with cells resident in other organs, located in distant parts of
their lining cells according to the osmotic status of the the body. How such long-range cooperation between cells of
internal milieu. different organs became established during evolution of the
species is largely unknown.
There are many other examples of such cooperation The transport of coordinating signals is accomplished via
among cells of different developmental lineages in separate the blood, tissue fluids, specialised cell junctions and nerves,
body locations to achieve diverse purposes such as the depending on the function the relevant cells are performing.
regulation of glucose levels, blood pressure control, etc., It can also involve active transport of molecules, or passive
which are too numerous to consider here. However, despite diffusion or ionic currents in charged fields. In other cir-
the large number and variety of vital body processes cumstances, signals may be carried by flow of fluids (i) in-
requiring coordination, to sustain the life of large, compli- side cells or (ii) across interstitial spaces or (iii) within high
cated organisms such as humans, they all demonstrate how pressure (arteries) and low pressure (veins, capillaries and
precise regulation of the function of an organ or groups of lymphatics) vascular channels. Coordination occurs without
organs, consisting of billions of cells, requires efficient a specific leader, central authority or hierarchical command
24 1 Understanding the Nature of Cancer–General Principles

structure. Examples of how such intricate and complicated often fatal effects upon the host are discussed in more detail
harmonisation occurs and of how it fails in cancer, are dis- the following Chapters.
cussed in later chapters.
These concepts are especially important in relation to the
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 The Phenomenon of Inappropriate Gene
Expression and Its Biological and Clinical 2
Consequences

Abstract
2.1 A Fundamental Characteristic
In multicellular organisms, coordination within and
between cell populations performing diverse functions Inappropriate gene expression is a crucially important and
for the organism is achieved and regulated by orderly gene signature feature of neoplasia. It characterises all malignant
expression within each cell and signalling between cell tumours and lies at the mechanistic heart of cancer formation
groups. Gene expression networks provide adaptability to and behaviour. The evidence is presented and reviewed
changes in cellular environments and can compensate for below. By definition, cancerous cells display this phe-
some inbuilt or externally induced defects. However, nomenon, but it is essential to recognise that it also occurs in
decompensation in gene expression and signalling net- non-neoplastic processes, some of which are discussed in
works, once initiated, can spread and result in either cell this chapter. In brief, this event is therefore necessary but not
death or various types of dysfunction, including disorderly always sufficient to cause neoplastic change in a community
behaviour characteristic of cancer. Surviving disorderly of cells. Sometimes concomitant cellular processes need to
cells undergoing neoplastic transformation show inappro- occur in the cells at risk, for the inappropriate expression to
priate expression of genes that are atypical for their cell trigger neoplastic change. Once the reader has considered
type of origin. This Chapter discusses the histopathological the multiple inter-related hierarchical processes operating at
and pathophysiological changes accompanying abnormal differing levels of organisation in a healthy body, described
gene expression during tumour formation, invasion and in Chap. 1, it becomes easier to understand that inappro-
metastasis and compares them with those in non-malignant priate gene expression in a group of cells can lead to either
conditions such as wound healing. It describes and their elimination or to self-propagation of disease.
evaluates data from investigations in vivo and in vitro,
using many different techniques including optical and
electron microscopy, immunohistochemistry, fluorescent 2.2 Defining Inappropriate Gene Expression
cell labelling, biochemistry, and methods from cell and and Its Potential Effects
molecular biology. The findings demonstrate remarkable
changes in cell and tissue organisation, signalling When a gene is activated and expressed at an unusual time in
molecules, blood chemistry and cellular receptors during the life history of a multicellular organism, or in an atypical
tumour progression, which can be valuable in tumour cell, tissue or organ in the body, the event qualifies to be
diagnosis and treatment and in understanding the remote regarded as an example of inappropriate gene expression.
effects of the tumour on the host, called paraneoplastic A special category of this process, where the expression of a
syndromes. The narrative also describes how random gene normally restricted to a specific cell lineage of defined
variability in gene expression in cancer can result in pitfalls embryological origin, and with specific postembryonic fea-
in diagnosis, including both under- and over-diagnosis. tures and functions, occurs in an entirely different lineage in
the body, is defined as lineage infidelity. Both inappropriate
expression and its close relative, lineage infidelity, can only
occur in multicellular organisms, since changes in expres-
Publisher’s Note: This Chapter examines and expands upon sion in free-living unicellular organisms are difficult to
conclusions discussed in Tarin [1] with additional evidence from classify as inappropriate. For example, the activation of an
several other personal studies including Tarin [8], [28], [40], [113],
[123], Matsumura and Tarin [18], etc. “oncogene” or the silencing of a “tumour suppressor” gene

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 27

D. Tarin, Understanding Cancer,
https://doi.org/10.1007/978-3-030-97393-3_2
28 2 The Phenomenon of Inappropriate Gene Expression and Its Biological and Clinical Consequences

in a free-living unicellular amoeba proteus or paramecium in The aberrant expression of a gene in an unusual cell type
a country pond, may give the individual’s progeny a pro- or at an unusual time in the life of the organism can have
liferative survival advantage in the wild, but whether the simple or complicated consequences depending on the
timing or location (in one individual versus another) is context. It can:
inappropriate is open to debate. However, when this event
occurs unexpectedly in a differentiated cell lineage, within • via a short, direct pathway affect the expression of a
the multicellular community composing a metazoan organ- single non-pathogenic phenotypic property such eye
ism, there is considerable possibility of incoordination, colour or melanin pigmentation of a tissue or alteration of
social disorder, disease and misdiagnosis. This and other the expression of a marker protein for a tissue type.
Chapters of this book will demonstrate that this • via a network of downstream pathways alter structural or
under-recognised phenomenon of inappropriate gene behavioural properties of cell lineages of organs resulting
expression is highly relevant to investigations on (i) cancer in distortion of organ architecture or invasion or metas-
diagnosis, (ii) paraneoplastic syndromes experienced by tasis into other territorial domains.
cancer patients, (iii) emergence of tumour heterogeneity, • via extracellular secretion of a protein or other gene
(iv) progression to metastasis, (v) the development of drug product cause long range hormonal or immunologically
resistance and (vi) fundamental mechanisms causing neo- mediated effects upon other organs (see Chap. 10 on
plasia in general. It therefore deserves to be widely appre- paraneoplastic syndromes for discussion of mechanisms).
ciated and understood for its impact on clinical management
of disease and on laboratory research on pathogenetic The full scope of the topic of inappropriate gene
mechanisms of malignancy. expression in health and disease is, therefore, vast. Conse-
Inappropriate gene expression occurs in many organisms quently, this overview will focus mainly on the importance
across the animal and plant kingdoms and is an important of this phenomenon in human cancer although some
mechanistic factor in human disease in general and cancer in examples of its significance in other species will be included.
particular. Study of this topic is necessary for understanding
how the chaotic mixture of evolving and cascading regula-
tory genetic interactions in an advancing cancer produces its 2.3 Inappropriate Gene Expression
clinical effects and for designing practical methods for in Neoplasia
controlling or mitigating the disease. The topic also warrants
much more attention in research and in clinical practice than In large multicellular organisms including humans, reliable
it currently receives, because of the added value it brings to control of cell type, location and numbers is essential for
refining cancer diagnosis (specific examples discussed creating, maintaining and repairing tissue and body archi-
below) and treatment and to the assessment of prognostic tecture and function. This is powerfully illustrated by the fact
markers. It is particularly relevant to understanding the that the microscopic histology of healthy organs (e.g. liver,
aetiology and extensive clinical manifestations of paraneo- kidney, breast etc.) is always recognisably similar between
plastic syndromes affecting multiple organs remote from the different individual members of the species and distinctively
tumour and the treatment or amelioration of the substantial different from the histology of tumours of the same organ,
morbidity that they cause [1]. where such stable control is compromised, or absent. In turn,
In addition, inappropriate expression can be responsible this organisational regularity of cellular arrangement in
for several non-neoplastic diseases affecting the nervous healthy organs is dependent upon orderly control of the tim-
system [2], muscles and other organs, as well as for ing, coordination and monitoring of gene expression and of
embryonic developmental abnormalities and malformations. silencing of expression in specific cell types, throughout life.
Although the phenomenon is relevant to the pathogenesis Failure to maintain such equilibrium can result in defective
and manifestations of disease, its effects are not always cellular phenotypes and in interference with interactions with
harmful. It occurs in many animal species as well as in plants neighbouring cells, leading to disruption of orderly cellular
and can implement evolutionary change, if the inappropriate arrangement, and misaligned tissue architecture which is
expression is induced in stable manner by heritable muta- diagnostically characteristic of malignant tumours.
tions or by insertion of retroviral elements, DNA viruses or For example, in studies of gene expression profiles in
transposons into the genome of the germline, and subjected freshly-excised primary human breast carcinomas [3, 4] and
to environmental selection pressure over aeons of time. in breast cancer xenografts [5], we noticed that several
2.3 Inappropriate Gene Expression in Neoplasia 29

