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Energy Balance and Cancer 12

Ofer Reizes
Nathan A. Berger Editors

Adipocytokines,
Energy Balance,
and Cancer
Energy Balance and Cancer
Volume 12

Series Editor:
Nathan A. Berger,
Case Western Reserve University, School of Medicine,
Cleveland, OH, USA

More information about this series at http://www.springer.com/series/8282

Ofer Reizes • Nathan A. Berger
Editors

Adipocytokines,
Energy Balance, and Cancer
Editors
Ofer Reizes Nathan A. Berger
Department of Cellular and Molecular Center for Science, Health and Society
Medicine Case Western Reserve University
Cleveland Clinic Lerner Research Institute Cleveland, OH, USA
Cleveland, OH, USA

ISSN 2199-2622 ISSN 2199-2630 (electronic)

Energy Balance and Cancer
ISBN 978-3-319-41675-5 ISBN 978-3-319-41677-9 (eBook)
DOI 10.1007/978-3-319-41677-9

Library of Congress Control Number: 2016948729

© Springer International Publishing Switzerland 2017

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Preface

Adipose tissue, composed of adipocytes, stromal cells, immune and inflammatory

cells, and vascular components, was initially considered a depot, storing fuel in the
form of fats during times of energy excess and providing fuel for body functions in
time of energy needs. Regulation of storage, release, and utilization has been found
to be due to the interaction of a complex array of signaling factors that may act
locally and/or systemically by autocrine, paracrine, and endocrine mechanisms.
These include a variety of growth factors, hormones, and other regulatory agents
synthesized in brain, endocrine organs, muscle, gastrointestinal, and adipose tissue
itself. When synthesized and secreted in adipose tissues, these factors are designated
adipocytokines; they have major physiologic and behavioral effects and their con-
centrations fluctuate in response to expansion and concentration of adipose tissue,
body composition, and a variety of other physiologic signals. In addition to the role
of adipocytokines in regulating multiple aspects of energy metabolism, excess adi-
pose tissue has been identified as a source of chronic low-grade inflammation lead-
ing to the synthesis of a variety of proinflammatory signals. It is now apparent that
in addition to their role in regulating energy metabolism, adipocytokines also con-
tribute significantly to many of the comorbidities associated with the current world-
wide obesity pandemic including diabetes, cardiovascular disease, and cancer.
The goal of this volume on Adipocytokines, Energy Balance, and Cancer is to
describe recent advances in understanding adipocytokines, their physiologic role in
normal regulatory processes, and their mechanistic contributions to the multiple
malignancies that increase in response to changes in body mass. These mediators
and their effects will be discussed also as potential interventional targets for cancer
prevention and control.
This volume begins with an analysis of the components and molecular biology of
adipose tissue and differences in activities and interactions related to body distribu-
tion. Subsequent chapters deal with both the physiologic and pathologic functions of
the major adipocytokines including their regulatory role, their role in energy metab-
olism, and their role in cancer etiology, promotion, and progression. Adipocytokines
to be discussed include Leptin, Adiponectin, Visfatin, Retinol-Binding Protein,
Apelin, Macrophage Chemotactic Factor-1, Plasminogen Activator Inhibitor-1,

v
vi Preface

Chemerin, C-Reactive Protein, and Resistin as well as Gastrointestinal Regulatory

Peptides including Ghrelin, Glucagon-Like Peptide, and others.
This volume on Adipocytokines, Energy Balance, and Cancer is unique in examin-
ing in depth the multiplicity of adipocytokines, their physiologic regulatory mecha-
nisms, and their pathologic role in promoting cancer. We have been fortunate to
assemble chapters authored by an international group of authors with expertise in the
multiple signaling molecules, and we are grateful for their contribution to this volume.
Chapter 1, written by Caner Saygin and Ofer Reizes (Case Western Reserve
University Lerner College of Medicine) and Nathan A. Berger (Case Western
Reserve University School of Medicine), provides an overall introduction to adi-
pose tissue as a secretory organ and identifies the major adipocytokines and their
functions. Chapter 2 by V.B. O’Leary (Helmholtz Zentrum Munich Institute of
Radiation Biology) and J.P. Kirwan (Case Western Reserve University Lerner
College of Medicine) focuses on molecular aspects of adiponectin secretion, its
regulatory roles in cellular signaling activities, and its contribution to tumor metab-
olism. In Chap. 3, Margot Cleary (University of Minnesota) and Marta Torroella-
Kouri (University of Miami School of Medicine) focus on leptin and its association
with cancer while in Chap. 4, Neeraj K. Saxena (University of Maryland School of
Medicine) and Dipali Sharma (Johns Hopkins University School of Medicine) dis-
cuss cancer therapeutic strategies targeted at leptin. Chapter 5, written by Daniel
C. Berry (University of Texas Southwestern Medical Center) and Noa Noy (Case
Western Reserve University Lerner College of Medicine), provides a comprehen-
sive analysis of the role of Retinol Binding Protein 4 in Vitamin A metabolism and
its relation to diabetes and cancer. In Chap. 6, Maria Dalamaga and Gerasimos
Socrates Christodoulatos (University of Athens) describe the interesting intra- and
extracellular relation of Visfatin/Nicotinamide Phosphoribosyl Transferase and its
relation to obesity and cancer. Chapter 7, written by Stefanie Kälin (Technical
University Munich) and Roland Kälin (Ludwig-Maximilians University Munich),
provides an introduction to Apelin, one of the most recently identified adipocyto-
kines and its role in physiologic and pathologic conditions especially tumorigene-
sis. E. Angela Murphy (University of South Carolina) in Chap. 8 provides insight
into several novel adipocytokines including Monocyte Chemotactic Protein-1,
Plasminogen Activator Inhibitor-1, and Chemerin and their potential dysregulated
effects on obesity and cancer. The contribution of resistin to insulin resistance, obe-
sity, and cancer is described in Chap. 9, written by Zhenzhen Zhang, Jackilen
Shannon (Oregon Health and Science University), and Hanrui Zhang (Perelman
School of Medicine, University of Pennsylvania). C-Reactive Protein, generally
considered an acute phase reactant but also categorized as an adipocytokine associ-
ated with inflammation and cancer, is discussed by Helen Swede (University of
Connecticut School of Medicine) and Dejana Braithwaite (University of California
San Francisco). In addition to the host of adipocytokines described in preceding
chapters, there is yet another series of peptide signaling molecules, the gastrointestinal
regulatory peptides, secreted from the GI tract that regulate hunger, satiety, gastro-
intestinal motility, and other physiologic functions. Their activities and impact on
obesity and cancer are described in Chap. 11 by Debora Bruno and Michael Wolfe
(Case Western Reserve University School of Medicine).
Preface vii

Overall, this volume on Adipocytokines, Energy Balance, and Cancer provides a

valuable addition to the Energy Balance and Cancer series to inform readers of the
most recent information on both the normal and disease promoting activities of
these adipocyte-derived signaling molecules. This volume should be useful to all
students, researchers, and clinicians involved or interested in mechanisms by which
obesity contributes to its associated comorbidities, especially cancer, and should
serve as a foundation to stimulate research to develop adipocytokine-targeted inter-
ventions to disrupt these processes.

