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 SERIES EDITOR
D. ROLLINSON
Life Sciences Department
The Natural History Museum, London, UK
[email protected]

EDITORIAL BOARD
M. G. BASÁÑEZ R. E. SINDEN
Professor in Parasite Epidemiology, Immunology and Infection Section,
Department of Infectious Disease Department of Biological Sciences,
Epidemiology Faculty of Medicine Sir Alexander Fleming Building, Imperial
(St Mary’s Campus), Imperial College, College of Science, Technology and
London, London, UK Medicine, London, UK

S. BROOKER D. L. SMITH
Wellcome Trust Research Fellow and Johns Hopkins Malaria Research
Professor, London School of Hygiene and Institute & Department of Epidemiology,
Tropical Medicine, Faculty of Infectious Johns Hopkins Bloomberg School of Public
and Tropical, Diseases, London, UK Health, Baltimore, MD, USA

R. B. GASSER R. C. A. THOMPSON
Department of Veterinary Science, Head, WHO Collaborating Centre for
The University of Melbourne, Parkville, the Molecular Epidemiology of Parasitic
Victoria, Australia Infections, Principal Investigator,
Environmental Biotechnology CRC
N. HALL (EBCRC), School of Veterinary and
School of Biological Sciences, Biomedical Sciences, Murdoch University,
Biosciences Building, University of Liverpool, Murdoch, WA, Australia
Liverpool, UK
X. N. ZHOU
R. C. OLIVEIRA Professor, Director, National Institute of
Centro de Pesquisas Rene Rachou/ Parasitic Diseases, Chinese Center for
CPqRR - A FIOCRUZ em Minas Gerais, Disease Control and Prevention, Shanghai,
Rene Rachou Research Center/CPqRR - People’s Republic of China
The Oswaldo Cruz Foundation in the State
of Minas Gerais-Brazil, Brazil
Academic Press is an imprint of Elsevier
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14 15 16 17 12 11 10 9 8 7 6 5 4 3 2 1
CONTRIBUTORS

Verónica H. Agramunt
Departamento de Parasitologia, Facultad de Farmacia, Universidad de Valencia, Valencia,
Spain
Francisco J. Ayala
Department of Ecology and Evolutionary Biology, University of California, Irvine,
California, USA
Teun Bousema
Department of Infection and Immunity, London School of Hygiene and Tropical Medicine,
London, United Kingdom, and Department of Medical Microbiology, Radboud University
Nijmegen Medical Centre, Nijmegen, The Netherlands
Chris Drakeley
Department of Infection and Immunity, London School of Hygiene and Tropical Medicine,
London, United Kingdom
Holly A. Swain Ewald
Department of Biology, University of Louisville, Louisville, Kentucky, USA
Paul W. Ewald
Department of Biology, University of Louisville, Louisville, Kentucky, USA
Götz Froeschke
Evolutionary Genomics Group, Department of Botany and Zoology, Stellenbosch
University, Matieland, South Africa
Santiago Mas-Coma
Departamento de Parasitologia, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain
David L. Smith
Department of Epidemiology; Malaria Research Institute, Johns Hopkins Bloomberg School
of Public Health, Baltimore, and Fogarty International Center, NIH, Bethesda, Maryland,
USA
Michel Tibayrenc
Maladies Infectieuses et Vecteurs Ecologie, Génétique, Evolution et Contrôle, MIVEGEC
(IRD 224-CNRS 5290-UM1-UM2), IRD Center, Montpellier, France
Lucy S. Tusting
Department of Disease Control, London School of Hygiene and Tropical Medicine,
London, United Kingdom
Marı́a Adela Valero
Departamento de Parasitologia, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain
Sophie von der Heyden
Evolutionary Genomics Group, Department of Botany and Zoology, Stellenbosch
University, Matieland, South Africa

vii
MEMORIAM

John Baker (1931–2013)

It is with great sadness that we report that John Baker, a former editor of
Advances in Parasitology, died on 23 August 2013.
Many past authors will have known John as a meticulous editor with a
keen eye for detail. With a quiet determination and a guiding hand, he
worked closely with authors to ensure that their finished manuscript would
be of the highest quality. His contribution dates back to 1978 when he
joined forces with Ralph Muller and W.H.R. Lumsden as a co-editor of
the series. His long-standing editorship spanned from Volume 16 all the
way through to Volume 64 in 2007. John ensured that ‘Advances’
maintained a high standard and he helped to build the outstanding reputa-
tion of the series for authoritative and state-of-the-art reviews taking per-
sonal responsibility for the majority of the protist papers.
John shared his great interest in the biology of parasites with his many
friends and colleagues. He contributed enormously to the discipline with
outstanding scientific research particularly on the biology of trypanosomes
and authored several textbooks on parasitic protozoa and medical parasitol-
ogy. His editorial skills were in much demand, and later in his career he
worked as the editor of the Transactions of the Royal Society of Tropical Medicine
and Hygiene.

ix
x Memoriam

John was a quiet and most charming man, indeed a gentleman of the old
school. Always modest, he would arrive at editorial meetings in London on
his trusty old bicycle with enormous enthusiasm for the forthcoming vol-
ume and a characteristic smile that could help solve most problems. John will
be greatly missed by his family, friends and colleagues and by many parasi-
tologists around the world.
 CHAPTER ONE

Joint Infectious Causation

of Human Cancers
Paul W. Ewald1, Holly A. Swain Ewald
Department of Biology, University of Louisville, Louisville, Kentucky, USA
1
Corresponding author: e-mail address: [email protected]

Contents
1. Introduction 2
2. Essential and Exacerbating Causes 5
3. Joint Essential Causes 7
3.1 Background 7
3.2 Hepatitis B virus and hepatitis C virus 8
4. Essential with Exacerbating Infections 8
4.1 Overview 8
4.2 Human immunodeficiency virus 8
4.3 Hepatitis D and B viruses 9
4.4 Cancers caused by trematodes 9
5. Joint Exacerbating Infections 10
6. Uncertainties in Assignment of Exacerbating and Essential Causation 11
6.1 Overview 11
6.2 Endogenous retroviruses 11
6.3 Burkitt's lymphoma 12
7. Implications for Cancers of Uncertain Cause 13
7.1 Overview 13
7.2 Breast cancer 13
8. Implications for the Control of Cancer 15
Acknowledgements 19
References 19

Abstract
Joint infectious causation of cancer has been accepted in a few well-studied instances,
including Burkitt's lymphoma and liver cancer. In general, evidence for the involvement
of parasitic agents in oncogenesis has expanded, and recent advances in the application
of molecular techniques have revealed specific mechanisms by which host cells are
transformed. Many parasites evolve to circumvent immune-mediated detection and
destruction and to control critical aspects of host cell reproduction and survival: cell
proliferation, apoptosis, adhesion, and immortalization. The host has evolved tight reg-
ulation of these cellular processes—the control of each represents a barrier to cancer.