melanocyte-related genes are commonly expressed in these dermo-epidermal boundary (Compare Fig. 2.1b and c),
tumours (Fig. 2.1a). Further analysis showed that they are long before any recognisable tumours emerge. These
also expressed in several human breast cancer cell lines [4, changes begin with breaks in the basement membrane
6]. The levels of expression sometimes exceeded those of delineating the epidermis from the dermis, followed by
genes that are unequivocally involved in mammary function, the appearance, in the same vicinity, of fragments of
including milk production. As the melanocytic genes encode basement membrane-like material (Fig. 2.1c). Over time,
proteins involved in melanin synthesis and turnover, they are these coalesce to form re-duplications of the basement
routinely expressed in melanocytes and frequently in mela- membrane (Fig. 2.1c–d) and this is accompanied by
noma cells. However, their expression in the epithelial cells changes in the organisation of collagen fibrils in the
of mammary tumours is atypical and somewhat unexpected, superficial dermis (Fig. 2.1d) which become variable in
because normal breast tissue is not pigmented and pig- thickness and disorderly in arrangement. At this time the
mented breast carcinomas are uncommon. Melanocytic gene treated area of skin is macroscopically thickened and
expression in breast cancer cells is not directly pathogenic denuded of hair, but no tumours are yet visible.
but is a benign sentinel sign of abnormal gene expression • Subsequently, macroscopically visible papillomas appear
among the malignant cell population. This leads us into (Fig. 2.1e, left) and some of these progress in size and
considering the impact of inappropriate expression upon depth of penetration to form carcinomas. At this stage, the
cancer diagnosis, tumour behaviour, the tumour microenvi- electron microscope shows that the carcinogen-treated
ronment and broader interactions between the tumour and epithelial cells begin to extend bulbous-ended, narrow-
the host that it is parasitising. necked processes into the dermal stroma. The necks of
these constrict and sever from the epidermal cells to
release vesicles (now called exosomes) containing gran-
2.3.1 Tumour Invasion and Metastasis: ular material, but no cytoplasmic organelles, into the
A Striking Example of Semi-coordinate dermis. Most of these rupture and release lytic material
Inappropriate Gene Expression (see section on proteases, below) which dissolve the
surrounding collagen fibres and intervening amorphous
When tumour cells cross the boundaries of the territorial matrix (Fig. 2.1f) resulting in numerous lacy holes in the
domains to which they were assigned in embryonic devel- stroma. This permits the expanding epidermal cell mass
opment, and which they have since inhabited during juvenile to extend into the empty spaces thus created and to pro-
and adult life, they immediately enter adjacent areas in gressively invade the dermis. Surplus exosomes and
which the environmental conditions are substantially differ- empty vesicles are engulfed and removed by local mac-
ent. If some members of the invading cell population pro- rophages (Fig. 2.1g) confirming that these are separate
ceed to penetrate lymphatic and blood vessels and vesicular bodies in the dermal stroma. Later observations
disseminate to form secondary tumours in distant organs, confirmed that the vesicular activity by the epithelial cells
they come into contact with many further environmental and the destruction of the original orderly fibrous dermal
conditions that are foreign to them. Survival of the cells stroma progressed to become severe and the cancer cells
which have embarked on this invasion of local and distant invaded through the sub-dermal adipose tissue (Fig. 2.1e,
territory depends upon the ability to adapt to these new right) into muscle below.
conditions, to kill or stifle resistance [7] and to attract local • Identical fine structural changes are seen at the epithelial-
support for their growth needs. These novel forms of cellular stromal boundary at consecutive stages during mammary
behaviour, deployed during colonisation of a new domain, carcinogenesis (Fig. 2.2a–g) irrespective of whether it is
cause marked local destruction, remodelling and disorder [8] initiated by viruses, hormones or carcinogenic chemicals
but they are not completely disorganised activities. Here, we [10]. Comparison of the features shown in this photo-
shall consider the sequential progression of such events and montage of changes in mammary cancers with those
see that they are coordinated and orderly, although not described above, seen in skin cancer, confirms this con-
appropriate, phenomena. The concomitant structural and clusion. Similar changes be seen at the epithelial-stromal
molecular changes accompanying invasion and metastasis boundary in cancers of several other organs in humans
also provide evidence indicating that they are initiated and and other animals [11–15].
sustained by inappropriate gene expression in the field of the • Such specific sequential changes at the dermo-epidermal
developing/spreading tumour. junction are not seen in skin treated with irritant
non-carcinogenic chemicals, such as turpentine, or ben-
• In sequential electron microscopic studies of experimen- zene, for prolonged periods [16] ( Fig. 2.3a). We also
tal mouse skin carcinogenesis [8, 9] induced by methyl- examined the sequence of changes at the dermo-epidermal
cholanthrene, a distinctive series of changes occurs at the junction during wound healing in the skin, where the
30 2 The Phenomenon of Inappropriate Gene Expression and Its Biological and Clinical Consequences