Cleveland, OH, USA Ofer Reizes

Nathan A. Berger
Contents

1 Adipocytes, Adipocytokines, and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Caner Saygin, Ofer Reizes, and Nathan A. Berger
2 Adiponectin, Obesity, and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
V.B. O’Leary and J.P. Kirwan
3 Leptin in Cancer: Epidemiology and Mechanisms . . . . . . . . . . . . . . . . . 39
Margot P. Cleary and Marta Torroella-Kouri
4 Leptin-Signaling Pathways as Therapeutic Targets in Cancer. . . . . . . . 67
Neeraj K. Saxena and Dipali Sharma
5 Retinol Binding Protein 4: Role in Diabetes and Cancer . . . . . . . . . . . . 89
Daniel C. Berry and Noa Noy
6 Visfatin, Obesity, and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Maria Dalamaga and Gerasimos Socrates Christodoulatos
7 Apelin and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Stefanie Kälin and Roland E. Kälin
8 Novel Adipocytokines: Monocyte Chemotactic Protein-1,
Plasminogen Activator Inhibitor-1, Chemerin . . . . . . . . . . . . . . . . . . . . 161
E. Angela Murphy
9 Resistin, Obesity, and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Zhenzhen Zhang, Jackilen Shannon, and Hanrui Zhang
10 Role of C-Reactive Protein in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Helen Swede and Dejana Braithwaite
11 GI Peptides, Energy Balance, and Cancer . . . . . . . . . . . . . . . . . . . . . . . 253
Debora S. Bruno and M. Michael Wolfe

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

ix
Contributors

Nathan A. Berger, M.D. Department of Medicine, Biochemistry, Oncology,

Genetics, Case Comprehensive Cancer Center, Case Western Reserve University,
Cleveland, OH, USA
Daniel C. Berry, Ph.D. Division of Endocrinology, Department of Internal
Medicine, Graff Lab, Dallas, TX, USA
Dejana Braithwaite, Ph.D. Department of Epidemiology and Biostatistics,
University of California San Francisco, San Francisco, CA, USA
Debora S. Bruno, M.D. Hematology/Oncology, MetroHealth Medical Center,
Cleveland, OH, USA
Case Western Reserve University, Cleveland, OH, USA
Department of Medicine, MetroHealth Medical Center, Case Western Reserve
University, Cleveland, OH, USA
Gerasimos Socrates Christodoulatos, M.D. Department of Clinical Biochemistry,
University of Athens, “Attikon” General University Hospital, Athens, Greece
Margot P. Cleary, Ph.D. The Hormel Institute-University of Minnesota, Austin,
MN, USA
Maria Dalamaga, M.D., M.Sc., M.P.H., Department of Clinical Biochemistry,
University of Athens, “Attikon” General University Hospital, Athens, Greece
Department of Biological Chemistry-Clinical Biochemistry, University of Athens
Medical School, Athens, Greece
Roland E. Kälin Neurosurgical Research, University Clinics Munich, Ludwig-
Maximilians-University, Munich, Germany
Stefanie Kälin Institute for Diabetes and Obesity, Helmholtz Centre for Health
and Environment and Technical University Munich, Munich, Germany

xi
xii Contributors

J.P. Kirwan, Ph.D. Department of Pathobiology, Lerner Research Institute

(NE4-209), The Cleveland Clinic Foundation, Case Western Reserve University
Lerner College of Medicine, Cleveland, OH, USA
E. Angela Murphy, Ph.D. Department of Pathology, Microbiology & Immunology
School of Medicine, University of South Carolina, Columbia, SC, USA
Noa Noy, Ph.D. Department of Cellular and Molecular Medicine, Lerner Research
Institute, Cleveland Clinic, Cleveland, OH, USA
V.B. O’Leary, Ph.D. Helmholtz Zentrum Munich, Institute of Radiation Biology,
Neuherberg, Germany
Ofer Reizes, Ph.D. Department of Cellular and Molecular Medicine, Lerner
Research Institute, Cleveland Clinic, Cleveland, OH, USA
Department of Cellular and Molecular Medicine, Case Comprehensive Cancer
Center, Case Western Reserve University Lerner College of Medicine, Cleveland,
OH, USA
Neeraj K. Saxena, Ph.D. Department of Medicine, University of Maryland School
of Medicine, Baltimore, MD, USA
Caner Saygin, M.D. Department of Cellular and Molecular Medicine, Lerner
Research Institute, Cleveland Clinic, Cleveland, OH, USA
Jackilen Shannon, Ph.D., R.D. OHSU-PSU School of Public Health, Oregon
Health and Science University, Portland, OR, USA
Dipali Sharma, Ph.D. Department of Oncology, Sidney Kimmel Comprehensive
Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Helen Swede, Ph.D. Department of Community Medicine and Health Care,
University of Connecticut School of Medicine, Farmington, CT, USA
Marta Torroella-Kouri, Ph.D. Department of Microbiology and Immunology,
University of Miami Miller School of Medicine, Miami, FL, USA
M. Michael Wolfe, M.D. Department of Medicine, MetroHealth Medical Center,
Case Western Reserve University, Cleveland, OH, USA
Hanrui Zhang, B.Med., Ph.D. Department of Medicine, Columbia University
Medical Center, New York, NY, USA
Zhenzhen Zhang, Ph.D., M.P.H. OHSU-PSU School of Public Health, Oregon
Health and Science University, Portland, OR, USA
Chapter 1
Adipocytes, Adipocytokines, and Cancer

Caner Saygin, Ofer Reizes, and Nathan A. Berger

Abstract Obesity is now a well-established promoter of cancer progression and

decreased overall patient survival. Ever since the association between obesity and
cancer was appreciated, adipose tissue, adipocytes, and secreted fat-derived factors
have been a focus of the mechanism underlying this link. Adipose-secreted factors
cytokines are referred to as adipocytokines and represent the group of molecules
thought to link adipose or fat cells to initiation and promotion of various cancers.
There are over 20 identified adipokines, of which, a subset has been implicated in
cancer. In this chapter, we will provide a concise review of the current literature on
the subset of adipose-derived factors linked to cancer.

Keywords Adipocytes • Leptin • Adiponectin • Visfatin • Resistin • Apelin

• Chemerin • Omentin • Nesfatin • Vaspin • Retinol-binding protein-4

C. Saygin, M.D.
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic,
9500 Euclid Avenue, NC10, Cleveland, OH 44195, USA
e-mail: [email protected]
O. Reizes, Ph.D. (*)
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic,
9500 Euclid Avenue, NC10, Cleveland, OH 44195, USA
Department of Cellular and Molecular Medicine, Case Comprehensive Cancer Center,
Case Western Reserve University Lerner College of Medicine,
9500 Euclid Avenue, NC10, Cleveland, OH 44195, USA
e-mail: [email protected]
N.A. Berger, M.D. (*)
Department of Medicine, Biochemistry, Oncology, Genetics, Case Comprehensive Cancer
Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2017 1

O. Reizes, N.A. Berger (eds.), Adipocytokines, Energy Balance, and Cancer,
Energy Balance and Cancer 12, DOI 10.1007/978-3-319-41677-9_1
2 C. Saygin et al.

Adipose Tissue

Adipose tissue is a loose connective tissue that consists primarily of adipocytes.

These cells are terminally differentiated from a progenitor population called
preadipocytes. Adipose tissue also contains fibroblasts, blood vessels, and immune
cells that collectively constitute the stromal fraction. Adipose tissue is distributed
throughout the body, and its development, growth, and energy storage capacity are
controlled by genetic, environmental, epigenetic, and pharmacological factors [1].
Adipose tissue was long thought to have a very limited physiological role, relegated
to energy storage, support, and heat insulation. However, accumulating evidence
indicates that adipose tissue is in fact a multifaceted organ with endocrine, meta-
bolic, and immune regulatory functions. Moreover, adipocytes, which constitute
over 80 % of the cells and 90 % of the volume, have high metabolic activity and
influence normal homeostasis via secretion of adipocytokines that activate various
autocrine, paracrine, and endocrine pathways. This chapter will survey the adipocy-
tokines and their physiological functions and role in cancer.
While adipose tissue is widely distributed, it is not homogenous across the body
and exhibits distinct functional and metabolic profiles based upon localization such
as abdominal, subcutaneous, and visceral adipose sites. Adipose tissue can be fur-
ther classified based on adipocyte coloration and is divided into brown, white, and
beige [1]. Brown adipose tissue is multilocular (i.e., each adipocyte contains mul-
tiple fat globules), expresses uncoupling proteins (e.g., thermogenin), which enable
non-shivering thermogenesis, and declines in abundance as the person ages [2]. On
the other hand, white adipose tissue is unilocular and is the primary energy store and
lacks expression of uncouplers. In addition, there is a unique yellow adipose tissue
found in bone marrow, which fills trabecular cavities and is involved in systemic
energy regulation and management of insulin sensitivity [3].
Obesity is defined as expansion of fat tissue as a consequence of
both hypertrophy and hyperplasia of adipocytes. Current prevalence of obesity in
the USA is estimated to be 34.9 % among US adults [4]. In the mid-1990s, no US
state had a prevalence of greater than 15 %, but over the past 20 years the frequency
has risen dramatically with all US states reporting greater than 20 % prevalence. In
addition to its well-known general association with various chronic diseases includ-
ing diabetes and cardiovascular disease, recent studies highlight the association of
obesity with development, recurrence, and chemoresistance of multiple cancers [5].
Approximately 20 % of all cancers are caused by excess weight, and recurrence
rates are higher among obese cancer survivors compared to lean patients [5–7]. In
addition, the Million Women Study has shown that 50 % of cancers in postmeno-
pausal women are associated with obesity [8]. Among the proposed mechanisms
linking obesity to high cancer risk are the adipose-derived cytokines and their sig-
naling pathways including consequent insulin resistance/hyperinsulinemia and
inflammation/oxidative stress. In this chapter, we review the impact of adipose
tissue on tumorigenesis and cancer progression by highlighting the major
adipocytokine pathways. Detailed descriptions of these adipocytokines and their
specific roles in tumor biology will be discussed in subsequent chapters.
1 Adipocytes, Adipocytokines, and Cancer 3