#
Advances in Parasitology, Volume 84 2014 Elsevier Ltd 1
ISSN 0065-308X All rights reserved.
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2 Paul W. Ewald and Holly A. Swain Ewald

These barriers need to be compromised for oncogenesis to occur. The abrogation of a

barrier is therefore referred to as an essential cause of cancer. Alternatively, some aspects
of cellular regulation restrain but do not block oncogenesis. Relaxation of a restraint is
therefore referred to as an exacerbating cause of cancer. In this chapter, we explore past
and current evidence for joint infectious causation of cancer in the context of essential
and exacerbating causes. We stress that discovery of joint infectious causation may pro-
vide great improvements in controlling cancer, particularly through the identification of
many additional nonhuman targets for synergistic interventions for prevention and
treatment.

1. INTRODUCTION
Evidence implicating parasites (defined broadly to include mul-
ticellular, cellular, and subcellular agents) as causes of cancer has been accu-
mulating and broadening for over a century. The first major advance was
reported in 1910, when Rous showed that a nonfilterable agent caused a
cancer of chickens, Rous sarcoma (Rous, 1910, 1911). Although Rous’s
finding and the subsequent identification of the Rous sarcoma virus
(RSV) was slow to influence research on human cancer, it led to discoveries
of viral causes of mammalian cancer during the middle third of the twentieth
century: a papillomavirus in rabbits (Shope and Hurst, 1933), mouse mam-
mary tumour virus (MMTV) in mice (Bittner, 1942), murine leukaemia
virus in mice (Gross, 1951), and simian virus 40 in hamsters (Rabson and
Kirschstein, 1962).
In 1964, Epstein reported the first viral cause of a human cancer (Epstein
et al., 1964). The virus is now known as the Epstein–Barr virus (EBV) and
the cancer as endemic Burkitt’s lymphoma. Prior to this discovery, Epstein
had been working on RSV but was searching for viral causes of human can-
cer (Epstein, 2005). In 1962, Epstein attended a talk given by Burkitt, who
had recently defined cases of Burkitt’s lymphoma (Burkitt, 1958). In the lec-
ture, Burkitt described the epidemiological correlation between Burkitt’s
lymphoma and mosquito density. Thinking that malaria was a cause of
Burkitt’s lymphoma, Burkitt suggested Plasmodium falciparum as an
aetiological agent (Kafuko and Burkitt, 1970). Epstein tested lymphoma
samples sent to him by Burkitt for viral infection and soon discovered
EBV (Epstein et al., 1964). Since then, the overall trend has been towards
acceptance of the idea that these pathogens jointly cause endemic Burkitt’s
lymphoma. In tropical medicine, joint causation has been accepted by
Joint Infectious Causation of Human Cancers 3

experts for decades (e.g. Manson-Bahr and Apted, 1982, p. 12), but a causal
role for P. falciparum has been questioned by some, largely because the
incriminating evidence has been epidemiological (Carpenter et al., 2008;
Orem et al., 2007). Recent work, however, has demonstrated the
co-occurrence of serological positivity for EBV and malaria in Burkitt’s lym-
phoma patients (Carpenter et al., 2008; Mutalima et al., 2008). This finding
together with studies documenting activation of EBV by P. falciparum has
reinforced what is now a widely held conclusion that these two pathogens
act as cofactors in the aetiology of endemic Burkitt’s lymphoma (Chêne
et al., 2009; Molyneux et al., 2012; Rochford et al., 2005).
Over the same decades during which infectious correlates of endemic
Burkitt’s lymphoma were being recognized, trematode infections were
implicated in causing human cancer—opisthorchids for cholangiocarcinoma
(liver-associated cancers originating from gall bladder ductal cells) and
Schistosoma haematobium for bladder cancer (Gelfand et al., 1967; Hou,
1956; Manson-Bahr and Apted, 1982; Mustacchi and Shimkin, 1958). Since
then, causal roles for these helminths have been generally accepted, and
attention has shifted to an increasing variety of cellular and especially viral
agents (Afzan and Suresh, 2012; Bouvard et al., 2009; Ewald, 2009;
Ferreri et al., 2009; Lax and Thomas, 2002; Samaras et al., 2010; Thomas
et al., 2012; Zhang and Begg, 1994; zur Hausen, 2010). Currently, infec-
tious causation is accepted for about 20% of human cancer (de Martel
et al., 2012; zur Hausen, 2008). This percentage may grossly underestimate
the true extent of infection-induced cancers because infectious causation has
not been adequately evaluated for most human cancers and can be ruled out
for only a very small portion.
The growing list of infectious agents associated with human cancer draws
attention to the need to clarify their roles and mechanisms. Are the associ-
ated parasites contributing to oncogenesis? If so, are they instigating or exac-
erbating influences, and when more than one parasite is implicated in a
particular cancer, are they acting separately or in concert? For most cellular
parasites that are associated with cancer, causal roles are still uncertain. For
the few that are generally accepted or strongly suspected causes of human
cancer, such as typhoid Salmonella, Helicobacter pylori, P. falciparum, and
opisthorchid trematodes (Bhandari and Crowe, 2012; McColl, 2010;
Nath et al., 2010; Samaras et al., 2010), the exact mechanisms are still not
well understood.
Although Burkitt’s lymphoma was the first human cancer for which joint
infectious causation was accepted, it has been viewed more as an anomaly
4 Paul W. Ewald and Holly A. Swain Ewald