E
C
a b

C
c d

Fig. 2.1 Changes tumour cells and in the tumour microenvironment in skin and variable in shape and diameter (encircled area). The epidermis
chemically induced skin cancer. a Immunohistochemical demonstration (E) and the original basement membrane are visible (white arrow) at top
of heterogeneous expression of the melanocyte related MART-1 gene left. (20,000). From Tarin [9]. e Histological sections viewed with a
in NM2C5 breast cancer cell line cells. The arrow shows a highly standard optical microscope showing a papilloma (left) and a carcinoma
expressing cell stained red (arrow). Weakly expressing cells and (right). These pictures show marked overgrowth of the epidermis
non-expressing cells are also present. Immunofluorescence analysis was (asterisks) and dermis in the region of the tumours and fibrous scarring
performed on cultured cells using the anti-MART-1 antibody. Nuclei extending down into the adipose tissue below (arrows). The overgrowth
were stained with DAPI (blue). (250). From Tarin [4]. b Sec- of the neoplastic epidermis and derangement of its organisation is more
tion through normal mouse skin cut perpendicular to the surface, marked in the carcinoma than in the papilloma. From Tarin [8]. f Ten
viewed with an electron microscope. The image shows a sharply weeks treatment (carcinoma stage): In this electron micrograph, the
demarcated junction (arrow) between the epidermis (E) and an orderly boundary between epidermis and dermis (between large arrows) is now
arrangement of abundant collagen fibres in the dermal connective tissue highly irregular and the advancing epidermal carcinoma (E) cells (in
(C), known as the dermis. The rectangle indicates the area depicted in top of picture, above the arrowheads) are extending bulbous-ended
the subsequent figures, c–e (1500). From Tarin [9]. c Five weeks pseudopodia (P) with narrow necks (arrows) into the disintegrating
treatment with methylcholanthrene: Extensive fragmented basement dermis (below large arrows marking the dermo-epidermal junction).
membrane-like material is present in the superficial dermis between the Epidermal cytoplasmic vesicles (asterisks) are seen releasing their
hyperplastic epidermis (E) and the dermis (C). In places (arrows) it is contents into the tumour microenvironment and many large punctuate
coalescing to form reduplications of the basement membrane which is holes (H) represent areas where the dermal collagen has been lysed.
normally a single lamina at the dermo-epidermal junction (large arrows) (8000). From Tarin [9]. g Uptake (arrow) of empty vesicles (V) by
(3000) From Tarin [9]. d Seven weeks treatment (papilloma stage): dermal phagocytes. Portions of two of these cells are seen in the lower
Multiple extensive reduplications of the basement membrane are seen part of the image engulfing the vesicular envelopes. From Tarin [9]
and the dermal collagen fibrils are disorganised, compared to normal
2.3 Inappropriate Gene Expression in Neoplasia 31

E
E *
*
*
*
*
P e

H V V

Fig. 2.1 (continued)

epidermis invades the dermis in the early stages of the creating widespread damage, which facilitates invasion of
process, but ceases to advance and restores a continuous adjacent tissues.
surface epithelial covering, upon coming into contact with Concomitant with these ultrastructural changes during
a tightly packed wall of mesenchymal cells (Fig. 2.3b), carcinogenesis, one can detect molecular changes, such as the
which gathers below and blocks its deeper advance [17]. appearance of many aberrant alternatively-spliced CD44
In these studies on wounds, we did observe some pseu- RNA transcripts (Fig. 2.3d), in the tumour [18, 19]. There is
dopodial blebbing and release of exosomes, from the also an elevation of CD44 protein isoforms, detectable
bases of the epidermal cells, during the resorption of fibrin immunohistochemically, in the cancer cells (Fig. 2.4b–c, e, f),
and remodelling of the local dermal collagen (Fig. 2.3c), but not in healthy counterparts (Fig. 2.4a), as well as increased
but not the full and progressive sequence of changes seen release of collagen specific lytic proteases [6, 20–23] into the
during carcinogenesis [8]. Following the arrest of invasion adjacent stroma. These events, including the exaggerated and
of wounded epidermis, by direct contact with the wall of varied expression of genes in combinations not seen in cor-
dermal mesenchymal cells, the blebbing and vesicle pro- responding normal, healthy tissues, are good examples of how
duction by the epithelium promptly ceased, the fibrous this phenomenon of inappropriate gene activity contributes to
connective tissue of the dermis was repaired, and an the disorderly behaviour of cancerous lesions.
orderly dermo-epidermal junction was restored. It should The electron microscopic data described above led to the
be mentioned that blebbing and vesicle production by the realisation that dynamic tissue interactions responsible for
epidermis is also seen during the active growth of normal forming tissues and organs during embryogenesis and
hair follicles, during which they penetrate into the dermis, maintaining them throughout adult life [24, 25] are pro-
but this ceases when growth stops and surrounding dermal gressively disrupted in developing neoplasms [8–11]. This
structure is rebuilt. ultimately led to the understanding that these interactions
occur within, and contribute to, the expanding tumour
From all of these observations, one can conclude that the microenvironment. Subsequent studies on human and animal
carcinogenic process unleashes changes seen in orderly cancer metastasis [26–32] revealed that the microenviron-
remodelling and repair processes in several human and ment in various host organs determines whether metastatic
animal organs. However, in carcinogenesis they are unco- behaviour triggered in tumour cells will reach fulfilment in
ordinated in time and space and continue indefinitely, the form of secondary neoplasms in distant organs, or
32 2 The Phenomenon of Inappropriate Gene Expression and Its Biological and Clinical Consequences