Adipocytokines and Cancer

“Adipokines” or “adipocytokines” represent over 20 different hormones and sig-

naling molecules secreted from adipocytes, which act both locally in their micro-
environment as either autocrine or paracrine factors, as well as at distant sites in
an endocrine manner as hormones (Table 1.1). Adipokines are implicated in regu-
lation of multiple physiologic processes including but not limited to energy bal-
ance (e.g., glucose homeostasis, insulin resistance), angiogenesis, blood pressure,
and inflammatory processes [9].

Table 1.1 Summary of the mechanism of action and effects of adipocytokines

Mechanism of
action Physiological effects Pathophysiological effects
Leptin JAK/STAT, Inhibits hunger/ Increased cell proliferation,
MAPK, PI3K stimulates satiety growth, survival, angiogenesis,
pathways invasion/migration,
inflammation, and dysregulated
cytokine signaling
Adiponectin AMPK and Glucose and lipid Hypoadiponectinemia causes
PPAR-alpha homeostasis, insulin insulin resistance and loss of
pathways, sensitivity inhibitory effect on cell
increased proliferation, survival,
ceramidase migration, and inflammation
activity
Visfatin ERK, MAPK, and B cell and vascular Increased cell survival,
cytokine pathways smooth muscle cytokine production, migration,
maturation, NAD increased antioxidative
biosynthesis, insulin enzymes
mimetic (?)
Resistin PI3K, MAPK, and Energy homeostasis Increased inflammation, cell
NF-kB pathways survival, adhesion, migration
and metastasis, insulin
resistance (?)
Apelin G-protein-coupled Blood pressure control Increased cell proliferation,
receptor, PI3K, and angiogenesis, migration, survival,
and ERK histamine and insulin lymphangiogenesis, and
pathways release, fluid angiogenesis
homeostasis
Chemerin G-protein-coupled Adipocyte Increased inflammation and
receptor, MAPK/ differentiation, invasion, recruitment of
ERK pathways chemoattractant immune cells
Omentin Akt, AMPK/ Modulation of insulin Promotes apoptosis, glucose
eNOS pathways action, increased cell intolerance (?)
differentiation and
suppression of
inflammation
Nesfatin AMPK, Akt Anorexigenic, glucose Promotes apoptosis
metabolism, insulin
sensitivity
(continued)
4 C. Saygin et al.

Table 1.1 (continued)

Mechanism of
action Physiological effects Pathophysiological effects
Vaspin AMPK, Akt Glucose and lipid Impaired insulin sensitivity,
metabolism, ER stress
anorexigenic, improves
glycemia
Retinol- Carries retinol to Retinol transport, fuel Insulin resistance (?)
binding peripheral tissues, sensing
protein JAK/STAT
(RBP)-4
Cytokines
TNF-alpha JNK-fos, MAPK, Immune responses, cell Pro-inflammatory, insulin
NF-kB death resistance, transcription of cell
survival genes vs. stimulation
of apoptosis
IL-6 JAK/STAT, Immune responses Pro-inflammatory, impaired
SOCS1 and 3 insulin signaling

In 1993, the first adipocyte-derived protein described was TNF-α, which is a pro-
inflammatory cytokine and elevated in obese rodents and in humans [10]. Subsequent
studies greatly emphasized the link between adipose tissue and inflammation, eluci-
dating the role of other adipose-secreted cytokines (i.e., interleukin-6; IL-6 and
IL-1B), chemokines (i.e., monocyte chemoattractant protein [MCP]-1), and special
adipokines, including leptin, which suppresses appetite and is pro-inflammatory as
well as adiponectin, which stimulates appetite and is anti-inflammatory [11].
In 1994, a team led by Jeffrey Friedman at the Rockefeller University identified
the gene responsible for the obese (ob/ob) mutation in mice and named the hormone
leptin [12]. The mutant mice exhibit early-onset obesity as a consequence of excess
feeding and reduced metabolism. Early physiological analyses suggested a circulat-
ing factor was deficient in ob/ob mice [13]. The discovery of leptin as the circulat-
ing factor secreted from adipose tissue solidified adipose tissue as an endocrine
tissue. The studies provided a molecular link for communication between adipose
tissue and the central nervous system.
It has long been known that certain common cancers including but not limited to
breast, colon, endometrium, kidney, prostate, and pancreas have a strong associa-
tion with obesity [5]. Epidemiological studies investigating the relationship between
specific circulating adipocytokines and cancer began in the late 1990s. It is now
well appreciated that adipokines constitute an important link between obesity and
high cancer risk or cancer mortality via their specific effects on cell proliferation,
metabolism, survival, migration and invasion, angiogenesis, and tumor microenvi-
ronment (e.g., inflammation) (Fig. 1.1).
Obesity is a global epidemic and a serious health concern that is accepted as a
major risk factor for the development of various cancers [7]. Moreover, obesity
increases the likelihood of dying from cancer and represents a poor prognostic fac-
tor for recurrence as well as associated with chemotherapy resistance. The most
1 Adipocytes, Adipocytokines, and Cancer 5

Fig. 1.1 Major adipokine signaling pathways promoting tumor growth and progression.
Adipokines via their cell surface receptors activate major signaling hubs including Janus kinase
(JAK)/signal transducer and activator of transcription (STAT), MAP/ERK, AMP kinase, and PI3K/
AKT. These signaling pathways then lead to gene transcription activation that regulate cell prolif-
eration, metabolism, survival, migration and invasion, angiogenesis, and tumor microenvironment.
The major adipokines can activate complementary signaling and may be synergistic in activation
of the common cell proliferation and survival effector pathways. Of note, Nampt is identical to
visfatin, but here we refer to intracellular visfatin as Nampt to denote its nicotinamide phosphori-
bosyltransferase enzymatic activity

common malignancies observed among high-risk obese patients are cancers of the
endometrium, colorectum, kidney, prostate, breast, and esophagus [14]. However,
lesser degrees of association are also present for thyroid cancers, leukemia, non-
Hodgkin’s lymphoma, melanoma, and myeloma [15] (Fig. 1.2).
Based on epidemiological, pathophysiological, and mechanistic studies, adipo-
cytokines constitute a major link between obesity and cancer [9]. Adipocytokines
are implicated in carcinogenesis, tumor progression, recurrence, and metastasis. In
addition to direct products of adipocytes, macrophages and other stromal cells play
an important role in obesity-associated local inflammation which is particularly impor-
tant for cancers arising and growing in fat-rich environments, including breast carcinoma,
as well as for cancers that have a propensity to metastasize to fat-rich sites, such as gastric
and ovarian cancers [2]. Adipocytokines can provide autocrine and paracrine signaling
loops; however, they can also have systemic effects as they enter blood circulation to
reach distant sites.
6 C. Saygin et al.

Fig. 1.2 Cancers associated with obesity. The schematic indicates the major organ site and associ-
ated increase in cancer incidence in obese patients. Percentages represent the cases attributable to
being overweight and obese (BMI of 25 or above), combined for both genders [15]

Leptin

Leptin, also known as the “satiety hormone,” is an adipokine, which was first
identified in 1994 [12]. Leptin is primarily secreted from adipose cells within
the adipose tissue though other tissues including the gut are able to secrete this
cytokine. Of note, circulating leptin levels are proportional to body fat mass
[16]. Leptin enters the circulation and originally was thought to interact solely
with receptors in the brain. However, subsequent studies indicated that leptin
has widespread targets including targets in muscle, liver, and adipose tissue
[9]. Leptin is a cytokine, and the leptin receptor is a member of the GP130 fam-
ily of cytokine receptors. There are six leptin receptor (LEPR) isoforms, also
referred to as ObRa-ObRf, all encoded by a single gene [2]. Among these alter-
nate splice isoforms, ObRb is of particular importance because it is the longest
isoform and is mutated in the db/db mutant mouse [17]. The db mouse is a
phenocopy of the ob mouse but is deficient in LEPR signaling [17]. LEPR is a
single transmembrane protein that signals intracellularly via the Janus kinase 2
(JAK2)—signal transducer and activator of transcription 3 (STAT3) and
1 Adipocytes, Adipocytokines, and Cancer 7

mitogen-activated protein kinase (MAPK) signal transduction pathways [17].