than a model for understanding oncogenesis. More generally, joint infec-

tious causation of cancer has not been a central focus of cancer research, per-
haps because the involvement of parasites acting individually has been so
contentious that scientists have been hesitant to propose joint infectious cau-
sation. We believe that this neglected area of research may be critically
important for understanding the oncogenesis and the range of feasible
options for treatment and prevention.
Targeting parasites tends to be safer and more effective than targeting
human biomolecules, because natural selection inevitably leads to intercon-
nectedness of human biochemical processes and because human molecules
that are contributing to cancer will tend to have important normal functions
(Ewald and Swain Ewald, 2011, 2012). Discovering additional infectious
causes for a cancer will generate more nonhuman targets. But the effective-
ness of interventions against cancers caused jointly by different parasites
depends on the way in which each contributes to oncogenesis.
Inflammation, whether initiated by infection, autoimmunity, or muta-
tion associated with inflammatory pathways, has been implicated in cancer.
Once triggered, activation of transcription factors, such as STAT3 and
NF-kB, leads to increased production of proinflammatory cytokines and
chemokines and recruitment of inflammatory cells such as macrophages
and neutrophils. This proinflammatory environment has been associated
with increased cell proliferation and survival, inhibition of adaptive immu-
nity, angiogenesis, and metastasis (for an overview, see Mantovani et al.,
2008). Mechanisms of cancer promotion may include damage to DNA asso-
ciated with reactive oxygen species, inflammation-initiated epigenetic mod-
ifications, and alteration of signalling pathways involved in cell cycle and
apoptosis (Trinchieri, 2012). In support of the role of inflammation and can-
cer, the use of nonsteroidal anti-inflammatory drugs has been correlated
with reduced risk and decreased mortality for certain cancers (Mantovani
et al., 2008; Trinchieri, 2012).
These aspects of inflammatory processes can all be initiated by infection,
and it is often assumed that parasites exacerbate cancer by stimulating inflam-
mation. Some aspects of this presumption are supported by molecular evi-
dence (e.g. Moss and Blaser, 2005; Nath et al., 2010; Trinchieri, 2012). But
the complexity of immunologic interactions associated with infection makes
it difficult to determine the actual contributions of inflammation and infec-
tion to oncogenesis.
The historical tendency to emphasize inflammation has led to interpre-
tations that are at odds with current evidence. It is still claimed, for example,
Joint Infectious Causation of Human Cancers 5

that inflammation rather than direct viral induction of cell transformation is

the mechanism by which hepatitis viruses foster oncogenesis (Trinchieri,
2012). Molecular evidence, however, shows that hepatitis B and C viruses
directly compromise anticancer mechanisms employed by host cells (Ewald
and Swain Ewald, 2012). Distinguishing between these alternatives has
implications for medical intervention because it bears on the value of immu-
nomodulatory treatment as opposed to targeting of causal pathogens.
In this chapter, we explore past and current evidence for the generation
of cancer through the joint activity of two or more parasites. Our goal is to
clarify the roles played by coinfecting parasites, facilitate the discovery of
joint causation, and suggest implications for treating and preventing cancer.

2. ESSENTIAL AND EXACERBATING CAUSES

Parasites may influence development and progression of cancer by dif-
ferent mechanisms, which may vary in their importance. We suggest that an
integrated understanding of these mechanisms can be fostered by the barrier
theory of cancer, an evolutionary framework for understanding oncogenesis
(Ewald and Swain Ewald, 2013).
This framework is built on the distinction between barriers and restraints
(Ewald and Swain Ewald, 2013). Barriers prevent oncogenesis. Important
barriers are cell-cycle arrest, apoptosis, repression of telomerase, cell adhe-
sion, and asymmetric cell division. When barriers are in place and function-
ing, oncogenesis is thwarted. A cell cannot become metastatically cancerous
if it is not dividing, is destroyed by apoptosis, has only a limited number of
future cell divisions, or remains adherent to adjacent cells. Whether these
barriers are in place, however, depends on the cell type (Ewald and
Swain Ewald, 2013). Asymmetric division, for example, is a barrier for stem
cells but not for most other cell types,
Restraints are mechanisms that impede but do not prevent oncogenesis.
Mechanisms that suppress angiogenesis, for example, are restraints because
oncogenesis can proceed even without altering control of angiogenesis.
The reason is that angiogenesis is normally initiated in response to physio-
logical changes associated with precancerous cell growth, such as reduced
oxygen concentration. Similarly, regulation of the rate of proliferation in
dividing cells is a restraint because oncogenesis can still proceed in a slowly
dividing cell.
This separation of barriers from restraints provides the basis for a distinc-
tion between essential and exacerbating causes of cancer. Oncogenic events
6 Paul W. Ewald and Holly A. Swain Ewald

that abrogate barriers are essential causes of cancer. Those that relax restraints
are exacerbating causes. Distinguishing essential from exacerbating causes is
important because the blocking of essential causes will prevent cancer. In
contrast, blocking exacerbating causes will tend to hinder oncogenesis or
the damage associated with the cancer.
Three selective processes provide evolutionary structure to this concep-
tual framework for understanding oncogenesis (Ewald and Swain Ewald,
2013). Natural selection acts on multicellular organisms to create and adjust
barriers and restraints. Natural selection may also act on parasites to compro-
mise barriers and restraints when these protective mechanisms inhibit the
ability of parasites to multiply and persist within a host. A third selective pro-
cess, oncogenic selection, causes normal cells to evolve into cancerous cells
as well as evolutionary changes in cancer cells.
Parasites may contribute to oncogenesis in two general ways. They may
haphazardly disturb the normal functioning of cells and tissues, for example,
by altering the presence of mutagenic compounds or proliferative signals
during inflammatory reactions. Alternatively, they may have evolved spe-
cific mechanisms to compromise barriers and restraints. The former category
has generally been presumed to be the main route by which parasites con-
tribute to oncogenesis. This presumption, however, is tenuous because nat-
ural selection can generate sophisticated mechanisms by which parasites
interfere with barriers or restraints. Indeed, investigations of tumour virus
proteins have revealed precise mechanisms for abrogating barriers to onco-
genesis. All well-studied viruses that have been accepted as direct causes of
human cancer—human papillomavirus (HPV), EBV, Kaposi sarcoma-
associated herpesvirus (KSHV), human T-lymphotropic virus type 1
(HTLV1), hepatitis B virus (HBV), and hepatitis C virus (HCV)—are
known to encode proteins that directly compromise cell-cycle arrest, apo-
ptosis, telomerase regulation, and cell adhesion (reviewed by Ewald and
Swain Ewald, 2012). These barriers to cancer are also barriers to long-term,
productive persistence of the viruses within hosts (Ewald and Swain Ewald,
2013). Natural selection acting on viruses to favour persistence therefore
appears to cause infected cells to be pushed towards the brink of cancer, with
additional mutations being necessary to complete the transformation.
Being intracellular parasites with capabilities to alter cell replication,
viruses are the most obvious infectious candidates for encoding multiple
essential causes of cancer. Cellular parasites, however, might also benefit
by compromising barriers to cancer. If intracellular bacteria or protozoa
can replicate along with the host cell, they, like viruses, could benefit from
Joint Infectious Causation of Human Cancers 7

