Cancer Letters 345 (2014) 174–181

Contents lists available at ScienceDirect

Cancer Letters
journal homepage: www.elsevier.com/locate/canlet

Mini-review

Virus induced inflammation and cancer development

Scott A. Read a, Mark W. Douglas a,b,*
a
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
b
Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity University of Sydney at Westmead Hospital, Sydney, Australia

a r t i c l e i n f o a b s t r a c t

Keywords: Chronic inflammation as a result of viral infection significantly increases the likelihood of cancer devel-
Cancer opment. A handful of diverse viruses have confirmed roles in cancer development and progression, but
Viruses
the list of suspected oncogenic viruses is continually growing. Viruses induce cancer directly and indi-
Inflammation
rectly, by activating inflammatory signalling pathways and cytokines, stimulating growth of infected cells
Review
and inhibiting apoptosis. Although oncogenic viruses induce inflammation by various mechanisms, it is
generally mediated by the MAPK, NFjB and STAT3 signalling pathways. This review will explore the
unique mechanisms by which different oncogenic viruses induce inflammation to promote cancer initi-
ation and progression.
Ó 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction are present in a typical cancer genome, including 10–20 in

Viruses contribute significantly to cancer development
worldwide, with up to 15% of human cancers attributed to chronic
viral infection [1,2]. Human papillomavirus (HPV) and hepatitis B
virus (HBV) are the most significant contributors, but the list of
tumourigenic viruses is much longer [1]. Epstein–Barr virus
(EBV), human T-lymphotropic virus-I (HTLV-I), hepatitis C virus
(HCV), Kaposi’s sarcoma herpesvirus (KSHV) and Merkel cell
polyomavirus (MCV) all have confirmed roles in cancer induction,
with a significantly longer list of viruses also suspected to play a
role in tumourigenesis.
The acute inflammatory response to virus infection is an
essential component of the antiviral response, inducing genes
responsible for antiviral activity, immune cell recruitment and
cell fate [3]. Unfortunately, excessive inflammation can arise dur-
ing persistent infection and is generally damaging, having muta-
genic effects on the host genome [4]. Chronic inflammation
plays a role in a number of disease states, including diabetes,
arthritis, Alzheimer’s disease, and over a longer period, cancer
[5]. In the context of cancer development, chronic inflammation
has been linked not only to tumourigenesis, but also to increased
cell proliferation, survival, invasion, angiogenesis and metastasis
[5,6].
Tumourigenesis usually follows the accumulation of muta-
tions in gene coding regions, resulting in uncontrolled cell
growth. It is estimated that around 100 coding region mutations
* Corresponding author. Storr Liver Unit, Westmead Millennium Institute,
University of Sydney at Westmead Hospital, Sydney, Australia. Tel.: +61 298457705.
E-mail address: mark.douglas@sydney.edu.au (M.W. Douglas).
genes actively contributing to oncogenesis [7,8]. This implies
that cancer development is usually a slow process, largely unaf-
fected by acute infections which resolve. For this reason, viruses
and bacteria with the potential to develop chronic infections are
significantly over-represented among tumourigenic pathogens
[9].
Cancer initiation during viral infection can generally be di-
vided into two categories, based on the capacity of the virus
to directly contribute to oncogenesis. Oncogenic viruses encode
proteins that stimulate cell proliferation and/or interfere with
cell apoptosis, and therefore play a direct role in carcinogene-
sis [10]. Most viral oncogenes target similar cell growth path-
ways to counteract the growth arrest that occurs in response
to viral infection. Other viral oncogenes inhibit apoptosis
and immune cell recognition, thus allowing ongoing viral
replication.
Viral carcinogenesis can also occur indirectly, if chronic infec-
tion leads to oxidative stress and inflammation [10]. Cytokine
secretion by the infected cell and surrounding tissues creates an
inflammatory milieu which can promote cancer development,
principally mediated by IL-1B, TNF-a and IL-6 [4,11]. Inflammatory
stimuli and direct effects of the virus activate signalling pathways
responsible for cancer development, including NF-jB, STAT3 and
the MAPKs [12,13].
Inflammation alone can increase the oncogenic potential of a
cell, but the combination of direct and indirect factors present dur-
ing chronic viral infections explains the high rates of virus-associ-
ated cancers. This review will focus on the role of virus-induced
inflammation in cancer development, highlighting the similarities
and differences among oncogenic viruses.

0304-3835/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.canlet.2013.07.030
 S.A. Read, M.W. Douglas / Cancer Letters 345 (2014) 174–181
2. Oncogenic viruses of the liver: HBV and HCV
HBV and HCV are both hepatotropic viruses which can establish
persistent infection. HCV is unusual among oncogenic viruses, as it
does not integrate into the host genome or demonstrate viral la-
tency, yet sustains chronic infection in approximately 50–80% of
untreated individuals [14]. Chronic HCV infection dramatically in-
creases the likelihood of developing liver fibrosis (scarring) and
steatosis (fat accumulation), with approximately 20% of patients
developing cirrhosis, and 4% developing hepatocellular carcinoma
(HCC) [15]. In countries where HBV is not endemic, including the
United States, Europe, Egypt and Japan, HCV contributes to 60%
of diagnosed HCC [16]. Conversely, approximately 54% of HCC
cases worldwide are attributed to HBV, particularly in endemic re-
gions such as East Asia and sub-Saharan Africa where up to 8% of
the population have chronic HBV infection [17–19].
HCV (Flaviviridae family) and HBV (Hepadnaviridae family) have
significantly different genomes, which contribute to their unique
mechanisms of establishing chronic infection in the liver and even-
tually cancer. The HCV genome is a single positive RNA strand,
which is replicated by a low fidelity RNA polymerase, creating a
diverse population of quasispecies capable of evading the immune
response [20,21]. In contrast, after entering the nucleus, the double
stranded DNA HBV genome forms covalently closed circular DNA
(cccDNA), which is very stable and persists as an episome
[18,22]. HBV is capable of integrating into the host genome [23],
which is not required for HBV oncogenesis, but is seen in approx-
imately 80% of HBV related HCCs, and increases in frequency with
chronic inflammation [24,25].
Both HBV and HCV encode proteins that affect signalling path-
ways mediating cell growth, apoptosis and antiviral immunity,
thus favouring viral replication and facilitating chronic infection.