E E

B
S
C
F

EE

C
L E

B
a b

E
B

* *
S

*
B
c d e

Fig. 2.2 Sequential changes in the tumour microenvironment in connective tissue (S). Fragmented material (F) is being incorporated in
virus-induced breast cancer. a Transverse section of normal breast the formation of new laminae (arrows) creating arcades and festoons
ductule (2000) showing central lumen (L), lining epithelium (E) and (asterisk) of basement membranes at the epithelial stromal junction.
surrounding collagenous connective tissue (C). The rectangle marks a The collagen fibres forming the periductal sheath seen in panel a) have
comparable region of a duct from an early murine mammary cancer disappeared and the remaining stromal matrix (S) is perforated by
shown in panel (b) of this Figure. Inset shows the epithelial-stromal ragged holes. From Tarin [10]. d Comparison of a collagen fibril and a
(E-S) boundary and basement membrane (B) (14,000). From Tarin strand of basement membrane material. The collagen fibril (asterisk)
[1]. b Tumour host interface in early mammary cancer (14,000) shows 640 Å periodicity and the basement membrane material (arrow)
showing accumulation of fragmented basement membrane-like material is amorphous demonstrating that the reduplicated membranes are
(F) in the connective tissue (C) adjacent to the carcinoma cells (E). distinct from stromal collagen fibres. e–g This sequence of pictures
Portions of the original basement membrane (B) are visible at the shows epithelial cells (E) extruding (e) narrow-necked vesicles
boundary between epithelium and connective tissue. From Tarin [10]. (asterisk) into the stroma (S), where they rupture (f), release their
c Established mammary tumour: epithelio-mesenchymal junc- contents (asterisk) and are then ingested (stages 1–4) by local
tion.  9500. Marked reduplication of the basement membrane has macrophages (g). The collagen fibres in the stroma have been lysed
occurred. The position of the original basement membrane is indicated by enzymes in the vesicles (exosomes), but some fragments of original
(B). The increased number of laminae lie between epithelium (E) and basement membrane (B) remain. From From Tarin [10]
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Cross reception then and there. Only two hours more until train
time, and the old lady had to rush me down to the house for lunch—
and me with the rest of my life to eat in!
But I shook her and the kid sister at last, and got Susie alone. I tried
to tell her—and I couldn’t. I could say that I was going to do my
best and maybe die for my country, and there I stalled and balked,
her looking the other way all pretty and pink, and giving me not a
word either way to bless myself with. Says I finally:
“And if I come back, I suppose that you’ll be married, Susie?” and
she says:
“No, I don’t think that I’ll be married when you come back; I don’t
think that I’ll ever marry unless he’s a man that I can be proud of.”
Then she looked at me, her big eyes filling—her big eyes, coloured
like the edge of the mountains after sunset. I’ve figured it out since
that she was more than half proud of me already—me, in a clean,
blue suit, and the buttons shiny; me, a ten-cent, camp volunteer.
And then the old woman broke in with a bottle of Eilman’s
Embrocation for use in camp.
Never another chance had I that side of the station. Of course, she
kissed good-by, but that’s only politeness for soldiers. They all did
that. So, although it was just like heaven, I knew that it didn’t mean
anything particular from her, because her mother did it and her
sister, and pretty darned near every other girl in Striped Rock, seeing
that the news about having a real hero in town had spread.
Only, when we pulled away and I was leaning out of the window
blowing kisses, being afraid to blow at Susie in special because I
didn’t like to give myself away, she ran out of the crowd a ways and
held up her little finger to show me something over the knuckle, and
pulled her hand in quick as if nothing had happened. It was the play
kid-ring that I gave her out of the grab-bag, to show that I was
going to marry her when I grew up.
That was the last sight of Striped Rock that I got—Susie waving at
the station as far as I could see her. It made you feel queer to ride
past the fences and the bunch-grass and the foot-hills getting
grayey-green with sage-brush, and the mountains away off, all
snowy on top, and know that chances were you’d never see them
again grayey. And I won’t, I won’t—never again.
Muster at Denver, and the train, and away we went, packed like a
herd around salt, and the towns just black, like a steer in fly-time,
with people coming out to see us pass, and Red Cross lunches every
time the train had to stop for water; next ’Frisco and Camp Merritt.
The first time that I saw this town, gray all over like a sage-hill,
made out of crazy bay-window houses with fancy-work down the
front, I knew that something was going skewgee.
The night before we went up for our final medical examination by
the regular army surgeon, Captain Fletcher called me into his tent.
“Drake, how about your eyes?” says he.
I hadn’t thought of that, supposing that it could be fixed the same
as it was at Range City. I told him so, and he said it couldn’t, not
with the regular army surgeons. But says he:
“You’re a good soldier, and I got you to raise my reserves. They
won’t let you in if you can’t pass the eye-test, glasses or no glasses.
If it should happen that you learned a little formula that tallies with
the eye-card, you wouldn’t let on that I gave it to you, I suppose?”
“I’m good at forgetting,” I says.
“Burn it when you’ve learned it,” he says, and he gave me a paper
with long strings of letter on it. I learned it backward and forward,
and so on that I could begin in the middle and go both ways. I lay
awake half the night saying it over.
Naked as I was born, I floated in on the examiners for my physicals.
Lungs, as they make them in the cow-country; weight, first-class;
hearing, O. K. They whirled me and began to point. Taking a tight
squint—you see better that way—I ripped through the formula: P V X
C L M N H—I can see it yet. I could just see what line on the card he
was pointing at, and never a darned bit more.
They make that sort of a doctor in hell. He saw me squint—and he
began skipping from letter to letter all over the card. No use—I
guessed and guessed dead wrong. “Rejected!” just businesslike, as if
it was a little matter like a job on a hay-press. I went out and sat all
naked on my soldier-clothes—my soldier-clothes that I was never
going to wear any more—and covered up my head. It was the
hardest jolt that I ever got—except one.
Captain Fletcher hadn’t any pull; he couldn’t do anything. Some of
the twenty that I rounded into Range City talked about striking, they
were so mad, but that wouldn’t do any good. I watched them sworn
in next day, shuffling into the armory in new overall clothes. I stood
around camp and saw them drill. I saw them go down the streets to
the transport—flowers in their gun-barrels, wreaths on their hats,
and the people just whooping. I sneaked after them onto the
transport, and there I broke out and cussed the regular army and
everything else. Old Fletcher saw it. He wasn’t sore; he understood.
But I wish I had killed him before I let him do what he did next. He
said:
“He can’t be with us, boys, and it ain’t his fault. But Striped Rock is
going to have its hero. I am going to be correspondent for the
Striped Rock Leader. If we have the luck to get into a fight, he’ll be
the hero in my piece in the paper, and the man that gives away the
snap ain’t square with Company N. Here’s three cheers for Admeh
Drake, the hero of Company N!” he said. When they pulled out,
people were cheering them and they cheering me. It heartened me
up considerably, or else I couldn’t have stood to see them sliding
past Telegraph Hill into the stream and me not there with them.
First, I was for writing to Susie and telling her all about it, but I just
couldn’t. I put it off, saying that I’d go back and tell her all about it
myself, and I went to mooning around camp like a ghost. And then
along came a copy of the Leader that settled it. All about the big
feed that they gave the regiment at Honolulu, and how Admeh
Drake had responded for the men of Company N. Captain Fletcher
was getting in his deadly work. It said that I was justly popular, and
my engagement to one of Striped Rock’s fairest daughters was
whispered. It treated me like I was running for Congress on the
Leader ticket. I began to wonder if I saw a way to Susie.
After they got to the Islands, I dragged the cascos through the surf
and rescued a squad of Company N from drowning. All that was in
the Leader. The night they scrapped in front of the town, I stood
and cheered on a detachment when they faltered before the foe.
After they got to Manila and did nothing but lay around, Captain
Fletcher had me rescue a man from a fire.
After that, I began to get next to myself, knowing that I’d have done
best to stop it at the start and go straight back to Striped Rock. I’d
been a darned fool to put it off so long. Now I could never go back
and face the joshing. I wrote the captain a letter about it, and he
never paid any attention. Instead of that, he sent me back a bunch
of her letters. Knowing how things stood, what I was doing and
what she thought that I was doing, I could hardly open them. They
made me feel as small as buckshot in a barrel. They hinted about
being proud of me—and prayed that I’d come home alive—and I
knew, in spite of being ashamed, that I had her.
Next thing, the natives got off the reservation. There’s where
Captain Fletcher went clean, plumb loco. One day the Leader came
out with circus scare-heads about the “Hero of Pago Bridge.” They
printed my biography and a picture of me. It didn’t look like me, but
it was a nice picture. I’d broke through a withering fire and carried a
Kansas lieutenant across to safety after he had been helplessly
wounded—and never turned a hair.
What was I doing all that time? Laying pretty low. I was afraid to
leave town because I wanted to keep an eye on the Leader, which
was coming regularly to the Public Library, and afraid to get a
regular daylight job for fear that somebody from Striped Rock would
come along and see me. I was nearly busted when I ran onto old
Doctor Morgan, the Indian Root Specialist. He gave me a job as his
outside man. All I had to do was to hang around watching for sick-
looking strays from the country. You know the lay. I told them how
Doctor Morgan had cured me of the same lingering disease and how
I was a well man, thanks to his secrets, babying them along kind of
easy until they went to the doctor. He did the rest, and I collected
twenty-five per cent.
Striped Rock acted as though I was the mayor. They named their
new boulevard Drake Way. Come Fourth of July, they set me up
alongside of Lincoln. They talked about running me for the
Assembly. There came another bunch of her letters—I had answered
the last lot that Cap sent, mailed them all the way to the Philippines,
to be forwarded just to gain time—they were heaven mixed with
hell.
The regiment was coming back in a week, and then I began to think
it over and cuss myself harder than ever for a natural-born fool that
didn’t have enough sand to throw up the game at first and go home
and face the music. It was too late then, and I couldn’t go back to
Striped Rock and take all the glory that was coming to me and face
Susie knowing that I was a fake. Besides, I knew the boys from
Range City were liable to go up to Striped Rock any time and tell the
whole story, and it froze me, inside. I didn’t know what to do, but
the first thing that I had on hand was to catch them at the dock and
tell them all that it meant to me and get them to promise that they
wouldn’t tell. Whether I’d dare to go back and try to get Susie, I
couldn’t even think.
I threw up my job with the doctor and went down to the transport
office to see just when they expected the boys. Little house on the
dock; little hole rooms that you could scarcely turn around in. They
said that the boss transport man was in the next room. I walked in.
There—face to face—was Susie—Susie, pinky and whitey, her eyes
just growing and growing. I couldn’t turn, I couldn’t run, I could just
hang tight onto the door-knob and study the floor. The transport
man went out and left us alone.
And she said:
“Admeh Drake, what are you?”
My inwards, me saying nothing all the time, said that I was a fool
and a thief and a liar. I could have lied, told her that I came home
ahead of the regiment, if it had been anyone but Susie. But I told
her the truth, bellowed it out,—because my soul was burned paper.
“I came out to see you come back,” she said, and then:
“I thought that I could be proud of you.” Never another word she
said, and she never looked at me again, but she threw out her hand
all of a sudden and something dropped. It was the play kid-ring I
gave her the night that I wish I had died.
I tried to talk; I tried to hold the door; I might as well have tried to
talk to the wall. The last I saw of her, the last that ever I will see,
was her molassesy-gold hair going out of the big gate.
I spilled out over the transport man and—O God—how I cried! I ain’t
ashamed of it. You’d have cried, too. After that—I don’t know what I
did. I walked over a bigger patch of hell than any man ever did
alone. But the regiment’s come and gone and never found me, and I
don’t know why I ain’t dead along with my insides.
And they mustered out at Denver, and the boys split up and went
home. Company N went back to Range City—cottonwoods shedding
along the creeks, ranges all white on top, sagey smell off the foot-
hills, people riding and driving in from the ranches by hundreds to
see them and cheer them and feed them and hug them—but there
wasn’t any hero for Striped Rock, because he had bad eyes and was
a darn fool—a darn fool!
 CHAPTER V
THE DIMES OF COFFEE JOHN