making host cells proliferate. Typhoid Salmonella may be an example of such

an intracellular parasite. It is strongly associated with liver and gall bladder
cancers and weakly with pancreatic, colorectal, and lung cancers (Nath
et al., 2010; Samaras et al., 2010). Similarly, H. pylori, which can infect intra-
cellularly or extracellularly (Deen et al., 2013), contributes to two cancers of
the stomach: gastric cancer and mucosa-associated lymphoid tissue lympho-
mas. It enhances telomerase activity (Chung et al., 2002; Hur et al., 2000;
Kameshima et al., 2000) but has complex sometimes contradictory effects on
other barriers (Cheng et al., 2013; Wang et al., 2012a); for example, it
encodes a protein that exerts antiapoptotic effects that counter the host cell’s
apoptotic responses to another one of its proteins (Oldani et al., 2009).
H. pylori also relaxes restraints by stimulating proinflammatory and growth
factor signalling (Ashktorab et al., 2007; Suzuki et al., 2009). How all of
these effects interact and offset each other is still unclear, but on balance,
the evidence suggests that H. pylori can compromise at least three of the four
barriers to oncogenesis that are abrogated by tumour viruses. The curative
effects of antibiotic treatment on H. pylori-induced stomach cancers (Gisbert
and Calvet, 2011; Kuo et al., 2012; Nakamura et al., 2012) indicate that
H. pylori abrogates barriers rather than just restraints.
This conceptual framework should be useful for developing our under-
standing of joint infectious causation in two important ways. First, it allows
for an assessment of the relative roles of different infections that contribute to
a particular cancer and hence the relative value of targeting the different par-
asites. If one parasite functions as an exacerbating cause and the other as an
essential cause, targeting the former will tend to be less effective than
targeting the latter. Second, it helps identify important parts of the causal
picture that are missing. These missing parts could involve insufficient
knowledge about the mechanism of causation for particular parasites or
the presence of an additional cause in the oncogenic process. These ideas
are discussed later with reference to particular examples of demonstrated
or suspected infectious causation.

3. JOINT ESSENTIAL CAUSES

3.1. Background
Although substantial research has implicated joint infectious causation of
cancer, surprisingly little research has evaluated whether joint infectious cau-
sation is associated with a greater potential for controlling cancer. If two par-
asites that compromise different barriers infect the same cell, the cell’s set of
8 Paul W. Ewald and Holly A. Swain Ewald

barriers will be more completely compromised than would be the case if

only one parasite infected the cell. But even if two parasites compromise
the same barriers, the joint infection may increase oncogenicity because nat-
ural selection probably favours parasites that compromise, but do not
completely block, barriers to cancer (Ewald and Swain Ewald, 2013).

3.2. Hepatitis B virus and hepatitis C virus

HBV and HCV each cause cancer by compromising all four of the barriers
listed earlier for non-stem cells (Ewald and Swain Ewald, 2012). Joint infec-
tion of individuals can be fairly common because both viruses can be trans-
mitted by the same routes, particularly by contaminated blood or injection
materials, and in some areas by sexual contact (Ewald and Swain Ewald,
2012). Joint infection increases the risk of hepatocellular cancer (HCC)
(Cho et al., 2011; Oh et al., 2012). The main uncertainty is whether the risk
is additive, subadditive, or supra-additive (Cho et al., 2011). Several studies,
including the most recent meta-analysis (Oh et al., 2012), indicate supra-
additive effects. The current state of knowledge therefore suggests that con-
trol of either virus will provide similarly powerful control of cancer.

4. ESSENTIAL WITH EXACERBATING INFECTIONS

4.1. Overview
Parasites may exacerbate oncogenesis by damaging cells and altering immuno-
logic processes. Immunosuppression induced by one parasite may reduce the
control of other oncogenic parasites. Immune activation can increase pro-
proliferative effects and mutational damage through generation of reactive
molecules (as discussed in Section 1). This duality is considered later in the
context of joint infection with parasites that act as essential causes of cancer.

4.2. Human immunodeficiency virus

Human immunodeficiency virus (HIV) is the most transparent example of a
pathogen that increases the risk of cancer through immunosuppression. HIV
increases the risk of several cancers for which other infectious agents encode
essential causes: KSHV, cervical and anal cancer (caused by HPV), hepato-
cellular carcinoma (caused by HBV and HCV), and B-cell lymphomas
(Burkitt’s lymphoma, diffuse large B-cell lymphoma with centroblastic fea-
tures, and Hodgkin’s disease, all probably caused at least in part by EBV)
(Bernstein et al., 2006; Chiao and Krown, 2003; Grulich et al., 2007;
Joint Infectious Causation of Human Cancers 9

Mbulaiteye et al., 2010). HIV is also a risk factor for cholangiocarcinomas,

which are associated with HBV and HCV (Shaib et al., 2005).
Leiomyosarcoma, a rare smooth muscle cancer generally of adults, is more
common in HIV-infected children and is associated with EBV (Bhatia et al.,
2012; McClain et al., 1995).
Evidence indicates that immunosuppression is an important mechanism
for the increased incidence of cancer in HIV-infected individuals. There is
significant overlap between the types of cancer that are increased in HIV-
positive individuals and transplant recipients (Grulich et al., 2007). In the
case of leiomyosarcomas, for example, incidence is higher in transplant
patients and in HIV-infected adults, with all showing greater than 80%
EBV positivity (Bhatia et al., 2012). Many cancers associated with HIV
infection have declined in incidence in the post-HAART era, suggesting
a protective effect of improved immune function (van Leeuwen et al.,
2009). With regard to the issue of joint infectious causation, HIV-associated
cancers are almost always demonstrated or suspected to be caused by infec-
tious agents (Grulich et al., 2007). These considerations indicate that HIV’s
contributions to oncogenesis are often immunosuppressive exacerbations of
essential infectious causes.