Most notable are the HCV proteins core, NS5A and NS3/4A; and
HBV proteins HBx and pre-S2. These proteins restrict immune rec-
ognition and response, increase cell survival and proliferation, and
inhibit apoptosis [16,26]. However, HCC resulting from HCV and
HBV infection typically takes decades to develop, and is often asso-
ciated with cirrhosis and steatosis [18,27,28]. Therefore the main
driving force in HBV and HCV induced liver cancer is most likely
chronic liver damage, resulting from years of inflammation, oxida-
tive stress, cell death and regeneration [16,29,30].
A major source of harmful, pro-inflammatory cytokines during
chronic HBV/HCV infection is liver infiltrating lymphocytes [31].
Viral persistence causes enrichment in the liver of both pro-inflam-
matory T cells and innate immune lymphocytes, including natural
killer (NK) cells [32,33]. Many infiltrating lymphocytes display a
high level of activation and low level of specificity, resulting in
the inflammatory pathologies associated with chronic infection
[31]. Following HBV and HCV infection, hepatocytes and infiltrat-
ing lymphocytes secrete increased amounts of TNF-a, IL-6 and
IL-1b, all of which are associated with HCC development and pro-
gression [34–39].
Inflammation and leukocyte infiltration trigger activation of
resident hepatic stellate cells, making them responsive to trans-
forming growth factor b (TGF-b) [40,41]. TGF-b promotes hepatic
fibrogenesis and apoptosis, and is associated with HCC carcinogen-
esis, progression and prognosis [42,43]. Interestingly, both HBV
and HCV increase TGF-b mediated signalling, but shift it from a tu-
mour suppressive (apoptotic) phenotype to a proliferative, pro-fi-
brotic phenotype [41,44,45].
HBV and HCV induced inflammation is tightly linked to oxida-
tive stress [18,30]. Both HBV and HCV infection induce endoplas-
mic reticulum (ER) stress, which increases intracellular levels of
reactive oxygen species (ROS), leading to an increase in inflamma-
tory gene expression by activating NF-jB, AP-1 and STAT3 [46–50].
175
HCV core induces lipid accumulation, increases ROS and inflamma-
tion due to lipid peroxidation, and promotes development of HCC
in transgenic mice [51,52]. Inflammation associated NF-jB not
only promotes growth and suppresses apoptosis, but stimulates
growth factor production, resulting in oncogenesis and cancer pro-
gression [53]. Pro-apoptotic JNK signalling is also activated by
inflammation, but during chronic viral hepatitis is likely inhibited
by viral oncoproteins [16]. Since HBV and HCV do not infect the en-
tire liver, JNK signalling in uninfected ‘‘bystander’’ hepatocytes
may result in cell death, as they lack ‘‘protective’’ viral oncopro-
teins [54,55]. The death of uninfected hepatocytes appears to drive
compensatory cell proliferation, further stimulating cancer pro-
gression [56].
Taken together, these data demonstrate that chronic HBV/HCV
infection induces an inflammatory phenotype, characterised by
perpetual cell death and regeneration in the liver. Antiviral treat-
ment to reduce viral replication can considerably reduce inflam-
mation in the liver, but is expensive and can be associated with
side effects [57]. There is nonetheless hope for reduced HCC rates
in the future as antiviral treatments improve. The development
of direct acting antivirals against HCV has increased cure rates to
over 70%. The likely availability of all oral, interferon free options
in the next few years would provide effective, convenient treat-
ment with fewer side effects, which should increase community
take up rates and reduce HCC incidence. New oral antivirals against
HBV effectively inhibit viral replication for many years, with min-
imal side effects, reducing the risk of HCC. However complete erad-
ication of HBV with treatment is still rare, reinforcing the
importance of HBV vaccination and education programs [58,59].
3. Human T lymphotropic virus (HTLV-1)
Following an exhaustive worldwide search for a human retrovi-
rus, HTLV-1 was identified in 1980 [60,61]. HTLV-1 was the first
retrovirus to be associated with human cancer, termed adult T-cell
leukaemia (ATL) [62]. The HTLV-1 genome is positive sense RNA,
which is reverse transcribed and integrates randomly into the gen-
ome of predominantly CD4+ T cells [63]. Following integration, clo-
nal expansion of the infected T cells is induced by the viral trans-
activator protein Tax, which interferes with the NF-jB, AKT, p53
and pRb signalling pathways, to name a few [64]. Although Tax
is required to immortalise cells in vitro, it is often silenced follow-
ing progression of ATL in vivo, and is seen in only 40% of cases
[65,66]. Conversely, viral HTLV-1 basic leucine zipper factor
(HBZ) transcripts are found in all ATLs, and it is thought that HBZ
may be responsible for maintaining the leukaemic state [67].
HTLV-1 Tax and HBZ contribute directly to T cell oncogenesis
by increasing growth potential, modulating immune recognition
and increasing genetic instability. Nonetheless, HTLV-1 induced
ATL is rare, occurring in only 5–10% of infected individuals over
a lifetime [60,63]. Persistent activation of NF-jB by the Tax pro-
tein occurs following HTLV-1 infection in vitro and in vivo, and
contributes significantly to the oncogenic potential of the virus
[68,69]. Tax activates IKK, which phosphorylates the IjB regula-
tors of NF-jB, targeting them for proteosomal degradation and
activating NF-jB [70–72]. HBZ on the other hand does not affect
the regulatory components of NFjB signalling, and instead inhib-
its the canonical NF-jB pathway by interacting directly with p65,
leaving the non-canonical pathway stimulated by the Tax protein
alone [73].
HTLV-1 stimulates the expression of a number of cytokines that
stimulate both the canonical and non-canonical NF-jB pathways,
including IL-1, IFN-c, TNF-a/b, and Bcl-3 [74–78]. However, few
studies have examined the association between inflammatory
cytokine production and ATL initiation and progression. Elevated
176 S.A. Read, M.W. Douglas / Cancer Letters 345 (2014) 174–181
TNF-a expression, as a result of genetic polymorphism of the TNF-
a gene, has been shown to enhance the susceptibility of some Jap-
anese patients to ATL [79]. Inflammatory cytokines IFN-c and TNF-
a produced by infected CD4+ T cells have in fact been shown to
weaken the anti-inflammatory Th2 immune response to infection,
which may indirectly promote the oncogenic potential of HTLV-1
[80,81].