In the context of cancer, JAK2-induced activation of STAT3 and 5 induce tran-
scription of genes involved in cell proliferation, invasion/migration, angiogen-
esis, and inflammation. SHP2 phosphorylation leads to activation of ERK/
MAPK signaling pathway including activation of cell cycle inducers and inac-
tivates tumor suppressor protein p53 [17].
Leptin is a cytokine secreted from the adipose tissue and elevated in obese
individuals. Due to its role in regulation of body weight and link to obesity as
well as its activation of mitogenic pathways, leptin has been an important focus
of studies investigating the link between obesity and cancer [18]. Indeed, where
studied, leptin has been shown to be mitogenic, antiapoptotic, pro-angiogenic,
and pro-inflammatory and promote invasion and migration [9, 19]. It is impli-
cated in cancers of the breast, colon, prostate, pancreas, ovary, and lung [9].
Multiple studies in breast cancer patients indicate that increased levels of circu-
lating leptin is associated with higher risk of tumor progression suggesting it is
an indicator of poor prognosis [19]. The growth-promoting effects of leptin are
mediated through JAK/STAT, ERK, and PI3K signaling that ultimately lead to
increased proliferation, cell survival, invasion and angiogenesis [9]. These cel-
lular functions are the cardinal events taking place during oncogenesis.
Moreover, in breast cancer models, leptin can inhibit apoptosis via upregulation
of the bcl antiapoptotic genes (i.e., bcl-xL, bak, and bax) and induce angiogen-
esis through increased vascular endothelial growth factor (VEGF) production
via stimulation of HIF-1α and NF-kB [16]. Furthermore, leptin causes an
increase in aromatase activity and decrease in tumor suppressor protein p53 in
MCF-7 cells which favors the survival of this estrogen receptor-positive breast
cancer cell line [18]. In recent studies, leptin has been shown to increase sur-
vival of cancer stem cells in obese mouse models [20]. Subsequent studies indi-
cated that leptin receptor is necessary for maintenance of cancer stem cells via
regulation of the master regulators of stem cell self-renewal NANOG, SOX2,
and OCT4 [21].
Similar to the association observed in breast cancer, patients with advanced pros-
tate cancer have higher levels of circulating leptin compared to patients with benign
prostate hyperplasia. Further, prostate cancer stage is correlated with circulating
leptin levels, suggesting that leptin might be used as a biomarker for prostate cancer
stage and prognosis [22].
In a cohort of patients with gastroesophageal adenocarcinoma, tumor leptin
expression was associated with poor response to chemotherapy, a finding that
supports the use of leptin as a biomarker of treatment responsiveness and a com-
panion diagnostic [23]. In patients with gastric cancer, leptin was shown to
increase invasiveness via Rho/ROCK signaling [24]. Leptin correlates with the
aggressiveness of colorectal cancer [25], and its inhibitory effect on mitochon-
drial respiration has been linked to colorectal cancer progression [26]. Similarly,
leptin promoted the growth of HepG2 liver cancer cells and inhibited apoptosis
through blocking ER stress signals [27].
8 C. Saygin et al.

Adiponectin

Adiponectin is a protein hormone secreted exclusively from adipose tissue that reg-
ulates glucose homeostasis and fatty acid oxidation [9]. Circulating levels of adipo-
nectin are inversely related to body fat stores and it is one of the few known
adipokines with beneficial effects on health [28]. Adiponectin interacts with several
receptors of which AdipoR1 and AdipoR2 are the best characterized [29]. These
receptors are widely expressed in multiple tissues, including skeletal muscle, liver,
vascular endothelium, hypothalamus, and white adipose tissue. Although AdipoR1
and R2 exhibit similarities to seven transmembrane domain receptors, they do not
interact with G proteins, rather they activate the 5′-adenosine monophosphate-
activated protein kinase (AMPK) and peroxisome proliferator-activated receptor
(PPAR)-α pathways. AMPK activation leads to increased energy expenditure and
fatty acid oxidation, while increased expression of PPAR-α target genes (e.g., CD36,
uncouplers, acyl-coenzyme oxidase) improves insulin sensitivity [11]. Moreover,
activation of AMPK causes inhibition of PI3K/Akt pathway, and this effect causes a
decrease in glycogen synthase kinase (GSK) activity and inhibits GLUT4 transport.
These combined effects lead to decrease in cell growth and proliferation. Additionally,
inhibition of mTOR causes loss of activation of S6K/eIF4E, which in turn leads to
decrease in translation of cell cycle and angiogenesis genes [11].
Hypoadiponectinemia and decreased expression of AdipoR1 and AdipoR2 are
seen in obesity and have been proposed as a potential link to diabetes, hypertension,
atherosclerosis, and endothelial dysfunction [28]. In summary, adiponectin has
opposing actions to leptin in cancer by being antiproliferative, pro-apoptotic, anti-
inflammatory, and anti-migratory.
Reduced adiponectin levels are associated with cancers of the breast, colon,
esophagus, liver, and endometrium [9]. Moreover, recombinant adiponectin has
antitumor effects in myelomonocytic leukemia, breast adenocarcinoma, and fibro-
sarcoma [2]. Its anticarcinogenic effects have been demonstrated in different breast
cancer cell lines, including MCF-7, MDA-MB-231, and T47D, in which adiponec-
tin decreased cell proliferation and increased apoptosis [30]. Acting through AMPK
phosphorylation, adiponectin decreased expression of cyclin D1 and c-myc, while
increasing p53 and bax levels [31]. The anticancer effects are not limited to direct
cellular activities as adiponectin leads to decreased growth factor bioavailability,
including platelet-derived growth factor (PDGF), basic fibroblast growth factor
(FGF), and epidermal growth factor (EGF) [32].
Among other solid tumors, low levels of adiponectin predict an increased risk for
prostate cancer [33]. High molecular weight form of adiponectin was shown to inhibit
survival and proliferation of androgen-dependent and independent prostate cancer
cell lines [34]. Similarly, several reports demonstrated a relationship between adipo-
nectin and various GI cancers. Both increased leptin and decreased adiponectin, as
seen in patients with obesity, are independent risk factors for progression of Barrett’s
esophagus to esophageal adenocarcinoma [35]. In addition, AdipoR1 and AdipoR2
were shown to be downregulated in gastric cancer as compared to normal gastric
epithelium and thought to confer survival advantage for malignant cells [36]. An
1 Adipocytes, Adipocytokines, and Cancer 9

inverse correlation was shown between adiponectin level and the number of colorec-
tal adenomas, as well as the stage of colorectal cancer [37].
Decreased adiponectin expression is associated with high endometrial cancer risk
in postmenopausal women. Adiponectin suppresses endometrial cancer growth via
AdipoRs and increased expression of the adaptor molecule LKB1, which in turn
modulates cell proliferation, colony formation, invasion, and adhesion [38]. Decreased
AdipoR1 and AdipoR2 expressions are similarly also associated with higher histo-
logical grade, myometrial invasion, and lymph node metastasis [29]. Consistent with
these findings, a recent study indicated that adiponectin levels were significantly
lower in patients with endometrial cancer as compared to healthy controls [39].