4.3. Hepatitis D and B viruses

The infection cycle of the hepatitis D virus (HDV) appears to be dependent
on the presence of HBV infection, because HDV uses HBV’s virion capsule
for transmission between cells (Taylor, 2006). Although joint infection of
HDV and HBV is associated with an elevated risk of HCC relative to
that of HBV alone (Fattovich et al., 2000), HDV infection tends to lower
overall proliferation of infected cells relative to uninfected cells (Wang
et al., 2001). The HDV ribozyme inhibits rather than enhances telomerase
activity (Lu et al., 2011), and HDV does not appear to be oncogenic in the
absence of hepatitis B infection (Niro and Smedile, 2012). HDV therefore
tends to exacerbate liver damage (Taylor, 2006) and oncogenesis of HCC,
but does not appear encode essential causes. Its exacerbation of HCC may
result from its damage to the cell and the inflammation that this damage
stimulates.

4.4. Cancers caused by trematodes

It has been presumed that trematodes induce cancer through a combination
of pro-oncogenic inflammatory responses and oncogenic mutations
10 Paul W. Ewald and Holly A. Swain Ewald

(Mostafa et al., 1999). In recent years, however, investigations have linked

oncogenic viruses with trematode-induced cancers. HBV and HCV have
been documented as risk factors for intrahepatic cholangiocarcinoma
(Donato et al., 2001; Lee et al., 2008; Shaib et al., 2007; Zhou et al.,
2008). HPV and EBV have been associated with bladder cancer (Badawi
et al., 2008; Barghi et al., 2012; Gazzaniga et al., 1998; Husain et al.,
2009; Kim and Kim, 1995; Moonen et al., 2007; Noel et al., 1994;
Panagiotakis et al., 2013) as have other viruses that are suspected of causing
human cancer (Badawi et al., 2010; Fioriti et al., 2003). The linkage of
viruses with bladder cancer varies greatly among reports, with some
investigators failing to find evidence of the most commonly reported viral
correlate: oncogenic serotypes of HPV (e.g. Sano et al., 1995; Yavuzer
et al., 2011; Youshya et al., 2005). These discrepancies suggest variation
in the roles of particular viruses among patient populations or geographical
areas or variation in the accuracy of results. Where trematodes are absent,
viral associations with bladder cancer tend to occur in patients who are
immunocompromised due to advanced age or immunosuppressive
treatment (Husain et al., 2009; Noel et al., 1994; Panagiotakis et al.,
2013). This tendency mirrors the associations between EBV and nonen-
demic Burkitt’s lymphoma in immunocompromised patients (see later)
and raises the possibility that Schistosoma infections may be exacerbating
the oncogenic effects of viruses through immunosuppression (for immuno-
suppressive effects of Schistosoma, see Hu et al., 2012).

5. JOINT EXACERBATING INFECTIONS

Interestingly, we do not know of any examples of joint infectious cau-
sation for which all of the coinfecting parasites compromise only restraints.
This absence may be attributable to incomplete knowledge but may be due
at least in part to the possibility that parasites that impose only exacerbating
effects need to infect jointly with those that compromises barriers. This idea
runs contrary to conventional thinking that tends to presume parasites trig-
ger exacerbating causes such as pro-proliferative signals of inflammation.
A strong tendency for oncogenic parasites to compromise barriers would
imply a high potential for effective interventions—the greater the involve-
ment of parasites in compromising barriers, the greater the effect of anti-
parasite interventions in controlling cancer.
Joint Infectious Causation of Human Cancers 11

6. UNCERTAINTIES IN ASSIGNMENT OF EXACERBATING

AND ESSENTIAL CAUSATION
6.1. Overview
The incompleteness of knowledge about infectious mechanisms of onco-
genesis creates uncertainty over the extent to which infectious etiologies
of cancer involve essential causes. Endogenous retroviruses (ERVs) and
Burkitt’s lymphoma illustrate these issues.

6.2. Endogenous retroviruses

ERVs result from retroviruses that have integrated into host DNA after germ
line infection and are thus directly transmissible from parent to offspring
across generations. Some of the ERVs have been transmitted in this way
for over 80 million years; others are more recent (Romanish et al., 2010).
Like many retroviruses, ERVs have been implicated in certain cancers
(Stoye, 2012). Human ERVs (HERVs) or their partial sequences make
up approximately 8% of the genome, generally carry disabling mutations,
and have yet to be linked directly to any cancer (Romanish et al., 2010;
Ruprecht et al., 2008; Stoye, 2012). Natural selection should tend to weed
out HERVs that are essential causes of cancer unless they provide a compen-
sating fitness benefit. This possibility is illustrated by syncytin proteins,
which are of ERV origin and are aberrantly expressed in some breast cancers
but contribute to normal placental development (Ruprecht et al., 2008). It is
possible that the stability of evolved associations between HERVs and
human cells could be upset by other infectious agents. HERVs might con-
tribute to cancer in these situations through immunosuppression, viral pro-
tein expression, or effects on ‘host’ gene regulation (Romanish et al., 2010;
Stoye, 2012).
Joint infectious causation of cancer is suggested by reactivation of endog-
enous murine leukaemia virus (eMLV) in antibody-deficient mice, which
has been associated with lymphoma development in mice raised with stan-
dard husbandry but not in mice from germ-limiting environments (Young
et al., 2012). The eMLV reactivation may have involved recombination
with another ERV after both were stimulated by the presence of LPS, which
would normally have been cleared by antibodies. The associations of both
eMLV- and LPS-induced inflammation with lymphoma suggest that
LPS-laden bacteria may contribute an exacerbating cause through
12 Paul W. Ewald and Holly A. Swain Ewald