In summary, it appears that HTLV-1 associated ATL results pri-
marily from proviral oncogene expression, but may be facilitated
by virus-induced inflammation. Viral Tax and HBZ proteins are ex-
pressed at different phases during the progression of ATL, and ap-
pear to have opposing effects on a number of cell growth, immune
response and inflammatory pathways [82]. Additional research is
required to further understand the influence of these viral proteins
as well as external inflammatory stimuli on ATL development and
progression.
4. EBV
EBV infects 90% of the world’s population, primarily as an
asymptomatic infection in childhood [83]. Infection at a later stage
(often adolescence) results in infectious mononucleosis, character-
ised by fever, pharyngitis and/or tonsillitis, and tender cervical
lymphadenopathy [84]. EBV preferentially infects B lymphocytes,
but has also been shown to infect other cells types, primarily epi-
thelial cells [85,86]. Following acute infection, EBV establishes la-
tent infection in B lymphocytes, which persists for life. Infected
cells carry multiple episomal copies of the EBV genome, which ex-
press different subsets of viral genes, depending on the degree of
latency [87].
EBV infection is linked to a number of cancers, including Hodg-
kin’s lymphoma (HL), Burkitt’s lymphoma (BL), lymphomas in
immunosuppressed individuals, and a number of carcinomas
[87]. Interestingly, none of the EBV associated cancers are strongly
linked to inflammation apart from HL, which is strongly associated
with an inflammatory phenotype [88,89].
A number of viral genes have been linked to the oncogenic ef-
fect of EBV, but only the viral proteins latent membrane protein
1 (LMP1) and Epstein–Barr nuclear antigen 2 (EBNA2) induce cell
immortalisation [90–93]. EBNA2 regulates viral gene expression
and activates the notch signalling pathway to stimulate cell prolif-
eration, but is highly immunogenic and is rarely expressed in lym-
phomas [88,94]. LMP1 activates the TNF-a signalling pathway, by
interacting with signalling intermediates downstream of the
TNF-a receptor (TNFR), subsequently activating NF-jB and result-
ing in production of IL-6 [95,96]. In fact, NF-jB appears to be
central to the development and pathogenesis of HL, inducing the
expression of a number of pro-inflammatory and immune stimula-
tory cytokines [97,98].
Hodgkin’s lymphoma is characterised by malignant B cells
termed Hodgkin and Reed–Sternberg (HRS) cells, surrounded by
a large infiltrate of diverse, non-malignant inflammatory cells.
Cytokine signalling between HRS and the inflammatory infiltrate
is crucial to the survival of HRS cells, as cell death results from
its disruption in vitro [99]. Inflammatory cytokines, including IL-
5, IL-6, IL-7, IL-13, TNF-a, CCL5 (RANTES) and CCL28, contribute di-
rectly to disease progression. These cytokines recruit eosinophils,
monocytes, T cells and mast cells to the site of tumour develop-
ment, inducing their differentiation and proliferation [100–104].
EBV infected HRS cells also express significantly more IL-10 than
uninfected lymphocytes, inhibiting T cell activation and prolifera-
tion [105,106]. A viral homologue of IL-10 (vIL-10) is also ex-
pressed by EBV infected cells, but demonstrates a much weaker
affinity for the IL-10R and functions primarily to induce B cell pro-
liferation [107,108].
Approximately a third of HL cases are associated with EBV
infection, however HL by nature is mediated by inflammation
[109]. Inhibitors of NF-jB and STAT3 significantly decrease the
viability of lymphoma cells, both in vitro and in LMP1 transgenic
mice, supporting the role of inflammatory stimuli in EBV medi-
ated cancer progression [110,111]. The particular reliance of
HRS cell on inflammatory mediators and immune cell recruit-
ment for survival warrants further study, supporting the clinical
investigation of inflammatory signalling inhibitors for HL
treatment.
5. KSHV
Like EBV, KSHV is a gamma herpes virus that usually remains
latent as a nuclear episome, with occasional viral reactivation fol-
lowed by lytic replication. However unlike EBV, KSHV is usually
oncogenic only in immunosuppressed patients, either as a result
of AIDS or following organ transplant [112–114]. KSHV is associ-
ated with the development of Kaposi’s sarcoma (KS), primary effu-
sion lymphoma (PEL) and multicentric Castleman’s disease (MCD)
[115]. KSHV infection is more common in HIV infected homosexual
men, with prevalence rates of up to 30–65%, compared with 10–
15% in the general population [116].
The KHSV DNA genome consists of approximately 140 kilobases
and encodes over 90 open reading frames (ORFs) [117]. A signifi-
cant number of KSHV genes (representing 30% of the viral genome)
encode viral homologues of human genes, many of which interact
with inflammatory and immune signalling pathways, including
viral interferon regulatory factors (vIRFs) 1–4, viral interleukin 6
(vIL-6) and viral Fas-associated death domain-like IL-1-converting
enzyme inhibitory protein (vFLIP) [118]. vFLIP in particular has
been shown to induce NF-jB activation, possibly through the TNFR
signalling pathway, which increases survival and tumour forma-
tion in KSHV induced lymphomas [119–122]. Interestingly, vFLIP
and NF-jB activation correlate with in vitro expression of the che-
mokine CCL20 and its receptor CCL6, both of which are upregulated
in clinical samples of KS [123]. CCL20 is responsible for dendritic
cell and lymphocyte recruitment, suggesting that it may contribute
to the inflammatory infiltrate observed in KS lesions prior to trans-
formation [123,124].
The KS protein vIL-6 is a homologue of the human IL-6 protein;
it is expressed at low levels during latent infection but increases
during lytic replication [125]. vIL-6 has been shown to promote
angiogenesis and tumour growth in a T cell deficient mouse model,
but its limited expression during KSHV latency suggests that it
contributes differently to development of KS, PEL and MCD [126].
In KS tissue, vIL-6 is rarely detected; however cellular IL-6 is ex-
pressed, induced by viral proteins vFLIP and vPCR, via activation
of JNK signalling [127,128]. PEL tissues contain high levels of vIL-
6, stimulated by hypoxia-induced reactivation of KSHV [129,130],
as well as cellular IL-6 and IL-10, which promote autocrine growth
of PEL cells [130,131]. The waxing and waning inflammation that
often occurs in patients with MCD is attributed to vIL-6, IL-6 and
IL-10, expression of which correlate with the degree of inflamma-
tion [132].