Visfatin

Visfatin is secreted from adipose tissue, and blood visfatin levels positively corre-
late with body fat mass. While now recognized as a secreted protein, visfatin was
originally defined as pre-B cell colony-enhancing factor (PBEF) [40]. Visfatin was
also identified as nicotinamide phosphoribosyltransferase (Nampt), an enzyme cat-
alyzing the rate-limiting step in NAD biosynthesis [41]. In 2002, Rongvaux, et al.
showed that these PBEF and Nampt were the same gene [42]. Subsequent studies
reidentified Nampt/PBEF as visfatin, which is secreted from visceral adipose tissue
and initially proposed it to function in a similar manner to insulin, though this was
subsequently rejected [43]. There is a positive correlation between visfatin and
insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease.
Visfatin may be secreted from neutrophils, monocytes, and macrophages as well
[44]. Transcription of visfatin is regulated by pro-inflammatory cytokines, includ-
ing TNF-α and IL-6, and its levels are increased in patients with inflammatory dis-
eases [44]. Visfatin in turn increases the secretion of IL-1β, TNF, and IL-6 by
immune cells via JNK and NF-kB pathways [45]. IL-6 increases the active Nampt
in cells via STAT3 activation.
Visfatin has been implicated in cancer proliferation and invasion. Visfatin
increases the activity of NAD-dependent enzymes sirtuin (Sirt) 1 and 6, which are
associated with increased cell survival and TNF-α production, respectively [9]. A
recent study by Wen-Shih Huang, et al. showed that visfatin can increase the
expression of stromal cell derived factor-1 (SDF-1) in colorectal cancer via ERK
and MAPK pathways which are activated through β1 integrin-mediated signaling
[46]. This leads to increased cell survival and migration through chemokine recep-
tors. In summary, visfatin is a pro-inflammatory cytokine, which can increase cell
survival and migration and stimulates cytokine secretion.
Visfatin is associated with colon, breast, and ovarian cancers, as well as mela-
noma. It is closely linked to inflammation and enhances cell survival and SDF-1
expression. Colorectal cancer cells have chemokine receptors that can bind SDF-1,
which in turn increases survival and migration of these cells [46]. Visfatin can also
protect cancer cells from reactive oxygen species (ROS)-mediated damage via
increased activity of superoxide dismutase, catalase, and glutathione peroxidase, an
10 C. Saygin et al.

effect that was shown in Me45 malignant melanoma cells [47]. Shackelford et al.
have recently demonstrated that ovarian serous adenocarcinomas express signifi-
cantly higher Nampt protein, which is through increased STAT3 signaling [48].

Resistin

Resistin is a small adipokine secreted mainly from mononuclear inflammatory cells,

but also from adipose tissue in humans [9]. Therefore, it is highly linked to the
inflammatory state and is thought to be an important link between obesity and inflam-
mation [49]. The association between resistin and insulin resistance is less clear.
Resistin binds to Toll-like receptor 4 (TLR4) that in turn leads to the activation of
PI3K, p38 MAPK, and NF-kB pathways. The principal effect of TLR4 activation is a
surge in secretion of pro-inflammatory cytokines, which enhance the inflammatory
state [50]. Similar to visfatin, activation of p38 MAPK leads to increased SDF-1 pro-
duction, which underlies the observed cell migration. In addition, activation of PI3K
and MAPK is associated with cell survival, proliferation, and inhibition of apoptosis.
NF-kB is known to induce an increase in the expression of cell adhesion molecules,
an upregulation of intercellular adhesion molecule (ICAM)-1 and vascular cell adhe-
sion molecule-1 (VCAM-1) [51]. Collectively, the studies indicate that resistin is a
pro-inflammatory adipokine that leads to increased cell proliferation, migration, and
adhesion. Resistin is closely linked to inflammation and has been studied in several
cancers including colorectal, gastric, breast, prostate, and liver tumors. TLR4 signal-
ing and stimulation of PI3K pathway, together with NF-kB activation, can upregulate
the synthesis of various cytokines which in turn causes a detrimental inflammatory
response. Among the pro-inflammatory cytokines produced by these pathways, IL-6
has been shown to activate JAK/STAT and MAPK pathways and linked to epithelial-
mesenchymal transition and metastasis of head and neck tumors [52]. Similar to vis-
fatin, resistin induced expression of SDF-1 in gastric cancer cells through TLR4
signaling [53]. Recent studies highlight the role of resistin in increasing expression of
ICAM-1 and VCAM-1 in Sk-Hep1 HCC cells, which is a cardinal step for tumor cell
adhesion to endothelium. This carcinogenic effect was efficiently blocked by NF-kB
inhibition [54]. In summary, tumorigenic effects of resistin include promotion of
inflammatory milieu, immune cell extravasation, changes in expression of adhesion
molecules, survival, and metastasis of cancer cells.

Apelin

Apelin is a recently identified peptide expressed in various tissues including liver, kid-
ney, heart, lung, gastrointestinal tract, brain, adrenal gland, endothelium, and adipose
tissue. The apelin receptor (APJ) is a G-protein-coupled receptor and acts via activation
of ERK and PI3K/Akt pathways [55]. Apelin physiological functions include the
1 Adipocytes, Adipocytokines, and Cancer 11

control of blood pressure, angiogenesis, cardiac tissue remodeling, hypothalamic regu-

lation of food and fluid intake, and regulation of insulin and histamine release [56]. In
normal-weight individuals, it has anti-obesogenic and insulin-like effects, but plasma
levels are increased in obese patients as well as patients with type 2 diabetes [57].
Moreover, a recent study demonstrated that the pharmacological inhibitor of apelin
(F13A) was promising in enhancing liver regeneration after hepatectomy [58].
High circulating levels of apelin, as observed with obesity, have been considered
a risk factor for endometrial cancer [59]. Apelin was also suggested to have a role
in lymphangiogenesis and lymph node metastasis [60]. In summary, apelin is pro-
angiogenic, mitogenic, and can promote cell survival and migration.

Chemerin

Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2),

is a small protein expressed in human lung, liver, and white adipose tissue [61]. It
is a chemoattractant and acts via the G-protein-coupled receptor, CMKLR1, which
is predominantly expressed on adipocytes and immune cells (e.g., neutrophils,
macrophages, dendritic cells) [62]. Fat-derived chemerin has both autocrine and
paracrine effects, and the amount of circulating chemerin secreted increases as the
preadipocytes differentiate [61]. There is also a positive correlation between blood
chemerin levels, BMI, and metabolic syndrome. CMKLR1-induced signaling
includes both G-protein-coupled receptor-induced Ca2+ influx and cAMP increase
and activation of MAPK and ERK pathways [9]. Increase in local chemerin con-
centration is associated with expansion of fat mass and local inflammatory response
as evidenced by increased immune cell chemotaxis [62]. Therefore, chemerin con-
tributes to the obesity-associated metabolic dysregulation and underlying chronic
low-grade inflammation.
Chemerin is a pro-inflammatory cytokine of adipose tissue, which can enhance
inflammatory response of tumor-infiltrating macrophages [35, 63]. However, data on
the role of chemerin in tumorigenesis is limited, and the association has been best
characterized for gastric cancer [64]. Serum chemerin concentrations correlated with
the stage of gastric cancers and levels were higher in stage 1 patients as compared to
healthy controls [64]. The mechanism by which chemerin induces invasiveness and
metastasis in gastric cancers includes expression of VEGF, MMP-7, and IL-6 genes
as well as activation of MAPK, ERK1/2, and p38 signaling pathways. It was also
associated with poor postoperative prognosis and survival in gastric cancer [65].

Omentin

Omentin was originally recognized as intelectin-1, which is a lactoferrin receptor

produced by intestinal Paneth cells and was thought to be involved in gut immunity
[66]. Subsequent studies indicated that omentin is secreted from visceral adipose
12 C. Saygin et al.

tissue and enhances insulin-mediated glucose uptake in adipocytes via Akt signal-
ing [67]. Omentin is implicated in promoting cell differentiation and inflammation
via activation of AMPK/eNOS signaling and suppression of JNK activity, causing
increased cell differentiation and dampened immune responses [68]. Other effects
of omentin include vasodilation via eNOS activity and decreased expression of
VCAM-1 and ICAM-1 leading to decreased monocyte adhesion via inhibition of
ERK pathway. Blood levels of omentin are low in obesity, type 2 diabetes, and
hypertension. Therefore, omentin is suggested to be a nutritional marker to reflect
body weight and insulin resistance [69].
Omentin is an orphan adipocytokine, the role of which in carcinogenesis is not
clear. There has been anecdotal reports linking increased serum omentin levels to
prostate [70] and colorectal cancers [71], but its association with hepatocellular
carcinoma is more pronounced [72]. It promotes apoptosis via upregulating p21 and
increasing p53 and bax/bcl2 ratio [72].