inflammatory effects of LPS (Young et al., 2012). Associations of HERV

activation with immunologic changes suggest that a similar mechanism
may contribute to human lymphomas (Young et al., 2012).
If ERVs can be transmitted horizontally, oncogenic potential may be
maintained indefinitely over time because the success of such exogenous
viruses is not entirely dependent on the success of their hosts. In such cases,
the exogenous virus and ERV may act jointly. Whether HERVs are provid-
ing coessential causes or exacerbating causes depends on the genes they
control.
The middle ground between ERVs and exogenous retroviruses is not
well understood. MMTV is in this middle ground. It can be transmitted
in the germ line as an ERV but the extent to which exogenous MMTV
is transmitted to and from germ lines has not been well characterized.
Compromising three barriers, MMTV readily causes cancer in certain strains
of mice apparently in the absence of other viruses, but perhaps in conjunc-
tion with ERVs. A small study of MMTV in liver disease provides some sup-
port for joint causation involving MMTV and hepatocellular carcinoma. Of
the 21 cases investigated, three of the four MMTV positive tumours were
also positive for HBV accounting for 50% of all HBV-infected tumours
( Johal et al., 2009).

6.3. Burkitt's lymphoma

P. falciparum apparently exacerbates EBV induction of Burkitt’s lymphoma
by fostering replication and release of EBV (Chêne et al., 2007). One mech-
anism appears to be through the decline in immunologic control of EBV
virion production (Snider et al., 2012). Another involves activation and sur-
vival of infected B lymphocytes (Chêne et al., 2009; Rochford et al., 2005).
This proliferation could amplify the number of virus-infected lymphocytes
within a person, thereby increasing the probability of oncogenic mutations
in the population of infected cells. Although most of the demonstrated or
implicated mechanisms involve relaxation of restraints, activation or survival
of B lymphocytes might abrogate barriers (i.e. if it compromises cell-cycle
arrest or apoptosis), in which case joint infection with P. falciparum would
contribute to the essential causes. A finer understanding of the mechanism
will clarify whether or not the effect of P. falciparum is strictly exacerbating
the oncogenic process.
Results from a recent study of Ugandan children (Carpenter et al., 2008)
accord with synergistic joint causation, with EBV contributing a more
Joint Infectious Causation of Human Cancers 13

significant role than P. falciparum. The associations of Burkitt’s lymphoma

with EBV titre were much stronger than the association with malaria (as
measured by recent treatment for malaria). The joint occurrence of EBV
and malaria was associated with a fivefold increased risk of Burkitt’s
lymphoma.
EBV is also associated with globally distributed B-cell cancers that are
now considered to be variants of Burkitt’s lymphoma outside of malaria-
endemic areas. It is present in about half of the cases among HIV-infected
subjects (Bernstein et al., 2006; Mbulaiteye et al., 2013a) and about two-
thirds of cases associated with organ transplantation (Mbulaiteye et al.,
2013b). The elimination of EBV from Burkitt’s lymphoma cells causes them
to die by apoptosis, confirming the idea that EBV provides an essential cause
of the cancer rather than being simply a bystander (Vereide and Sugden,
2009; Vereide et al., 2013). On balance, this evidence supports the idea that
EBV contributes to Burkitt’s lymphoma in the absence of Plasmodium infec-
tion, particularly when immune function is compromised.

7. IMPLICATIONS FOR CANCERS OF UNCERTAIN CAUSE

7.1. Overview
The focus on barriers can help indicate whether a candidate parasite needs to
infect jointly with another candidate parasite to cause a particular cancer. It
also provides a sense of what studies need to be conducted to facilitate a more
complete understanding of joint infectious causation of cancer. Breast cancer
offers illustrations.

7.2. Breast cancer

Five pathogens have been linked to breast cancer through comparisons with
normal tissue: MMTV (also referred to as mouse mammary tumour-like
virus or HMTV to designate isolation from humans), EBV, HPV, bovine
leukaemia virus (BLV), and JC virus ( JCV) (Buehring et al., 2007; Glenn
et al., 2012; Hachana et al., 2012; Joshi and Buehring, 2012; Lawson and
Heng, 2010; Simoes et al., 2012; Wang et al., 2012b). For the first three
of these viruses, associations with breast cancer have been documented by
two or more different research groups, but the association has not been
found by at least one additional research group (Glenn et al., 2012;
Joshi and Buehring, 2012; Salmons and Gunzburg, 2013; Wang et al.,
2012b). Studies that report associations tend to find an elevated prevalence
14 Paul W. Ewald and Holly A. Swain Ewald

in breast cancer samples (or breast cancer patients) of roughly 20–50%. If

each virus caused breast cancer independently, they could collectively
account for nearly all human breast cancer. If joint infection is required,
however, this set of viruses might not be sufficient to explain the spectrum
of breast cancer.
Evidence indicates that MMTV compromises apoptosis and cell adhe-
sion (Katz et al., 2005; Lawson et al., 2010; Ouatas et al., 2002; Ross,
2010; Ross et al., 2006). MMTV oncogenesis involves activation of the
Wnt-1 pathway (Kim et al., 2012), which compromises cell-cycle arrest
(Niehrs and Acebron, 2012) though feasible mechanisms seem more com-
plicated than originally thought (Bearss et al., 2002; Michaelson and Leder,
2001; Rowlands et al., 2004). There has been no report of the abrogation of
telomerase regulation by MMTV. Evolutionary considerations suggest that
it is unlikely that MMTV would have this capability because its normal host,
Mus domesticus, does not regulate telomerase. Apparently, this barrier to cel-
lular immortalization regulation has not been favoured by natural selection
because fewer barriers to cancer are needed in mice; mice are small and
short-lived relative to humans and therefore have a lower probability of
acquiring oncogenic mutations during a normal lifespan (Caulin and
Maley, 2011; DeGregori, 2011; Seluanov et al., 2008).
These considerations suggest that research investigating the link between
MMTV and breast cancer would benefit especially from investigations of
joint infectious causation. The low positivity for MMTV in normal tissue
suggests that any complementary joint infection would need to be common
so that MMTV would be infecting in a background with a high prevalence
of one or more viruses that compromise the regulation of telomerase. EBV
would be the most obvious candidate among the four viruses that have been
correlated with breast cancer.
Glenn et al. (2012) evaluated whether these viruses tend to co-occur in
invasive breast cancer. They tested 50 invasive breast cancer samples for
DNA from EBV, MMTV, and oncogenic serotypes of HPV and found pos-
itivity in 68%, 78%, and 50%, respectively (compared with 35%, 32%, and
20%, respectively, for cell samples from normal breasts). Seventy-two per
cent of the samples were positive for two or more of these viruses. EBV
and HPV were found jointly in 38% of cancers but in only 10% of samples
from normal breasts. The analogous figures for MMTV were not given in
their report, but unpublished results from this research group showed that
joint infections with MMTV in the cancer specimens were greater than
expected by chance ( J. S. Lawson, personal communication).
Joint Infectious Causation of Human Cancers 15