Thus, although KS is clearly associated with KSHV infection,
immunosuppression favouring viral replication and oncogene
expression may be the most important contributor to cancer devel-
opment. Combined antiretroviral therapy (cART) for HIV infected
individuals has significantly reduced KS incidence, following an
increase of the CD4+ cell count [133]. Conversely, when KS occurs
in the post-transplant setting due to cyclosporine induced
 S.A. Read, M.W. Douglas / Cancer Letters 345 (2014) 174–181
immunosuppression, cyclosporine can be changed to rapamycin, a
mammalian target of rapamycin (mTOR) inhibitor, which
demonstrates anti-tumour as well as immunosuppressive activity
[134].
6. HPV
HPVs belong to the Papillomaviridae family, and are a diverse
group of small non-enveloped dsDNA viruses. The 120 types of
HPV identified to date can be subdivided based on their tissue tro-
pism, infecting either cutaneous or internal mucosal surfaces
[135]. The mucosal HPV types have further been divided based
on their oncogenic potential, with low risk types generally causing
benign genital warts, and high risk types associated with neoplasia
and subsequent cancers. High risk HPV types 16 and 18 account for
approximately 50% and 20% of cervical and ano-genital cancers,
respectively [136].
The potent tumourigenic potential of HPV is primarily the re-
sult of its tissue tropism, followed by its ability to establish per-
sistent infection. HPV infects basal keratinocytes, which become
mitotically inactive during differentiation, and therefore under
highly regulated transcriptional control. To facilitate the replica-
tion of its own DNA, HPV initiates cell growth by stimulating the
production and activation of cellular transcription factors
[137,138]. Growth deregulation seems to be initiated by the
HPV proteins E6 and E7, which interact with cellular proteins
p53 and pRb, are present in all cervical tumour samples, and
whose expression can immortalise primary human keratinocytes
in vitro [137,139–141]. Fortunately, the expression of E6 and E7
is not sufficient to immortalise cells in vivo, and additional host
cell mutations are required [10,142,143]. E5, E6 and E7 from the
highly oncogenic HPV type 16 have also been shown to induce
cyclooxygenase (COX) expression, with subsequent synthesis of
prostaglandins (PG) [144–146]. Prostaglandins are lipid media-
tors of tissue remodelling associated with inflammation, and
have been shown in many models to contribute to cancer forma-
tion and progression [147].
Following HPV infection, numerous cytokines are produced by
the infected and neighbouring keratinocytes, as well as by infil-
trating immune cells, including macrophages, natural killer cells
and lymphocytes [148]. Type I/II IFNs, TNF-a and IL-1 are all
produced in response to HPV infection, and all demonstrate anti-
viral activity in vitro, yet HPV is able to avoid the immune sys-
tem and establish persistent infection in a small subgroup of
people [149–151]. It remains poorly understood why some pa-
tients develop chronic HPV infection, but the mechanisms of vir-
al persistence likely include avoiding immune recognition and
inhibiting the immune response. HPV proteins E6 and E7 are
most likely involved, as they can inhibit IFN promoter activation,
through interactions with a number of signalling intermediates,
including interferon regulatory factors (IRFs) and STATs (re-
viewed in [152]).
Interestingly, it has been suggested that both TNF-a and IL-6
signalling are interrupted in HPV-16 infected cells, thus increas-
ing their growth potential. Resistance to TNF-a and resulting
NF-jB activation appears to be mediated by both E6 and E7,
which limit respectively its apoptotic and anti-proliferative ef-
fects [153–155]. Other reports suggest that HPV-18 but not
HPV-16 immortalized cell lines are resistant to TNF-a [156,157].
This is further complicated by evidence suggesting that TNF-a
stimulates the proliferation of both HPV-16 and -18 transformed
keratinocytes [158,159].The role of TNF-a in HPV oncogenesis
clearly requires further study in relation to viral genotype and cell
line resistance to TNF-a. High levels of IL-6 are seen in HPV in-
177
fected carcinoma cells, but with minimal downstream activation
of STAT3 [160]. It has been suggested that E6/E7 induced inter-
ruption of IL-6 signalling suppresses expression of monocyte che-
mo-attractant protein-1, limiting monocyte recruitment
[161,162]. Nonetheless, like TNF-a, elevated levels of IL-6 contrib-
ute to the increased incidence of cervical cancer associated with
HPV infection [163–165].
Unlike other oncogenic viruses, HPV replicates as the infected
keratinocytes differentiate, without virus particle release into the
bloodstream, and thus minimal immune recognition. To facilitate
this replication strategy, HPV down-regulates inflammatory signal-
ling, but inflammatory cytokines still seem to contribute to cancer
progression. In high risk individuals with HPV, co-infection with
other sexually transmitted infections induces inflammation, and
may therefore contribute to cancer initiation and progression
[166].
7. Conclusions
Chronic viral infection is increasingly being recognised as a
leading cause of cancer worldwide. As well as the direct oncogenic
role of some viruses, ongoing inflammation stimulated by chronic
viral infections also contributes significantly to tumour formation.
In addition to the viruses discussed above, mounting evidence now
implicates other viruses in the development of human cancers.
These include Merkel cell polyomavirus, which has been associated
with the majority of Merkel cell carcinomas following immunosup-
pression [167,168], as well as members of the Adenoviridae family,
human mammary tumour virus (HMTV), and human endogenous
retroviruses (HERVs) [169].
Identifying viruses that induce cancer provides an opportu-
nity for cancer prevention, either by preventing or treating
the virus infection. Vaccines against HBV and HPV are becom-
ing increasingly available worldwide, and have significantly re-
duced transmission of these viruses [58,170]. Long term
antiviral therapy against HBV inhibits virus replication and re-
duces the risk of HCC development and recurrence [171–173].