“W ell,” said the Harvard Freshman, after the last tale was told,
“I’m dead broke, and my brain seems to have gone out of
business.”
“I’m broke, and my heart’s broke, too,” said the Hero of Pago Bridge.
“I’m broke, similar,” said the ex-medium, “and my nerves is a-
sufferin’ from a severe disruption.”
Coffee John thumped his red fist upon the table.
“Bryce up, gents!” he exclaimed. “Remember there’s nothink in the
ryce but the finish, as the dark ’orse says, w’en ’e led ’em up to the
wire! They’s many a man ’as went broke in this ’ere tarn, an’ ’as
lived to build a four-story ’ouse in the Western Addition; an’ they’s
plenty more as will go broke afore the trams stop runnin’ on Market
Street! This ’ere is a city o’ hextremes, you tyke me word for thet! It
ain’t on’y that Chinatarn is a stone’s throw from the haristocracy o’
Nob Hill, an’ they’s a corner grocery with a side entrance alongside
of every Methody chapel. It ain’t on’y that the gals here is prettier
an’ homblier, an’ stryter an’ wickeder than anyw’eres else in
Christendom, but things go up an’ darn every other wye a man can
nyme. It’s corffee an’ sinkers to-dye an’ champyne an’ terrapin to-
morrer for ’arf the people what hits the village. They’s washwomen’s
darters wot’s wearin’ of their dimonds art on Pacific Avenoo, an’
they’s larst year’s millionaires wot’s livin’ in two rooms darn on
Minnie Street. It’s the wye o’ life in a new country, gents, but they’s
plums a-gettin’ ripe yet, just the syme, every bleedin’ dye, I give yer
my word! Good Lawd! Look at me, myself! Lemme tell yer wot’s
happened to me in my time!”
And with this philosophic introduction, Coffee John began
 THE STORY OF BIG BECKY