In addition to complementing each other’s oncogenicity, these viral

agents may more directly exacerbate oncogenic infections. Synergistic inter-
actions between EBV and HPV have also been reported (Hagensee et al.,
2011 cited by Glenn et al., 2012). MMTV is known to exacerbate infections,
including oncogenic viral infection, an effect attributable at least in part to its
Sag protein (Bhadra et al., 2006).
Underlying this evidence for viral associations with breast cancer is
uncertainty about whether the correlations reflect causation. Aside from
the widely recognized problems associated with causal interpretations of
correlative evidence, some aspects of the correlations themselves raise con-
cerns about causation. Calculations, for example, indicate a very low ratio of
EBV genomes relative to cellular genomes derived from the tumour
(Perkins et al., 2006; Perrigoue et al., 2005). Such low ratios could reflect
infiltration of tumour samples with EBV-infected cells rather than an onco-
genic role for EBV or infiltration of tumours by uninfected nontransformed
cells (e.g. leukocytes or fibroblasts). Variation in techniques among research
groups may have important effects on quantification of EBV load (Kimura
et al., 2008); insensitivity of measurement of viral genomes may therefore
also be a contributing factor. Comparison with ratios for cancers that are
known to be caused by the particular virus (e.g. nasopharyngeal cancers
for EBV) may be useful (De Paoli et al., 2007; Perrigoue et al., 2005) but
not definitive, because a virus may be more abundant in cell types that
are part of the normal transmission process than in those that are not.

8. IMPLICATIONS FOR THE CONTROL OF CANCER

The examples of demonstrated, probable, and possible joint infectious
causation discussed in this chapter have practical implications because the
greater the number of parasites that contribute to a particular cancer, the
greater the number of nonhuman targets for prevention and treatment.
The value of the parasite as a target is related to the number of essential causes
it compromises. It is therefore important to assess the extent to which
known or suspected causes of cancer compromise barriers.
Interfering with joint infectious causes that compromise only restraints
will tend to have less impact but still may be valuable because eliminating
exacerbating causes of cancer might retard oncogenesis or contribute to con-
trol of the aggressiveness of a cancer. Burkitt’s lymphoma provides an illus-
tration. Household use of insecticide is associated with an 80% reduction in
the risk of developing Burkitt’s lymphoma (Carpenter et al., 2008), and
16 Paul W. Ewald and Holly A. Swain Ewald

Burkitt’s lymphoma has declined in the wake of malaria control. The inci-
dence of Burkitt’s lymphoma is about 5- to 10-fold greater in areas where
P. falciparum is endemic than where it is absent (Orem et al., 2007). This dif-
ference provides a sense of the extent to which Burkitt’s lymphoma could be
reduced through malaria eradication. Still, the more predominant role of
EBV and its ability to compromise four barriers to cancer suggest that pre-
vention of EBV infection (e.g. through vaccination) should provide more
complete control of Burkitt’s lymphoma than would a comparable level
of prevention of P. falciparum infection. One caveat is that the current evi-
dence is not sufficient to rule out the possibility that P. falciparum could com-
promise barriers to cancer. Although P. falciparum does not infect the
cancerous cell type of Burkitt’s lymphoma (B lymphocytes), this possibility
still needs to be considered because P. falciparum could have extracellular
effects.
Cervical cancer provides a variation on this theme for a cancer that is
already being controlled by targeting a pathogen (HPV) that compromises
four barriers and causes virtually all cases. Substantial evidence indicates that
Trichomonas species contribute to cervical cancer (Afzan and Suresh, 2012;
Zhang and Begg, 1994). The aetiological role of Trichomonas has attracted
relatively little attention in the biomedical community, probably because
its contribution appears to be relatively small and it probably exacerbates
the oncogenesis of cervical cancer through inflammation. If, however, Trich-
omonas compromises one or more barriers to cervical cancer, then its impor-
tance may be greater than is generally presumed, and efforts to control
Trichomonas correspondingly more significant.
With regard to bladder cancer, infection control efforts have generally
focused on trematodes. The theoretical framework proposed in this chapter
suggests, however, that other infectious correlates of bladder cancer may
prove to be important targets for intervention. The correlations with
HPV (Badawi et al., 2008; Barghi et al., 2012; Husain et al., 2009; Kim
and Kim, 1995; Moonen et al., 2007; Noel et al., 1994), for example, suggest
that vaccination against HPV may prevent bladder cancer even in people
infected with S. haematobium. The focus on barriers suggests that
trematode-induced bladder cancer might as a rule require still other onco-
genic pathogens, which might be controlled similarly by vaccination. The
reported associations of bladder cancer with polyomaviruses and herpesvi-
ruses (Badawi et al., 2010; Fioriti et al., 2003; Gazzaniga et al., 1998)
have generated an array of candidate pathogens for such control. An analo-
gous argument applies to HBV and HCV relative to opisthorchid
Joint Infectious Causation of Human Cancers 17