Public Health interventions can also reduce transmission of
viruses such as HCV and HTLV-1, but have proven less effective
against endemic viruses such as EBV. Conversely, for viruses
where vaccines and/or specific antiviral treatments are not
available, drugs targeting host inflammatory pathways, medi-
ated by NF-jB and STAT3, can significantly reduce cancer
development and progression [174,175]. The benefits of low
dose aspirin in particular are becoming increasingly apparent
for the prevention and treatment of multiple cancers
[174,176]. Unfortunately, often the countries with the highest
rates of chronic viral infections are those least able to afford
expensive antiviral treatment, which is typically prolonged. In-
creased dietary intake of natural anti-inflammatory agents
may provide some protection against virus induced cancers,
as has been demonstrated with curcumin in turmeric and res-
veratrol in grapes [177,178]. Furthermore, inhibitors of inflam-
mation often target pathways utilised by oncogenic viruses to
establish persistent infections, suggesting that they may not
only reduce the incidence of virus mediated cancer, but also
synergise with ongoing antiviral treatment.
In summary, many cancers are caused by viral infection, either
through direct oncogenic effects or via virus-induced inflammation
(see Figure 1). A better understanding of the interactions between
viruses and their hosts therefore provides an opportunity to pre-
vent many cancer deaths around the world, through a combination
of Public Health interventions, anti-inflammatory treatment and
specific antiviral drugs.
178 S.A. Read, M.W. Douglas / Cancer Letters 345 (2014) 174–181

Fig. 1. Inflammation resulting from chronic viral infection contributes to cancer development. Following infection, oncogenic viruses utilise a number of mechanisms to
evade the host immune system, occasionally resulting in chronic infection. Chronic activation of inflammatory signalling can result, mediated directly by the virus or
indirectly as a result of viral propagation. Direct activation of inflammation is generally mediated by viral proteins capable of activating inflammatory signalling cascades and/
or host inflammatory cytokines. Conversely, some oncogenic viruses possess viral homologues of human inflammatory cytokines including vIL-6 (KSHV) and vIL-10 (EBV).
The hepatotrophic viruses HBV and HCV especially, induce significant indirect inflammation as a result of viral replication induced ROS, lipid accumulation and immune
recognition. As a result, a substantial amount of cell death and resulting hepatocyte regeneration occurs that contributes to cancer progression.

Conflict of interest
None.
References
[1] D.M. Parkin, The global health burden of infection-associated cancers in the
year, Int. J. Cancer 118 (2006) (2002) 3030–3044.
[2] H. zur Hausen, Viruses in human cancers, Curr. Sci. 81 (2001) 523–527.
[3] S.I. Grivennikov, F.R. Greten, M. Karin, Immunity, inflammation, and cancer,
Cell 140 (2010) 883–899.
[4] A. Kuraishy, M. Karin, S.I. Grivennikov, Tumor promotion via injury- and
death-induced inflammation, Immunity 35 (2011) 467–477.
[5] B.B. Aggarwal, S. Shishodia, S.K. Sandur, M.K. Pandey, G. Sethi, Inflammation
and cancer: how hot is the link?, Biochem Pharmacol. 72 (2006) 1605–1621.
[6] A. Mantovani, Cancer: inflammation by remote control, Nature 435 (2005)
752–753.
[7] E.D. Pleasance, P.J. Stephens, S. O’Meara, D.J. McBride, A. Meynert, D. Jones,
M.L. Lin, D. Beare, K.W. Lau, C. Greenman, I. Varela, S. Nik-Zainal, H.R. Davies,
G.R. Ordonez, L.J. Mudie, C. Latimer, S. Edkins, L. Stebbings, L. Chen, M. Jia, C.
Leroy, J. Marshall, A. Menzies, A. Butler, J.W. Teague, J. Mangion, Y.A. Sun, S.F.
McLaughlin, H.E. Peckham, E.F. Tsung, G.L. Costa, C.C. Lee, J.D. Minna, A.
Gazdar, E. Birney, M.D. Rhodes, K.J. McKernan, M.R. Stratton, P.A. Futreal, P.J.
Campbell, A small-cell lung cancer genome with complex signatures of
tobacco exposure, Nature 463 (2010) 184–190.
[8] P.J. Stephens, D.J. McBride, M.L. Lin, I. Varela, E.D. Pleasance, J.T. Simpson, L.A.
Stebbings, C. Leroy, S. Edkins, L.J. Mudie, C.D. Greenman, M. Jia, C. Latimer,
J.W. Teague, K.W. Lau, J. Burton, M.A. Quail, H. Swerdlow, C. Churcher, R.
Natrajan, A.M. Sieuwerts, J.W. Martens, D.P. Silver, A. Langerod, H.E. Russnes,
J.A. Foekens, J.S. Reis-Filho, L. van’t Veer, A.L. Richardson, A.L. Borresen-Dale,
P.J. Campbell, P.A. Futreal, M.R. Stratton, Complex landscapes of somatic
rearrangement in human breast cancer genomes, Nature 462 (2009) 1005–
1010.
[9] C. de Martel, S. Franceschi, Infections and cancer: established associations and
new hypotheses, Crit. Rev. Oncol. Hematol. 70 (2009) 183–194.
[10] P.S. Moore, Y. Chang, Why do viruses cause cancer? Highlights of the first
century of human tumour virology, Nat. Rev. Cancer 10 (2010) 878–
889.
[11] Y. Ben-Neriah, M. Karin, Inflammation meets cancer, with NF-kappaB as the
matchmaker, Nat. Immunol. 12 (2011) 715–723.
 S.A. Read, M.W. Douglas / Cancer Letters 345 (2014) 174–181
[12] Y. Fan, R. Mao, J. Yang, NF-kappaB and STAT3 signaling pathways
collaboratively link inflammation to cancer, Protein Cell 4 (2013) 176–185.
[13] T. Chiba, H. Marusawa, T. Ushijima, Inflammation-associated cancer
development in digestive organs: mechanisms and roles for genetic and
epigenetic modulation, Gastroenterology 143 (2012) 550–563.
[14] S.M. Kamal, Acute hepatitis C: a systematic review, Am. J. Gastroenterol. 103
(2008) 1283–1297.
[15] D.L. Thomas, L.B. Seeff, Natural history of hepatitis, C. Clin. Liver. Dis. 9 (2005)
383–398.
[16] A. Arzumanyan, H.M. Reis, M.A. Feitelson, Pathogenic mechanisms in HBV-
and HCV-associated hepatocellular carcinoma, Nat. Rev. Cancer 13 (2013)
123–135.