Nesfatin

Nesfatin is an anorexigenic peptide, originally shown to regulate satiety through its

action on hypothalamic nuclei [73]. Later studies demonstrated its expression in
stomach, pancreas, testis, and adipose tissue as well. It modulates glucose homeo-
stasis via AMPK and Akt signaling pathways and increases insulin sensitivity [74].
Nesfatin secretion is increased in obesity, and it might have a role in pathways lead-
ing to lipid accumulation [73]. A link between inflammation and nesfatin has also
been suggested by the increase in its secretion in response to pro-inflammatory
cytokines, including TNF-alpha and IL-6 [73]. Moreover, nesfatin-1 treatment
inhibited cell proliferation in HO-8910 ovarian epithelial carcinoma cell line and
promoted apoptosis in HO-9010 cells, which are due to effects on cell cycle and
mTOR signaling, respectively [75].

Vaspin

Vaspin is a serine protease inhibitor produced mainly by the visceral adipose tis-
sue, stomach, liver, pancreas, and the hypothalamus. Its levels are correlated with
the amount of body fat stores and are linked to diabetes, obesity, metabolic syn-
drome, impaired insulin sensitivity, and coronary artery disease [76]. In rodent
models, vaspin improves glycemia and reduces food intake [77]. Specifically, it
interacts with GRP78 and activates Akt and AMPK, which in turn regulates glu-
cose and lipid metabolism and improves metabolic dysfunction associated with
obesity. However, underlying mechanisms of action associated with the beneficial
effects of vaspin are not fully clarified.
1 Adipocytes, Adipocytokines, and Cancer 13

Reports on the association between vaspin and cancer are very limited and con-
troversial. The specific mechanisms of effect are also not fully clarified. It was
found to be low in patients with endometrial cancer while higher in patients with
colorectal cancer [9]. Therefore, at this point, it is hard to make a definitive state-
ment on its role in tumor biology.

Retinol-Binding Protein-4

Retinol-binding protein (RBP)-4 is the carrier of retinol in the blood; it is mainly

synthesized and delivered from the liver to peripheral tissues [9]. It is secreted also
from adipose tissue and can act as a signal of low blood glucose. Several studies
showed a positive correlation between RBP4 and insulin resistance or obesity, yet
these studies have been hard to reproduce [11]. Due to its association with Glut4,
RBP4 is thought to have a role in fuel sensing in adipocyte, though the mechanism
underlying insulin resistance is not clear. Apart from its role in retinol transport,
recent studies indicated that RBP4 can activate JAK/STAT signaling upon binding
to its receptor, STRA6, and knockdown of the STRA6 receptor significantly inhibits
growth of colon tumor cells in tissue culture and mice [78].

Cytokines

Expansion of fat mass, as seen in obesity, is associated with low-grade chronic

inflammation that might in part be due to adipokines secreted from adipocytes
(e.g., chemerin, visfatin). This leads to an increase in recruitment of macrophages
into adipose tissue, exacerbating the inflammatory milieu through secretion of
pro-inflammatory cytokines (e.g., IL-1B, TNF-α, IL-6, MCP-1). Moreover, obe-
sity is associated with changes in the phenotype of macrophages, which causes
them to convert into chronically active pro-inflammatory cells [11].
TNF-α is secreted from stromal macrophages and is known to disturb insulin
signaling. Circulating TNF-α levels are higher in patients with insulin resistance
[9]. TNF receptor signaling involves p38 MAPK, JNK, and NF-kB pathways,
which can potentially culminate in transcription of genes involved in inflammation
and cell survival. TNF-α also activates apoptotic pathways via activation of cas-
pase cascade [11].
Similar to TNF-α, IL-6 is also increased in adipose tissue of obese individuals
[11]. IL-6 impairs insulin signaling in adipocytes and hepatocytes through ubiq-
uitination and degradation of insulin receptor substrate (IRS) [11]. IL-6 also
functions via JAK/STAT signaling, and its significance in disease is a current
area of intense research. Indeed, the IL-6 has been the focus of studies examining
the link between obesity and cancer.
14 C. Saygin et al.

Adipocytes and Tumor Metabolism

As discussed earlier in the chapter, adipocytes are highly metabolically active,

and adipocyte-derived factors affect cellular metabolism of malignant cells within
the tumor. Fat cells promote growth, survival, and proliferation of malignant cells
as they interact with them, an effect clearly shown in cancers of the breast, pros-
tate, ovary, colon, and stomach [79]. An interesting study by Nieman et al. dem-
onstrated that ovarian cells induce fat cell-driven lipolysis and increase lipid
bioavailability for uptake by tumor cells in order to support the energy needs [80].
In parallel studies, prostate cancer cells have been shown to use beta-oxidation as
a main source of energy [81].
Cancer cells undergo metabolic reprogramming during oncogenic transforma-
tion which leads to increased expression of glycolytic enzymes and in turn leads to
high rates of glycolysis and lactate production independent from the presence of
oxygen. Lactate provides carbon sources and sufficient energy for lipogenesis in
rapidly dividing cancer cells [82]. Accumulation of fat in bone marrow has recently
been linked to increased risk of development and progression of skeletal metastases,
particularly in prostate cancer [83]. There are several hypotheses supporting this
association, including adipocyte lipids supplying energy source for metastatic cells
which induces proliferation, invasion, and motility and creation of an inflammatory
milieu in the bone which favors tumor growth [2]. Therefore, in addition to secret-
ing proteins, adipocytes generate metabolic products, including lipids and lactate,
which may affect tumor growth. Moreover, adipocytes in bone marrow might medi-
ate translocation of lipids to cancer cells. The complex interaction between lipid-
driven and inflammatory pathways in the bone requires further investigation in
order to fully clarify the role of marrow fat in metastasis.

Conclusion

Obesity is a systemic endocrine dysfunction with underlying chronic inflammatory

state, rather than just an expansion of fat mass. Adipocytes promote growth of
malignant cells via affecting and supporting their altered energy metabolism, par-
ticularly at sites where tumor cells are adjacent to fat tissue (e.g., skeletal metasta-
ses, ovarian and breast tumors). In addition, adipocytokines are cardinal mediators
of carcinogenesis and tumor progression through their paracrine and endocrine
effects. Single adipokines have independent roles in activating major intracellular
signaling pathways involved in cell proliferation, growth, survival, adhesion, migra-
tion, and invasion. In addition, combined effects of adipokines should also be
emphasized since they are dysregulated altogether in the setting of obesity.

Conflict of Interest None to declare.