W hen I fust struck this ’ere port, I was an yble seaman on the
British bark Four Winds art o’ Iquique, with nitrytes, an’ I was
abart as green a lad as ever was plucked. When I drored the nine
dollars that was a-comin’ to me, I went ashore an’ took a look at the
tarn, an’ I decided right then that this was the plyce for me. So I
calmly deserts the bark, an’ I ain’t set me foot to a bloomin’ gang-
plank from that dye to this, syvin’ to tyke the ferry to Oakland.
Me money larsted abart four dyes. The bleedin’ sharks at the sylor
boardin’-’ouse charged five, a femile in a box at the “Golden West”
darnce-hall got awye with three more, an’ the rest was throwed into
drinks promiscus. The fourth dye in I ’adn’t a bloomin’ penny to me
nyme, an’ I was as wretched as a cow in a cherry-tree. After abart
twelve hours in “’Ell’s Arf-Acre” I drifted into a dive, darn on Pacific
Street, below Kearney, on the Barbary Coast, as was the Barbary
Coast in them dyes! It was a well-known plyce then, an’ not like
anythink else wot ever done business that I ever seen, “Bottle
Myer’s” it was; per’aps yer may have heard of it? No?
Yer went in through a swing door with a brarss sign on, darn a
’allwye as turned into a corner into a wider plyce w’ere the bar was,
an’ beyond that to a ’all that might ’ave ’eld, I should sye, some sixty
men or thereabart. The walls was pynted in a blue distemper, but for
a matter of a foot or so above the floor there was wot yer might call
a dydo o’ terbacker juice, like a bloomin’ coat o’ brarn pynte. The ’all
smelled full strong o’ fresh spruce sawdust on the floor, an’ the rest
was whiffs o’ kerosene ile, an’ sylor’s shag terbacker an’ style beer,
an’ the combination was jolly narsty! Every man ’ad ’is mug o’ beer
on a shelf in front of ’is bench, an’ the parndink of ’em after a song
was somethink awful. On a bit of a styge was a row of performers in
farncy dress like a nigger minstrel show, an’ a beery little bloke sat
darn in front, bangin’ a tin-pan pianner, reachin’ for ’is drink with one
’and occysional, withart leavin’ off plyin’ with the other.
Well, after a guy ’ad sung “All through a lydy wot was false an’ fyre,”
an’ one o’ the ’ens ’ad cracked art “Darn the lyne to Myry,” or
somethink like that, Old Bottle Myer, ’e got up, with a ’ed like a
cannon-ball an’ cock eyes an’ eyebrars like bits o’ thatch, an’ a
farncy flannel shirt, an’ ’e says:
“If any gent present wants to sing a song, he can; an’ if ’e don’t
want to, ’e don’t ’ave to!”
Nar, I wa’n’t no singer myself, though I ’ad piped occysional, to me
mytes on shipboard, but I thought if I couldn’t do as well as them as
’ad myde us suffer, I ought to be jolly well ashymed o’ meself. Wot
was more to the point, I didn’t ’ave the price of a pot o’ beer to bless
myself with, an’ thinks I, this might be a charnst to pinch a bit of a
’aul. So I ups an’ walks darn to the styge, gives the bloke at the
pianner a tip on the chune, an’ starts off on old “Ben Bobstye.” They
was shellbacks in the audience quite numerous as I seen, an’ it done
me good to ’ear ’em parnd their mugs after I’d gort through. W’en I
picked up the abalone shell like the rest of ’em done, an’ parssed
through the ’all, wot with dimes an’ two-bit pieces I ’ad considerable,
an’ I was natchurly prard o’ me luck.
Old Bottle Myer come up an’ says, “’Ow much did you myke, me
friend? Five fifteen, eh? Well, me charge will be on’y a dollar this
time, but if yer want to come rarnd to-morrow night, yer can. If yer
do all right, I’ll tyke yer on reg’lar.”
Well, I joined the comp’ny sure enough, an’ sung every night, pickin’
up a feerly decent livin’ at the gyme, for it was boom times then, an’
money was easier to come by. I had me grub with all the other
hartists in a room they called the “Cabin,” darn below the styge,
connected to a side dressin’-room by a narrer styre. Nar, one o’ the
lydies in the comp’ny was the feature o’ the show, an’ she were a bit
out o’ the ord’n’ry, I give you my word!
She was a reg’lar whyle of a great big trouncin’ Jew woman as ever I
see. Twenty stone if she were an arnce, an’ all o’ six foot two, with
legs like a bloomin’ grand pianner w’en she put on a short petticoat
to do a comic song. She was billed as “Big Becky,” an’ by thet time
she was pretty well known abart tarn.
She ’ad started in business in San Francisco at the hextreme top o’
the ’Ebrew haristocracy of the Western Addition, ’avin ’parssed ’erself
off for a member o’ one o’ the swellest families o’ St. Louis, an’ she
did cut a jolly wide swath here, an’ no dart abart thet! She was
myde puffickly at ’ome everyw’eres, an’ flashed ’er sparklers an’ ’er
silk garns with the best o’ ’em. Lord, it must ’ave took yards o’ cloth
to cover ’er body! Well, she gort all the nobs into line, an’ ’ad
everythink ’er own wye for abart two months, as a reg’lar full-blowed
society favoryte. Day an’ night she ’ad a string o’ men after ’er, or ’er
money, w’ich was quite two things, seein’ she ’ad to graft for every
penny she bloomin’ well ’ad.
W’ile she were at the top notch of the social w’irl, as you might sye,
along come another Jewess from the East, reckernized ’er, an’ spoils
Big Becky’s gyme, like a kiddie pricks a ’ole in a pink balloon. She
was showed up for a hadventuress, story-book style, wot ’ad
’oodwinked all St. Louis a year back, an’ then ’er swell pals dropped
awye from ’er like she was a pest-’ouse. Them wot ’ad accepted ’er
invites, an’ ’ad ’er to dinner an’ the theatre an’ wot-not, didn’t myke
no bones abart it—they just natchully broke an’ run. Then all sorts o’
stories come art, ’ow she borrowed money ’ere, there an’
everyw’ere, put ’er nyme to bad checks, an’ fleeced abart every
bloomin’ ’Ebrew in tarn. She’d a bin plyin’ it on the grand, an’ on the
little bit too grand.
She was on trial for abart two dyes, an’ the city pypers was so full o’
the scandal that the swells she ’oodwinked ’ad to leave tarn till it
blew over, an’ San Francisco quit larfin at ’em. I give yer me word
the reporters did give art some precious rycy tyles, an’ every ’Ebrew
wot ’ad ’ad Big Becky at a five o’clock tea didn’t dyre go art o’ doors
dye-times.
Well, for the syke o’ ’ushin’ matters up, her cyse were compromised
an’ the prosecution withdrawed, she bein’ arsked in return to git art
o’ tarn. Instead o’ thet, not ’avin’ any money, she went an’ accepted
an offer from a dime museum here, an’ begun fer to exhibit of ’erself
in short skirts every afternoon an’ evenink reg’lar, to the gryte an’
grand delight of every chappie who ’adn’t been fooled ’imself. After
that she done “Mazeppa” at the Bella Union Theatre in a costume
wot was positively ’orrid. It was so rude that the police interfered,
an’ thet was back ten year ago, w’en they wa’n’t so partickler on the
Barbary Coast as they be naradyes. Then she dropped darn to Bottle
Myer’s an’ did serios in tights. She was as funny as a bloomin’
helephant on stilts, if so yer didn’t see the plyntive side of it, an’ we
turned men awye from the door every night.
I don’t expect Becky ever ’ad more’n a spoonful o’ conscience. But
with all ’er roguery, she was as big a baby inside as she were a giant
outside, w’en yer onct knew ’ow to tyke ’er, was Big Becky. ’Ard as
brarss she was w’en yer guyed ’er, but soft as butter w’en yer took
’er part, w’ich were somethink as she weren’t much used to, for
most treated ’er brutle. Some’ow I couldn’t help likin’ ’er a bit, in
spite o’ meself. I put in a good deal o’ talk with ’er, one wye an’
another, till I ’ad ’er confidence, an’ could get most anythink art of
’er I wanted. She told me ’er whole story, bit by bit, an’ it were a
reg’lar shillin’ shocker, I give yer my word!
Amongst other things, she told me that a Johnnie in tarn nymed
Ikey Behn ’ad gort precious balmy over ’er, before she was showed
up, an’ ’ad went so far as to tyke art a marriage license in ’opes,
when she seen ’e meant biz, she’d marry ’im. ’E’d even been
bloomin’ arss enough to give it to ’er, and she ’ad it yet, an’ was
’oldin’ it over ’is ’ed for blackmyle, if wust come to wust. She
proposed for to ’ave a parson’s nyme forged into the marriage
certificate that comes printed on the other side from the license.
Nar, things bein’ like this, one night I come up the styre from the
“Cabin” w’ere I’d been lyte to dinner, an’ went into the room w’ere
Becky was a-gettin’ ready to dress for ’er turn. There was a toff
there, in a topper, an’ a long black coat, an’ ’e was havin’ it art, ’ot
an’ ’eavy, with Becky. Just as I come up, ’e broke it off, cursink ’er
something awful, an’ she was as red as a bleedin’ ’am, an’ shykin’ a
herthquyke with ’er ’air darn, an’ ’er breath comin’ like a smith’s
bellus. The gentleman slum the door, an’ she says to me, “’Ere, Jock,
old man, will yer do me a fyvor? Just ’old this purse o’ mine an’ keep
it good an’ syfe till I get through my song, for that’s Ikey Behn wot
just went art, an’ ’e’ll get my license sure, if I leave it abart. I carn’t
trust nobody in this ’ole but you. It’s in there,” an’ she showed me
the pyper, shovin’ the purse into me ’and. I left an’ went darn front
w’ile she put on ’er rig an’ done ’er turn.
Art in the bar, there was the toff, talkin’ to one o’ the wyters, an’ I
knew ’e was tryin’ to tip somebody to frisk Big Becky’s pockets. W’en
I come up, ’e says, “’Ow de do, me man? I sye, ’ave a glarss with
me, won’t yer? Wot’ll yer ’ave?”
I marked ’is gyme then an’ there, an’ I sat darn to see ’ow ’e’d act.
’E done it ’andsome, ’e did; ’e was a thoroughbred, an’ no mistake
abart thet! ’E wan’t the bloke to drive a bargain like most would ’ave
done under the syme irritytin’ circumstances.
“See ’ere,” ’e says, affable, an’ ’e opens ’is wallet an’ tykes art a pack
o’ bills. “’Ere’s a tharsand in ’undred-dollar greenbacks. You get me
that pyper Big Becky’s got in ’er purse!”
There I was, sittin’ right in front of ’im, with the license in me
pocket, an’ there was a fortune in front o’ me as would ’ave set me
up in biz for the rest o’ me life. Wot’s more, if they’s anythink I do
admire, it’s a thoroughbred toff, for I was brought up to reckernize
clarss, an’ I seen at a wink that this ’ere Johnnie was a dead sport. I
knew wot it meant to ’im to get possession o’ thet pyper, for Becky
could myke it jolly ’ot for ’im with it. I confess, gents, thet for abart
’alf a mo I hesityted. But I couldn’t go back on the woman, seem’
she ’ad trusted me partickler, an’ so I shook me ’ed mournful, an’
refused the wad.
’E was a bit darn in the mouth at thet, not lookin’ to run up agin
such, in a plyce like Bottle Myer’s, I expeck. “See ’ere, me man,” ’e
says, “I just gort to ’ave thet pyper. I’ll tell yer wot, w’en I gort art
thet license, I swyre I thought the woman was stryte an’ all she
pretended to be. We was all of us took in. I wa’n’t after ’er money, I
was plum balmy on ’er, sure, an’ nar I’m engyged to the nicest little
gal as ever lived, an’ it’ll queer the whole thing if this ’ere foolishness
gets art!”
With my respeck for the haristocracy, I was jolly sorry for the chap,
but I wa’n’t a-goin’ to sell Becky art, not thet wye. I wa’n’t no holy
Willie, but I stuck at that. So I arsked, “Wot’s the gal’s nyme?”
“That’s none of your biz,” says Behn, gettin’ ’ot in the scuppers, “an’
that little gyme won’t do yer no good, nohow, for the gal knows all
abart this matter, ’an yer can’t trip me up there. Not much. I’ll pye
yer all the docyment’s worth, if yer’ll get it for me.”
“Yer won’t get it art o’ Becky not at no price,” I says, “an’ yer won’t
get it art o’ me, unless yer answer my questing. If yer want me to
conduck this ’ere affyre, I got to know all abart it, an’ yer gal won’t
be put to no bother, neither.”
’E looked me over a bit, an’ then ’e says, low, so that nobody
couldn’t ’ear, “It’s Miss Bertha Wolfstein.” Then ’e give me ’is
address, ’an left the matter for me to do wot I could.
I thought if anybody could work Becky, it would be me, an’ I
expected the gal’s nyme might come in ’andy, though I ’ad no idea
then how strong it would pull. So I goes up to the big woman after
she was dressed, and tykes ’er up to the “Poodle Dog” for supper.
She ’ad gort over the worry by this time, an’ was feelink as chipper
as a brig in a west wind.
“Did ever yer ’ear tell of a Bertha Wolfstein?” I says, off-hand.
Then wot does she do but begins to bryke darn an’ blubber. “She
was the on’y one in tarn as come to see me after I was pulled,” she
says. “I done all kinds o’ fyvors for lots of ’em, but Miss Wolfstein
was the on’y one who ’ad called me friend, as ever remembered it.
She was a lydy, was Miss Wolfstein; she treated me angel w’ite, she
did, Gawd bless ’er pretty fyce!”
Then I knowed I ’ad ’er w’ere I wanted ’er, ’an I give it to ’er tender
an’ soft, with all the sugar an’ cream she could stand. I let art Ikey
Behn’s story, hinch by hinch, an’ I pynted the feelinks o’ thet Bertha
Wolfstein with all the tack I knew how, till I gort Becky on the run
an’ she boohooed again, right art loud, an’ I see I ’ad win ’er over.
My word! she did look a sight for spectytors after she’d wiped a ’arf
parnd o’ pynte off’n ’er fyce with ’er napkin, sobbink awye, like ’er
’eart was as soft as a slug in a mud-puddle. She parssed over the
pyper art of ’er purse an’ she says, “Yer can give it to Ikey an’ get
the money. I don’t want to ’urt a ’air o’ thet gal’s ’ead.”
Seein’ she was so easy worked, I thought it was on’y right I should
be pyde for me trouble, for it ’ad stood me somethink for a private
room an’ drinks an’ such to get her into proper condition.
So I says, “Thet’s all right, Becky, an’ it’s jolly ’andsome o’ yer to be
willin’ to let go of the docky-ment, but I’ll be blowed if I see ’ow yer
can tyke ’is money, w’en yer feel that wye. If yer sell art the pyper,
w’ere does the bloomin’ gratitude to the gal come in, anywye?”
At this, Becky looked all wyes for a Sunday, an’ I perceeded to rub it
in. “Nar, see here, Becky, w’ich would yer rather do—get five ’undred
dollars for the license from Ikey, or let Miss Wolfstein know yer’d
made a present of it to ’er, for wot she done to yer?”
That was a ’ard conundrum for a woman like that, who ’ad fleeced
abart every pal she ever ’ad, an’ the money was a snug bit for
anybody who was as ’ard up as she was then. I thought I’d mark the
price darn a bit so’s to myke the sacrifice easier for ’er. I didn’t dyre
to trust her with a offer of the tharsand Ikey ’ad flashed at me.
Besides, I thought I see a charnst to myke a bit meself withart lyin’.
Sure enough, I ’ad read the weather in ’er fyce all right, an’ she was
gyme to lose five ’underd just to sye “thank you,” as yer might sye. I
farncy I’d found abart the only spot in ’er ’eart as wa’n’t rotten.
“I guess I’d rather ’ave ’er know I ain’t quite so bad as they think,”
she says, an’ she gulluped an’ rubbed ’er eyes. “You go to Ikey, an’
you tell ’im ’e’s a—” Well, I won’t sye wot she called ’im. “But Bertha
Wolfstein is the on’y lydy in tarn, an’ it’s on’y for ’er syke I’m givin’
up the license.”
Then she kerflummuxed again, an’ if yer think I left her time to think
it over, yer don’t know old John. I took the pyper before the words
was feerly art of ’er marth, an’ in ’arf an’ ’our I was pullin’ Ikey
Behn’s door-bell. When ’e seen me, ’e grinned like a cat in a cream-
jug, an’ ’e arsked me into the li’bry like I was a rich uncle just ’ome
from the di’mond fields.
Nar, yer might think as I was a-goin’ to try to sell ’im the pyper on
me own account, leavin’ ’im to think that Becky was gettin’ the price
of it, an’ me a percentage. Not much I wa’n’t; not on yer blessed
life! I was too clever for thet! I’ve seen reel toffs before, an’ I knew
Ikey for best clarss when I piped ’im off. ’Ave yer ever watched the
bootblacks in Piccadilly Circus? D’yer think they has a trades-union
price for a shine? Nar! W’en a bleedin’ swell comes along an’ gits a
polish an’ arsks ’ow much, it’s “Wot yer please, sir,” an’ “I leave it to
you, sir,” an’ the blackie gits abart four times wot ’e’d a-dared to
arsk, specially if the toff’s a bit squeegee. That’s the on’y wye to
treat a gentleman born, an’ I knew it. So I tipped ’im off the stryte
story, leavin’ nothing art to speak of, an’ ’e listens affable. I ’ands ’im
over the license at the end.
W’en ’e’d stuck the pyper in a candle ’andy, an’ ’ad lighted a big
cigar with it, offerink the syme an’ a drink to me, ’e says, as cool as
a pig before Christmas, says ’e, “Nar, me man, wot d’yer want for
yer trouble? Yer done me a fyvor, an’ no dart abart thet!”
“No trouble at all,” I says. “I’m proud to oblige such a perfeck
gentleman as you be,” an’ with that I picks up me ’at an’ walks
toward the door.
“Wyte a bit,” ’e says, “I’ll see if I ain’t gort a dollar on me,” an’ ’e
smiles cordial. But ’e watches me fyce sharp, too, as I seen in the
lookin-glarss. Then ’e goes to a writin’-desk an’ looks in a dror. “If
happen yer don’t want any o’ this yerself, yer can give it to Becky,”
he says, an’ ’e seals up a packet an’ gives it to me like ’e was the
bloomin’ Prince o’ Wyles. Sure, ’e was toff, clean darn to ’is boot-
pegs, I give yer my word!
When I gort out o’ doors an’ opened the packet, I near fynted awye.
They was a wad o’ hundreds as come to a cool four tharsand dollars.
I walked back on the bloomin’ hatmosphere!
I come into Bottle Myer’s, just as Big Becky was a-singin’ “Sweet
Vylets,” in a long w’ite baby rig an’ a bunnit as big as a ’ogshead.
Lord, old Myer did myke a guy o’ thet woman somethink awful! W’en
she come off, I was wytin’ in the dressin’-room for ’er.
“My Lawd, Jock!” she says, w’en she seen me, “yer didn’t give up
the pyper, did yer? Yer knew I was on’y foolin’, didn’t yer? Don’t sye
yer let Ikey get a-hold of it! It was good for a hunderd to me any
dye I needed the money, if I wanted to give it to the pypers.”
Well, that myde me sick, though I’d expecked as much. I was thet
disgusted thet she couldn’t stand by ’er word for a hour, thet I
couldn’t ’elp syin’, “An’ ’ow abart Miss Wolfstein, as was a friend to
yer, w’en all the other women in tarn went back on yer, Becky? Yer
know wot she’ll think of yer, don’t yer?”
Right then I seen abart as plucky a fight between good an’ bad
worked art on ’er fyce, as I ever seen in the ring, London Prize rules
to a finish. An’ if you’ll believe it, gents, the big woman’s gratitude to
the Wolfstein gal come art on top, an’ the stingy part of ’er was
knocked art flat.
It were a tough battle, though, I give yer my word, before I got the
decision. She bit ’er lip till the blood come through the rouge,
standin’ there, a great whoopin’ big mounting o’ flesh with baby
clothes an’ a pink sash on, an’ a wig an’ bunnit like a bloomin’ Drury
Lyne Christmas Pantymime. I just stood an’ looked at ’er! I’m blowed
if she didn’t git almost pretty for ’alf a mo, w’en she says:
“I’m glad yer did give it up, Jock; I’m glad, nar it’s all over. But thet
five hundred would ’ave syved me life, for old Myer ’as give me the
sack to-dye, an’ I don’t know wot’ll become o’ me.”
Wot did I do? I done wot the dirtiest sneak in the Pen would a did,
an’ ’anded art the envelope an’ split the pile with ’er.