[17] J. Ferlay, H.R. Shin, F. Bray, D. Forman, C. Mathers, D.M. Parkin, Estimates of
worldwide burden of cancer in 2008: GLOBOCAN, Int. J. Cancer 127 (2010)
(2008) 2893–2917.
[18] G. Fallot, C. Neuveut, M.A. Buendia, Diverse roles of hepatitis B virus in liver
cancer, Curr. Opin. Virol. 2 (2012) 467–473.
[19] L.R. Roberts, G.J. Gores, Hepatocellular carcinoma: molecular pathways and
new therapeutic targets, Semin. Liver Dis. 25 (2005) 212–225.
[20] T. Suzuki, H. Aizaki, K. Murakami, I. Shoji, T. Wakita, Molecular biology of
hepatitis C virus, J. Gastroenterol. 42 (2007) 411–423.
[21] P. Simmonds, Genetic diversity and evolution of hepatitis C virus – 15 years
on, J. Gen. Virol. 85 (2004) 3173–3188.
[22] D. Ganem, A.M. Prince, Hepatitis B virus infection – natural history and
clinical consequences, N. Engl. J. Med. 350 (2004) 1118–1129.
[23] M. Nassal, Hepatitis B viruses: reverse transcription a different way, Virus
Res. 134 (2008) 235–249.
[24] R. Bonilla Guerrero, L.R. Roberts, The role of hepatitis B virus integrations in
the pathogenesis of human hepatocellular carcinoma, J. Hepatol. 42 (2005)
760–777.
[25] C. Brechot, Pathogenesis of hepatitis B virus-related hepatocellular
carcinoma: old and new paradigms, Gastroenterology 127 (2004) S56–61.
[26] S.F. Wieland, F.V. Chisari, Stealth and cunning: hepatitis B and hepatitis C
viruses, J. Virol. 79 (2005) 9369–9380.
[27] S. Caldwell, S.H. Park, The epidemiology of hepatocellular cancer: from the
perspectives of public health problem to tumor biology, J. Gastroenterol. 44
(Suppl. 19) (2009) 96–101.
[28] J.R. Pekow, A.K. Bhan, H. Zheng, R.T. Chung, Hepatic steatosis is associated
with increased frequency of hepatocellular carcinoma in patients with
hepatitis C-related cirrhosis, Cancer 109 (2007) 2490–2496.
[29] B. Rehermann, M. Nascimbeni, Immunology of hepatitis B virus and hepatitis
C virus infection, Nat. Rev. Immunol. 5 (2005) 215–229.
[30] D.R. McGivern, S.M. Lemon, Virus-specific mechanisms of carcinogenesis in
hepatitis C virus associated liver cancer, Oncogene 30 (2011) 1969–1983.
[31] N.M. Valiante, A. D’Andrea, S. Crotta, F. Lechner, P. Klenerman, S. Nuti, A.
Wack, S. Abrignani, Life, activation and death of intrahepatic lymphocytes in
chronic hepatitis C, Immunol. Rev. 174 (2000) 77–89.
[32] L.G. Guidotti, T. Ishikawa, M.V. Hobbs, B. Matzke, R. Schreiber, F.V. Chisari,
Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes,
Immunity 4 (1996) 25–36.
[33] S. Nuti, D. Rosa, N.M. Valiante, G. Saletti, M. Caratozzolo, P. Dellabona, V.
Barnaba, S. Abrignani, Dynamics of intra-hepatic lymphocytes in chronic
hepatitis C: enrichment for Valpha24+ T cells and rapid elimination of
effector cells by apoptosis, Eur. J. Immunol. 28 (1998) 3448–3455.
[34] K. Falasca, C. Ucciferri, M. Dalessandro, P. Zingariello, P. Mancino, C. Petrarca,
E. Pizzigallo, P. Conti, J. Vecchiet, Cytokine patterns correlate with liver
damage in patients with chronic hepatitis B and C, Ann. Clin. Lab. Sci. 36
(2006) 144–150.
[35] R. Shukla, J. Yue, M. Siouda, T. Gheit, O. Hantz, P. Merle, F. Zoulim, V.
Krutovskikh, M. Tommasino, B.S. Sylla, Proinflammatory cytokine TNF-alpha
increases the stability of hepatitis B virus X protein through NF-kappaB
signaling, Carcinogenesis 32 (2011) 978–985.
[36] M.I. Radwan, H.F. Pasha, R.H. Mohamed, H.I. Hussien, M.N. El-Khshab,
Influence of transforming growth factor-beta1 and tumor necrosis factor-
alpha genes polymorphisms on the development of cirrhosis and
hepatocellular carcinoma in chronic hepatitis C patients, Cytokine 60
(2012) 271–276.
[37] K. Machida, H. Tsukamoto, J.C. Liu, Y.P. Han, S. Govindarajan, M.M. Lai, S.
Akira, J.H. Ou, C-Jun mediates hepatitis C virus hepatocarcinogenesis through
signal transducer and activator of transcription 3 and nitric oxide-dependent
impairment of oxidative DNA repair, Hepatology 52 (2010) 480–492.
[38] Y. Wang, N. Kato, Y. Hoshida, H. Yoshida, H. Taniguchi, T. Goto, M. Moriyama,
M. Otsuka, S. Shiina, Y. Shiratori, Y. Ito, M. Omata, Interleukin-1beta gene
polymorphisms associated with hepatocellular carcinoma in hepatitis C virus
infection, Hepatology 37 (2003) 65–71.
[39] R. Saxena, Y.K. Chawla, I. Verma, J. Kaur, Interleukin-1 polymorphism and
expression in hepatitis B virus-mediated disease outcome in India, J.
Interferon Cytokine Res. 33 (2013) 80–89.
[40] V. Hernandez-Gea, S.L. Friedman, Pathogenesis of liver fibrosis, Ann. Rev.
Pathol. 6 (2011) 425–456.
[41] K. Matsuzaki, Modulation of TGF-beta signaling during progression of chronic
liver diseases, Front Biosci. 14 (2009) 2923–2934.
[42] B.A. Teicher, Malignant cells, directors of the malignant process: role of
transforming growth factor-beta, Cancer Metastasis Rev. 20 (2001) 133–143.
[43] K. Okumoto, E. Hattori, K. Tamura, S. Kiso, H. Watanabe, K. Saito, T. Saito, H.