trematodes in cholangiocarcinomas. Prevention of hepatitis viruses by vac-

cination and blood screening may provide especially effective control of
cholangiocarcinoma in trematode endemic regions.
Although these considerations suggest that more effort should be
devoted to identifying and controlling pathogens that contribute to these
cancers, they do not negate the value of controlling the trematodes. Viral
vaccines and antiworm treatment may act powerfully in concert, especially
if the trematode infections compromise one or more barriers. The effective-
ness of treatment or prevention of schistosome infections will depend in part
on the extent to which schistosome-induced mutations compromise barriers
relative to restraints. Treating schistosomiasis with anti-helminthic drugs is
associated with a decline in the number of bladder cells that show chromo-
somal damage, perhaps because of reduced mutation-inducing inflammation
(Anwar, 1994). Some of these mutations may be abrogating barriers. The
combination of viral vaccination, inhibition of viral transmission (e.g. by
blood screening or condom use), and anti-helminthic drugs may therefore
act powerfully and synergistically to control cholangiocarcinoma and
bladder cancer.
When a parasite compromises several barriers to cancer and infects dif-
ferent cell types, the barrier theory of cancer suggests that it may be acting as
a packet of essential causes of different cancers (Ewald and Swain Ewald,
2013). Vaccinating against such parasites may therefore exert far greater con-
trol of cancer than would be assumed on the basis of infection-induced
inflammation or mutation (Ewald and Swain Ewald, 2013). The broadening
recognition of the spectrum of cancers caused by a particular pathogen coin-
cides with expansions in the number of candidate pathogens that have been
identified for particular cancers. These developments may reflect a wide-
spread occurrence of joint infectious causation and thus a pervasive benefit
of controlling any particular pathogen. HPV illustrates this point. HPV
attracted attention when it was shown to be a cause of cervical cancer. This
attention eventually led to approval of a vaccine against HPV to protect
against cervical cancer. Since then, it has been generally accepted that
HPV serotypes that cause cervical cancer also cause anal cancer, penile can-
cer, and some oropharyngeal cancer (Chaux and Cubilla, 2012; Frisch,
2002; Geissler et al., 2013; Marty et al., 2013; No et al., 2011;
Rosenquist, 2005). It is now expected that the HPV vaccines will protect
against these cancers directly and through herd immunity (e.g. Marty
et al., 2013). The same oncogenic serotypes have been associated with other
cancers, such as those of the breast (Damin et al., 2004; Glenn et al., 2012;
18 Paul W. Ewald and Holly A. Swain Ewald

Hennig et al., 1999; Kroupis et al., 2006) and urinary bladder (Badawi et al.,
2008; Barghi et al., 2012; Kim and Kim, 1995; Moonen et al., 2007). As
mentioned earlier, these cancers have been associated with other parasites
and are therefore prime candidates for joint infectious causation.
The value of controlling parasites that exacerbate oncogenesis is also
related to the number of cancers they exacerbate. HIV is perhaps the most
extreme example of a pathogen that is important to control even though its
effects on cancer are exacerbating rather than essential. By compromising
immunologic restraints, it exacerbates oncogenesis when other pathogens
function as essential causes. Preventing HIV infection would therefore have
major beneficial effects on control of cancer even though it would not pre-
vent any particular kind of cancer.
We can expect that recognition of joint infectious causation of cancer
will be increasingly important in the upcoming decades because cancers cau-
sed by a single pathogen are more conspicuously infectious and the most
conspicuous examples of infectious cancers will tend to be discovered first.
Epidemiological evidence of joint infectious causation may be more ambig-
uous because epidemiological patterns of disease will not accord neatly with
the geographical distribution of a causal pathogen. Similarly, clinical evi-
dence may be ambiguous because a candidate pathogen may be associated
with the disease in one study population but not in another if the joint infec-
tious cause is absent, because of differences in geography or patient selection
(e.g. a sexually transmitted pathogen may be of little importance in a patient
population that is not sexually active).
The treatment and control of infectious disease is one of the greatest
achievements of the health sciences. Historically, the discovery of an infec-
tious cause has almost always led to major advancement in the control of the
disease. The chances of failing to counter in some way one infectious cause
of cancer are therefore low. If two parasites are involved, the probability of
failing to counter at least one of the two is vastly lower. For this reason alone,
the search for joint infectious causes of cancers should be a priority. This idea
seems fairly obvious when the discovered causes cannot explain all of the
risk, as was the case with transfusion-associated HCC before HCV was dis-
covered. But such efforts need to continue even when a known infectious
cause explains much of the disease, in which case the roles of contributing
pathogens need to be understood in terms of essential and exacerbating cau-
ses. Clarity of hindsight makes this point apparent for AIDS-associated can-
cers, in which HIV acts as an exacerbating cause, but this point is also
illustrated by trematode-associated cancers, in which the essential causes
Joint Infectious Causation of Human Cancers 19

may have been overlooked, and by endemic Burkitt’s lymphoma and cer-
vical cancer, in which joint infectious causes appear to be exacerbating but
may also contribute in an essential way. In each case, determining the roles of
the jointly infecting parasitic causes has important implications for
interventions.
Past experience demonstrates that even after an effective intervention
against an infection-induced cancer has been developed and enacted, its
effectiveness will generally fall short of 100%. Vaccine coverage, for exam-
ple, becomes increasingly difficult as it approaches 100% because of difficul-
ties with access and compliance. Even when coverage is close to 100%,
effectiveness will often be limited for reasons specific to each vaccine. Pre-
vention of hepatocellular carcinoma by the current hepatitis B vaccine, for
example, is limited to about a 70% reduction largely because babies can
become infected prior to the earliest administration of the vaccine
(Chang et al., 2009). Prevention of cervical cancer by current HPV vaccines
is limited by the serotypes that have been included in the vaccines. Having
two different infectious targets will ameliorate such limits on maximal effec-
tiveness. If cholangiosarcoma is caused jointly by HBV and opisthorchid
trematodes, targeting both parasites will compensate for the incompleteness
of each approach. The same argument applies to viruses and schistosomes in
control of bladder cancer and HPV serotypes and Trichomonas in the control
of cervical cancer. An emphasis on joint causation of cancers might thus pro-
vide a spectrum of possibilities that brings control of infection-induced can-
cers into the range of effectiveness that has been achieved in the control of
acute infectious diseases.

ACKNOWLEDGEMENTS
The Rena Shulsky Foundation supported this work as part of a project to develop a unified
theory of oncogenesis. Frédéric Thomas and Caroline Doyle provided valuable input during
development of the ideas. We thank William Lawson for allowing us to cite unpublished
evidence of joint viral associations in breast cancer.

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