Coffee John fetched a deep sigh. “Well, gents, thet’s w’ere I got me
start. The wad didn’t larst long, for I was green an’ unused to
money, but I syved art enough to set me up here, an’ ’ere I am yet.
I never seen Big Becky sinct.
“Nar you see wot a man might ’appen to strike in a tarn like this.
Every bloomin’ dye they’s somebody up an’ somebody darn. I
started withart a penny, an’ I pulled art a small but helegant fortune
in a week’s time. So can any man.
“Gents, I give you this stryte: Life in San Francisco is a bloomin’
fayry tyle if a man knows ’is wye abart, an’ a bloke can bloomin’ well
blyme ’is own liver if ’e carn’t find a bit of everythink ’ere ’e wants,
from the Californy gal, w’ich is the noblest work o’ Gawd, to the
’Frisco flea, w’ich is a bleedin’ cousin to the Old Nick ’isself! They
ain’t no tarn like it, they ain’t never been none, an’ they ain’t never
goin’ to be. It ain’t got neither turf nor trees nor kebs, but it’s bloody
well gort a climate as mykes a man’s ’eart darnce in ’is bussum, an’
cable-cars wot’ll tyke a guy uphill to ’eaven or rarnd the bloomin’
next corner to ’ell’s cellar! They’s every sin ’ere except ’ypocrisy, for
that ain’t needed, an’ they’s people wot would ’ave been synted if
they’d lived in ancient times.
“An’ nar, I want to egspress somethink of wot I thinks o’ you bums.
As fur as I can see every one o’ yer is a ’ard cyse, ’avin’ indulged in
wot yer might call questingable practices, withart yet bein’, so to
speak, of the criminal clarss. It don’t go to myke a man particklerly
prard o’ ’umanity to keep a dime restaurant; ’arrivver, ’Evving knows
wot I’d do if I couldn’t sometimes indulge in the bloomin’ glow of
’ope. Vango, I allar you’ll be a bad ’un, and I don’t expeck to make a
Sunday-school superintendent o’ yer. Coffin uses such lengwidge as
mykes a man wonder if ’e ain’t a bleedin’ street fakir on a ’arf-’oliday,
so I gives ’im up frankly an’ freely an’ simply ’opes for the best. But
you, Dryke, is just a plyne ornery lad as ’as ’ad ’is eart broke, an’ you
’as me sympathy, as a man with feelinks an’ a conscience.
“Nar, I’ll tell yer wot I’ll do. I’ll styke the three of yer a dime apiece,
an’ yer git art o’ ’ere with the firm intentions o’ gettin’ rich honest.
Mybe yer won’t myke it, an’ then again mybe yer will, but it’s a good
gamble an’ I’d like to have it tried art. Anywye, come back ’ere to-
morrow at nine, an’ ’ave dinner on me, ’an tell me all abart it. Wot
d’yer sye?”
It was a psychological moment. The proposition, fantastic as it was,
seemed, under the spell of Coffee John’s enthusiasm, to promise
something mysteriously new, something grotesquely romantic. It
was a chance to turn a new leaf. The three vagabonds were each
stranded at a turn of the tide. The medium, with his nerves
unstrung, was only too willing to cast on Fate the responsibility of
the next move. The Harvard Freshman, with no nerves at all, one
might say, hailed the adventure as a Quixotic quest that would be
amusing to put to the hazard of chance. The hero of Pago Bridge
had little spirit left, but, like Vango, he welcomed any fortuitous hint
that would tell him which way to turn in his misery. All three were
well worked upon by the solace of the moment, and a full stomach
makes every man brave. Coffee John’s appeal went home, and from
the sordid little shop three beggars went forth as men. One after the
other accepted the lucky dime and fared into the night, to pursue
the firefly of Fortune.
In ten minutes the restaurant was dark and empty, and Coffee John
was snoring in a back room. Three Picaroons were busy at the
Romance of Roguery.
 CHAPTER VI
THE HARVARD FRESHMAN’S ADVENTURE: THE
FORTY PANATELAS