Togashi, S. Kawata, Possible contribution of circulating transforming growth
179
factor-beta1 to immunity and prognosis in unresectable hepatocellular
carcinoma, Liver Int. 24 (2004) 21–28.
[44] K. Matsuzaki, M. Murata, K. Yoshida, G. Sekimoto, Y. Uemura, N. Sakaida, M.
Kaibori, Y. Kamiyama, M. Nishizawa, J. Fujisawa, K. Okazaki, T. Seki, Chronic
inflammation associated with hepatitis C virus infection perturbs hepatic
transforming growth factor beta signaling, promoting cirrhosis and
hepatocellular carcinoma, Hepatology 46 (2007) 48–57.
[45] S. Battaglia, N. Benzoubir, S. Nobilet, P. Charneau, D. Samuel, A.L. Zignego, A.
Atfi, C. Brechot, M.F. Bourgeade, Liver cancer-derived hepatitis C virus core
proteins shift TGF-beta responses from tumor suppression to epithelial–
mesenchymal transition, PLoS One 4 (2009) e4355.
[46] G. Gong, G. Waris, R. Tanveer, A. Siddiqui, Human hepatitis C virus NS5A
protein alters intracellular calcium levels, induces oxidative stress, and
activates STAT-3 and NF-kappa B, Proc. Natl. Acad. Sci. USA 98 (2001) 9599–
9604.
[47] H.C. Wang, W. Huang, M.D. Lai, I.J. Su, Hepatitis B virus pre-S mutants,
endoplasmic reticulum stress and hepatocarcinogenesis, Cancer Sci. 97
(2006) 683–688.
[48] H.K. Cho, K.J. Cheong, H.Y. Kim, J. Cheong, Endoplasmic reticulum stress
induced by hepatitis B virus X protein enhances cyclo-oxygenase 2
expression via activating transcription factor 4, Biochem. J. 435 (2011)
431–439.
[49] I. Qadri, M. Iwahashi, J.M. Capasso, M.W. Hopken, S. Flores, J. Schaack, F.R.
Simon, Induced oxidative stress and activated expression of manganese
superoxide dismutase during hepatitis C virus replication: role of JNK, p38
MAPK and AP-1, Biochem. J. 378 (2004) 919–928.
[50] K.D. Tardif, K. Mori, A. Siddiqui, Hepatitis C virus subgenomic replicons
induce endoplasmic reticulum stress activating an intracellular signaling
pathway, J. Virol. 76 (2002) 7453–7459.
[51] K. Moriya, H. Fujie, Y. Shintani, H. Yotsuyanagi, T. Tsutsumi, K. Ishibashi, Y.
Matsuura, S. Kimura, T. Miyamura, K. Koike, The core protein of hepatitis C
virus induces hepatocellular carcinoma in transgenic mice, Nat. Med. 4
(1998) 1065–1067.
[52] M. Okuda, K. Li, M.R. Beard, L.A. Showalter, F. Scholle, S.M. Lemon, S.A.
Weinman, Mitochondrial injury, oxidative stress, and antioxidant gene
expression are induced by hepatitis C virus core protein, Gastroenterology
122 (2002) 366–375.
[53] S.P. Hussain, L.J. Hofseth, C.C. Harris, Radical causes of cancer, Nat. Rev. Cancer
3 (2003) 276–285.
[54] J.D. Stiffler, M. Nguyen, J.A. Sohn, C. Liu, D. Kaplan, C. Seeger, Focal
distribution of hepatitis C virus RNA in infected livers, PLoS One 4 (2009)
e6661.
[55] E. Rodriguez-Inigo, L. Mariscal, J. Bartolome, I. Castillo, C. Navacerrada, N.
Ortiz-Movilla, M. Pardo, V. Carreno, Distribution of hepatitis B virus in the
liver of chronic hepatitis C patients with occult hepatitis B virus infection, J.
Med. Virol. 70 (2003) 571–580.
[56] F. Chen, JNK-induced apoptosis, compensatory growth, and cancer stem cells,
Cancer Res. 72 (2012) 379–386.
[57] I. Gentile, M.A. Carleo, F. Borgia, G. Castaldo, G. Borgia, The efficacy and safety
of telaprevir – a new protease inhibitor against hepatitis C virus, Expert Opin.
Investig Drugs 19 (2010) 151–159.
[58] J.J. Ott, G.A. Stevens, J. Groeger, S.T. Wiersma, Global epidemiology of
hepatitis B virus infection: new estimates of age-specific HBsAg
seroprevalence and endemicity, Vaccine 30 (2012) 2212–2219.
[59] W.P. Hofmann, S. Zeuzem, A new standard of care for the treatment of chronic
HCV infection, Nat. Rev. Gastroenterol. Hepatol 8 (2011) 257–264.
[60] R.C. Gallo, Research and discovery of the first human cancer virus, HTLV-1,
Best Pract. Res. Clin. Haematol. 24 (2011) 559–565.
[61] B.J. Poiesz, F.W. Ruscetti, A.F. Gazdar, P.A. Bunn, J.D. Minna, R.C. Gallo,
Detection and isolation of type C retrovirus particles from fresh and cultured
lymphocytes of a patient with cutaneous T-cell lymphoma, Proc. Natl. Acad.
Sci. USA 77 (1980) 7415–7419.
[62] Y. Hinuma, K. Nagata, M. Hanaoka, M. Nakai, T. Matsumoto, K.I. Kinoshita, S.
Shirakawa, I. Miyoshi, Adult T-cell leukemia: antigen in an ATL cell line and
detection of antibodies to the antigen in human sera, Proc. Natl. Acad. Sci.
USA 78 (1981) 6476–6480.
[63] L.B. Cook, M. Elemans, A.G. Rowan, B. Asquith, HTLV-1: persistence and
pathogenesis, Virology 435 (2013) 131–140.
[64] M. Boxus, L. Willems, Mechanisms of HTLV-1 persistence and transformation,
Br. J. Cancer 101 (2009) 1497–1501.
[65] T. Akagi, H. Ono, K. Shimotohno, Characterization of T cells immortalized by
Tax1 of human T-cell leukemia virus type 1, Blood 86 (1995) 4243–4249.
[66] Y. Furukawa, R. Kubota, M. Tara, S. Izumo, M. Osame, Existence of escape
mutant in HTLV-I tax during the development of adult T-cell leukemia, Blood
97 (2001) 987–993.