1 Adipocytes, Adipocytokines, and Cancer 15

References

1. Sethi JK, Vidal-Puig AJ (2007) Thematic review series: adipocyte biology.Adipose tissue
function and plasticity orchestrate nutritional adaptation. J Lipid Res 48:1253–1262
2. Diedrich J, Gusky HC, Podgorski I (2015) Adipose tissue dysfunction and its effects on tumor
metabolism. Horm Mol Biol Clin Investig 21(1):17–41
3. Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM (2009) Marrow fat and the bone micro-
environment: developmental, functional, and pathological implications. Crit Rev Eukaryot
Gene Expr 19:109–124
4. Ogden CL, Carroll M, Kit BK, Flegal KM (2014) Prevalence of childhood and adult obesity
in the United States, 2011–2012. JAMA 311(8):806–814
5. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and
mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med
348:1625–1638
6. Jones DH, Nestore M, Henophy S, Cousin J, Comtois AS (2014) Increased cardiovascular risk
factors in breast cancer survivors identified by routine measurements of body composition,
resting heart rate and arterial blood pressure. Springerplus 3:150
7. Wolin KY, Carson K, Colditz GA (2010) Obesity and cancer. Oncologist 15:556–565
8. Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D (2007) Cancer incidence and mortal-
ity in relation to body mass index in the Million Women Study: a cohort study. Br Med
J 355:1314
9. Booth A, Magnuson A, Fouts J, Foster M (2015) Adipose tissue, obesity, and adipokines: role
in cancer promotion. Horm Mol Biol Clin Investig 21(1):57–74
10. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis
factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91
11. Rasouli N, Kern PA (2008) Adipocytokines and the metabolic complications of obesity. J Clin
Endocrinol Metab 93(11 Suppl 1):S64–S73
12. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning
of the mouse obese gene and its human homologue. Nature 372(6505):425–432
13. Muoio DM, Dohm G, Tapscott EB, Coleman RA (1999) Leptin opposes insulin’s effects on
fatty acid partitioning in muscles isolated from obese ob/ob mice. Am J Physiol 276(5 Pt
1):E913–E921
14. Gibson TM, Park Y, Robien K, Shiels MS, Black A, Sampson JN, Purdue MP, Beane Freeman
LE, Andreotti G, Weinstein SJ, Albanes D, Fraumeni JF Jr, Curtis RE, Berrington de
Gonzalez A, Morton LM (2014) Body mass index and risk of second obesity-associated
cancers after colorectal cancer: a pooled analysis of prospective cohort studies. J Clin Oncol
32:4004–4011
15. Bhaskaran K, Douglas I, Forbes H, dos-Santos Silva I, Leon DA, Smeeth L (2014) Body-mass
index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK
adults. Lancet 384:755–765
16. Garcia-Robles MJ, Segura-Ortega J, Fafutis-Morris M (2013) The biology of leptin and its
implications in breast cancer: a general view. J Interferon Cytokine Res 33:717–727
17. Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP,
Koniaris A (2011) Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol
Metab 301:E567–E584
18. Jarde T, Perrier S, Vasson MP, Caldefie-Chezet F (2011) Molecular mechanisms of leptin and
adiponectin in breast cancer. Eur J Cancer 47:33–43
19. Vona-Davis L, Rose D (2007) Adipokines as endocrine, paracrine, and autocrine factors in
breast cancer risk and progression. Endocr Relat Cancer 14:189–206
20. Zheng Q, Dunlap S, Zhu J, Downs-Kelly E, Rich J, Hursting SD, Berger NA, Reizes O (2011)
Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abro-
gates tumor initiating cell survival. Endocr Relat Cancer 18(4):491–503
16 C. Saygin et al.

21. Zheng Q, Banaszak L, Fracci S, Basali D, Dunlap SM, Hursting SD, Rich JN, Hilemeland AB,
Vasanji A, Berger NA, Lathia JD, Reizes O (2013) Leptin receptor maintains cancer stem-like
properties in triple negative breast cancer cells. Endocr Relat Cancer 20:797–808
22. Tewari R, Rajender S, Natu SM, Goel A, Dalela D, Goel MM, Tondon P (2013) Significance
of obesity markers and adipocytokines in high grade and high stage prostate cancer in North
Indian men—a cross-sectional study. Cytokine 63:130–134
23. Bain GH, Collie-Duguid E, Murray GI, Gilbert FJ, Denison A, McKiddie F, Ahearn T, Fleming
I, Leeds J, Phull P, Park K, Nanthakumaran S, Grabsch HI, Tan P, Welch A, Schweiger L,
Dahle-Smith A, Urquhart G, Finegan M, Petty RD (2014) Tumour expression of leptin is
associated with chemotherapy resistance and therapy-independent prognosis in gastro-
oesophageal adenocarcinomas. Br J Cancer 110:1525–1534
24. Dong Z, Fu S, Xu X, Yang Y, Du L, Li W, Kan S, Li Z, Zhang X, Wang L, Li J, Liu H, Qu X,
Wang C (2014) Leptin-mediated regulation of ICAM-1 is Rho/ROCK dependent and enhances
gastric cancer cell migration. Br J Cancer 110:1801–1810
25. Koda M, Sulkowska M, Kanczuga-Koda L, Surmacz E, Sulkowski S (2007) Overexpression
of the obesity hormone leptin in human colorectal cancer. J Clin Pathol 60(8):902–906
26. Yehuda-Shnaidman E, Nimri L, Tarnovscki T, Kirshtein B, Rudich A, Schwartz B (2013)
Secreted human adipose leptin decreases mitochondrial respiration in HCT116 colon cancer
cells. PLoS One 8, e74843
27. Xiong Y, Zhang J, Liu M, An M, Lei L, Guo W (2014) Human leptin protein activates the
growth of HepG2 cells by inhibiting PERK mediated ER stress and apoptosis. Mol Med Rep
10:1649–1655
28. Kadowaki T, Yamauchi T (2015) Adiponectin and adiponectin receptors. Endocr Rev
26:439–451
29. Yamauchi N, Takazawa Y, Maeda D, Hibiya T, Tanaka M, Iwabu M, Okada-Iwabu M, Yamauchi
T, Kadowaki T, Fukayama M (2012) Expression levels of adiponectin receptors are decreased in
human endometrial adenocarcinoma tissues. Int J Gynecol Pathol 31:352–357
30. Grossmann ME, Nkhata K, Mizuno NK, Ray A, Cleary MP (2008) Effects of adiponectin on
breast cancer cell growth and signaling. Br J Cancer 98:370–379
31. Dieudonne MN, Bussiere M, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R (2006)
Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer
cells. Biochem Biophys Res Commun 345:271–279
32. Wang Y, Lam K, Xu JY, Lu G, Xu LY, Cooper GJ, Xu A (2005) Adiponectin inhibits cell pro-
liferation by interacting with several growth factors in an oligomerization-dependent manner.
J Biol Chem 280:18341–18347
33. Goktas S, Yilmaz M, Caglar K, Sonmez A, Kilic S, Bedir S (2005) Prostate cancer and adipo-
nectin. Urology 65:1168–1172
34. Bub JD, Miyazaki T, Iwamoto Y (2006) Adiponectin as a growth inhibitor in prostate cancer
cells. Biochem Biophys Res Commun 340:1158–1166
35. Alexandre L, Long E, Beales IL (2014) Pathophysiological mechanisms linking obesity and
esophageal adenocarcinoma. World J Gastrointest Pathophysiol 5:534–549
36. Otani K, Kitayama J, Kamei T, Soma D, Miyato H, Yamauchi T, Kadowaki T, Nagawa H
(2010) Adiponectin receptors are downregulated in human gastric cancer. J Gastroenterol
45:918–927
37. Nakajima TE, Yamada Y, Hamano T, Furuta K, Matsuda T, Fujita S, Kato K, Hamaguchi T,
Shimada Y (2010) Adipocytokines as new promising markers of colorectal tumors: adiponec-
tin for colorectal adenoma, and resistin and visfatin for colorectal cancer. Cancer Sci
101:1286–1291
38. Moon HS, Chamberland JP, Aronis K, Tseleni-Balafouta S, Mantzoros CS (2011) Direct role
of adiponectin and adiponectin receptors in endometrial cancer: in vitro and ex vivo studies in
humans. Mol Cancer Ther 10:2234–2243
39. Erdogan S, Sezer S, Baser E, Gun-Eryilmaz O, Gungor T, Uysal S, Yilmaz FM (2013)
Evaluating vaspin and adiponectin in postmenopausal women with endometrial cancer. Endocr
Relat Cancer 20:669–675
1 Adipocytes, Adipocytokines, and Cancer 17

40. Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I (1994) Cloning and characterization of
the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol
14:1431–1437
41. Preiss J, Handler P (1957) Enzymatic synthesis of nicotinamide mononucleotide. J Biol Chem
225:759–770
42. Rongvaux A, Shea R, Mulks MH, Gigot D, Urbain J, Leo O, Andris F (2002) Pre-B-cell
colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nico-
tinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. Eur
J Immunol 32:3225–3234
43. Chen MP, Chung F, Chang DM, Tsai JCR, Huang HF, Shin SJ, Lee YJ (2006) Elevated plasma
level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus.
J Clin Endocrinol Metab 91:295–299
44. Andrade-Oliveira V, Camara NO, Moraes-Vieira PM (2015) Adipokines as drug targets in
diabetes and underlying disturbances. J Diabetes Res 2015:681612
45. Yun MR, Seo J, Park HY (2014) Visfatin contributes to the differentiation of monocytes into
macrophages through the differential regulation of inflammatory cytokines in THP-1 cells.
Cell Signal 26(4):705–715
46. Huang WS, Chen C, Sze CI, Teng CC (2013) Visfatin induces stromal cell-derived factor-1
expression by beta1 integrin signaling in colorectal cancer cells. J Cell Physiol
228:1017–1024
47. Bułdak RJ, Buldak L, Polaniak R, Kukla M, Birkner E, Kubina R, Kabała-Dzik A, Duława-
Bułdak A, Żwirska-Korczala K (2013) Visfatin affects redox adaptative responses and prolif-
eration in Me45 human malignant melanoma cells: an in vitro study. Oncol Rep 29:
771–778
48. Shackelford RE, Bui M, Coppola D, Hakam A (2010) Over-expression of nicotinamide phos-
phoribosyltransferase in ovarian cancers. Int J Clin Exp Pathol 3:522–527
49. Lehrke M, Reilly M, Millington SC, Iqbal N, Rader DJ, Lazar MA (2004) An inflammatory
cascade leading to hyperresistinemia in humans. PLoS Med 1:161–168
50. Silswal N, Singh A, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ (2005) Human resis-
tin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by
NF-kappaB-dependent pathway. Biochem Biophys Res Commun 334:1092–1101
51. Verma S, Li S, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA (2003) Resistin promotes
endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation
108:736–740
52. Yadav A, Kumar B, Datta J, Teknos TN, Kumar P (2011) IL-6 promotes head and neck tumor
metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signal-
ing pathway. Mol Cancer Res 9:1658–1667
53. Hsieh YY, Shen C, Huang WS, Chin CC, Kuo YH, Hsieh MC, Yu HR, Chang TS, Lin TH,
Chiu YW, Chen CN, Kuo HC, Tung SY (2014) Resistin-induced stromal cell-derived factor-1
expression through Toll-like receptor 4 and activation of p38 MAPK/ NFkB signaling pathway
in gastric cancer cells. J Biomed Sci 21:59
54. Yang CC, Chang S, Chao JK, Lai YL, Chang WE, Hsu WH, Kuo WH (2014) Activation of
AMP-activated protein kinase attenuates hepatocellular carcinoma cell adhesion stimulated by
adipokine resistin. BMC Cancer 14:112
55. Carpene C, Dray C, Attane C, Valet P, Portillo MP, Churruca I, Milagro FI, Castan-Laurell I
(2007) Expanding role for the apelin/APJ system in physiopathology. J Physiol Biochem
63:359–373
56. Boucher J, Masri B, Daviaud D, Gesta S, Guigné C, Mazzucotelli A, Castan-Laurell I, Tack I,
Knibiehler B, Carpéné C, Audigier Y, Saulnier-Blache JS, Valet P (2005) Apelin, a newly
identified adipokine up-regulated by insulin and obesity. Endocrinology 146:1764–1771
57. Castan-Laurell I, Dray C, Attane C, Duparc T, Knauf C, Valet P (2011) Apelin, diabetes, and
obesity. Endocrine 40:1–9
58. Yoshiya S, Shirabe K, Imai D, Toshima T, Yamashita Y, Ikegami T, Okano S, Yoshizumi T,
Kawanaka H, Maehara Y (2015) Blockade of the apelin-APJ system promotes mouse liver
18 C. Saygin et al.

regeneration by activating Kupffer cells after partial hepatectomy. J Gastroenterol

50:573–582
59. Altinkaya SO, Nergiz S, Küçük M, Yüksel H (2015) Apelin levels are higher in obese patients
with endometrial cancer. J Obstet Gynaecol Res 41:294–300
60. Berta J, Hoda M, Laszlo V, Rozsas A, Garay T, Torok S, Grusch M, Berger W, Paku S, Renyi-
Vamos F, Masri B, Tovari J, Groger M, Klepetko W, Hegedus B, Dome B (2014) Apelin pro-
motes lymphangiogenesis and lymph node metastasis. Oncotarget 5:4426–4437
61. Goralski KB, McCarthy T, Hanniman EA, Zabel BA, Butcher EC, Parlee SD, Muruganandan
S, Sinal CJ (2007) Chemerin, a novel adipokine that regulates adipogenesis and adipocyte
metabolism. J Biol Chem 282:28175–28188
62. Wittamer V, Franssen J, Vulcano M, Mirjolet JF, Le Poul E, Miggeotte I, Brezillion S, Tyldesley
R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D
(2003) Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand
from human inflammatory fluids. J Exp Med 198:977–985
63. Rama D, Esendagli G, Guc D (2011) Expression of chemokine-like receptor 1 (CMKLR1) on
J744A.1 macrophages co-cultured with fibroblast and/or tumor cells: modeling the influence
of microenvironment. Cell Immunol 271:134–140
64. Wang C, Wu W, Liu X, To KF, Chen GG, Yu J, Ng EK (2014) Increased serum chemerin level
promotes cellular invasiveness in gastric cancer: a clinical and experimental study. Peptides
51:131–138
65. Zhang J, Jin H, Zhu AK, Ying RC, Wei W, Zhang FJ (2014) Prognostic significance of plasma
chemerin levels in patients with gastric cancer. Peptides 61:7–11
66. Tsuji S, Uehori J, Matsumoto M, Suzuki Y, Matsuhisa A, Toyoshima K, Seya T (2001) Human
intelectin is a novel soluble lectin that recognizes galactofuranose in carbohydrate chains of
bacterial cell wall. J Biol Chem 276:23456–23463
67. Yang RZ, Lee M, Hu H, Pray J, Wu HB, Hansen BC, Shuldiner AR, Fried SK, McLenithan JC,
Gong DW (2006) Identification of omentin as a novel depot-specific adipokine in human adi-
pose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab
290:E1253–E1261
68. Ohashi K, Shibata R, Murohara T, Ouchi N (2014) Role of anti-inflammatory adipokines in
obesity-related diseases. Trends Endocrinol Metab 25:348–355
69. Smitka K, Marešová D (2015) Adipose tissue as an endocrine organ: an update on proinflam-
matory and anti-inflammatory microenvironment. Prague Med Rep 116(2):87–111
70. Uyeturk U, Sarıcı H, Kın Tekce B, Eroglu M, Kemahlı E, Uyeturk U, Gucuk A (2014) Serum
omentin level in patients with prostate cancer. Med Oncol 31:923
71. Uyeturk U, Alcelik A, Aktas G, Tekce BK (2014) Post-treatment plasma omentin levels in
patients with stage III colon carcinoma. J BUON 19:681–685
72. Zhang YY, Zhou L (2013) Omentin-1, a new adipokine, promotes apoptosis through regulating
Sirt1-dependent p53 deacetylation in hepatocellular carcinoma cells. Eur J Pharmacol
698:137–144
73. Ramanjaneya M, Chen J, Brown JE, Tripathi G, Hallschmid M, Patel S, Kern W, Hillhouse
EW, Lehnert H, Tan BK, Randeva HS (2010) Identification of nesfatin-1 in human and murine
adipose tissue: a novel depot-specific adipokine with increased levels in obesity. Endocrinology
151:3169–3180
74. Yang M, Zhang Z, Wang C, Li K, Li S, Boden G, Li L, Yang G (2012) Nesfatin-1 action in the
brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin
resistance. Diabetes 61:1959–1968
75. Xu Y, Pang X, Dong M, Wen F, Zhang Y (2013) Nesfatin-1 inhibits ovarian epithelial carci-
noma cell proliferation in vitro. Biochem Biophys Res Commun 440:467–472
76. Wada J (2008) Vaspin: a novel serpin with insulin-sensitizing effects. Expert Opin Investig
Drugs 17:327–333
77. Blüher M (2012) Vaspin in obesity and diabetes: pathophysiological and clinical significance.
Endocrine 41:176–182
1 Adipocytes, Adipocytokines, and Cancer 19

78. Noy N, Li L, Abola MV, Berger NA (2015) Is retinol binding protein 4 a link between adipos-
ity and cancer? Horm Mol Biol Clin Investig 23:39–46
79. Nieman KM, Romero IL, Van Houten B, Lengyel E (2013) Adipose tissue and adipocytes sup-
port tumorigenesis and metastasis. Biochim Biophys Acta 1831:1533–1541
80. Nieman KM, Kenny H, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL,
Carey MS, Mills GB, Hotamisligil GS, Yamada SD, Peter ME, Gwin K, Lengyel E (2011)
Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat
Med 17:1498–1503
81. Liu Y (2006) Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer.
Prostate Cancer Prostatic Dis 9:230–234
82. Baron A, Migita T, Tang D, Loda M (2004) Fatty acid synthase: a metabolic oncogene in pros-
tate cancer? J Cell Biochem 91:47–53
83. Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I (2014) Bone marrow fat: linking
adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev 33:527–543
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