J ames Wiswell Coffin, 3d, was the first of the three adventurers to
leave the restaurant, and as he turned up Kearney Street he had
a new but fully fledged philosophy buzzing in his brain.
Enlightenment had come in a hint dropped by Coffee John himself. It
took a Harvard man and a Bostonian of Puritan stock to hatch that
chick of thought, but, by the time the coffee was finished, the
mental egg broke and an idea burst upon him. It was this:
“Facts show that good luck is stable for a while and is then followed
by a run of misfortune. The mathematical ideal of alternate favorable
and unfavorable combinations does not often occur. There is where
the great Law of Probabilities falls down hard. The curve of fortune
is like a wave. It should then be played heavily while it ascends, and
lightly on the decline. Mine is undoubtedly rising. Go to! I shall
proceed to gamble!”
But how gamble at midnight with a capital of but one dime? In no
other city in the world is it so easy as in San Francisco, that quaint
rendezvous of saloons and cigar stands. There the goddess Fortuna
has a shrine on every street corner and the offerings of her devotees
produce a rattle as characteristic of the town as the slap of the cable
pulley in the conduit of the car lines. The cigar slot-machine or
“hard-luck-box” is a nickel lottery played by good and bad alike; for
it has a reputation no shadier than the church-raffle or the juvenile
grab-bag, and is tolerated as a harmless safety-valve for the lust of
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