[67] Y. Satou, J. Yasunaga, M. Yoshida, M. Matsuoka, HTLV-I basic leucine zipper
factor gene mRNA supports proliferation of adult T cell leukemia cells, Proc.
Natl. Acad. Sci. USA 103 (2006) 720–725.
[68] M. Watanabe, T. Ohsugi, M. Shoda, T. Ishida, S. Aizawa, M. Maruyama-Nagai, A.
Utsunomiya, S. Koga, Y. Yamada, S. Kamihira, A. Okayama, H. Kikuchi, K. Uozumi,
K. Yamaguchi, M. Higashihara, K. Umezawa, T. Watanabe, R. Horie, Dual
targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ,
a potent and selective inhibitor of NF-kappaB, as a strategy for chemoprevention
and therapy of adult T-cell leukemia, Blood 106 (2005) 2462–2471.
[69] S.C. Sun, S. Yamaoka, Activation of NF-kappaB by HTLV-I and implications for
cell transformation, Oncogene 24 (2005) 5952–5964.
180 S.A. Read, M.W. Douglas / Cancer Letters 345 (2014) 174–181
[70] K. Leung, G.J. Nabel, HTLV-1 transactivator induces interleukin-2 receptor
expression through an NF-kappa B-like factor, Nature 333 (1988) 776–778.
[71] D.W. Ballard, E. Bohnlein, J.W. Lowenthal, Y. Wano, B.R. Franza, W.C. Greene,
HTLV-I tax induces cellular proteins that activate the kappa B element in the
IL-2 receptor alpha gene, Science 241 (1988) 1652–1655.
[72] Z. Qu, G. Xiao, Human T-cell lymphotropic virus: a model of NF-kappaB-
associated tumorigenesis, Viruses 3 (2011) 714–749.
[73] T. Zhao, J. Yasunaga, Y. Satou, M. Nakao, M. Takahashi, M. Fujii, M. Matsuoka,
Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the
classical pathway of NF-kappaB, Blood 113 (2009) 2755–2764.
[74] Y. Yamada, Y. Ohmoto, T. Hata, M. Yamamura, K. Murata, K. Tsukasaki, T.
Kohno, Y. Chen, S. Kamihira, M. Tomonaga, Features of the cytokines secreted
by adult T cell leukemia (ATL) cells, Leuk Lymphoma 21 (1996) 443–447.
[75] E.W. Harhaj, N.S. Harhaj, C. Grant, K. Mostoller, T. Alefantis, S.C. Sun, B.
Wigdahl, Human T cell leukemia virus type I Tax activates CD40 gene
expression via the NF-kappa B pathway, Virology 333 (2005) 145–158.
[76] M. Higuchi, T. Matsuda, N. Mori, Y. Yamada, R. Horie, T. Watanabe, M.
Takahashi, M. Oie, M. Fujii, Elevated expression of CD30 in adult T-cell
leukemia cell lines: possible role in constitutive NF-kappaB activation,
Retrovirology 2 (2005) 29.
[77] E.P. Cowan, R.K. Alexander, S. Daniel, F. Kashanchi, J.N. Brady, Induction of
tumor necrosis factor alpha in human neuronal cells by extracellular human
T-cell lymphotropic virus type 1 Tax, J. Virol. 71 (1997) 6982–6989.
[78] H. Albrecht, A.N. Shakhov, C.V. Jongeneel, Trans activation of the tumor
necrosis factor alpha promoter by the human T-cell leukemia virus type I
Tax1 protein, J. Virol. 66 (1992) 6191–6193.
[79] K. Tsukasaki, C.W. Miller, T. Kubota, S. Takeuchi, T. Fujimoto, S. Ikeda, M.
Tomonaga, H.P. Koeffler, Tumor necrosis factor alpha polymorphism
associated with increased susceptibility to development of adult T-cell
leukemia/lymphoma in human T-lymphotropic virus type 1 carriers, Cancer
Res. 61 (2001) 3770–3774.
[80] J.B. Guerreiro, S.B. Santos, D.J. Morgan, A.F. Porto, A.L. Muniz, J.L. Ho, A.L.
Teixeira Jr., M.M. Teixeira, E.M. Carvalho, Levels of serum chemokines
discriminate clinical myelopathy associated with human T lymphotropic
virus type 1 (HTLV-1)/tropical spastic paraparesis (HAM/TSP) disease from
HTLV-1 carrier state, Clin. Exp. Immunol. 145 (2006) 296–301.
[81] S. Tattermusch, C.R. Bangham, HTLV-1 infection: what determines the risk of
inflammatory disease?, Trends Microbiol 20 (2012) 494–500.
[82] T. Zhao, M. Matsuoka, HBZ and its roles in HTLV-1 oncogenesis, Front
Microbiol. 3 (2012) 247.
[83] B.G. Bajaj, M. Murakami, E.S. Robertson, Molecular biology of EBV in relationship
to AIDS-associated oncogenesis, Cancer Treat Res. 133 (2007) 141–162.
[84] T. Bravender, Epstein–Barr virus, cytomegalovirus, and infectious
mononucleosis, Adolesc. Med. State Art Rev. 21 (2010) 251–264 (ix).
[85] C.M. Borza, L.M. Hutt-Fletcher, Alternate replication in B cells and epithelial
cells switches tropism of Epstein–Barr virus, Nat. Med. 8 (2002) 594–
599.
[86] M.A. Epstein, B.G. Achong, Y.M. Barr, Virus particles in cultured lymphoblasts
from Burkitt’s lymphoma, Lancet 1 (1964) 702–703.
[87] L.S. Young, A.B. Rickinson, Epstein–Barr virus: 40 years on, Nat. Rev. Cancer 4
(2004) 757–768.
[88] N. Raab-Traub, Novel mechanisms of EBV-induced oncogenesis, Curr. Opin.
Virol. 2 (2012) 453–458.
[89] G. Khan, Epstein–Barr virus, cytokines, and inflammation: a cocktail for the
pathogenesis of Hodgkin’s lymphoma?, Exp Hematol. 34 (2006) 399–406.
[90] K.M. Kaye, K.M. Izumi, E. Kieff, Epstein–Barr virus latent membrane protein 1
is essential for B-lymphocyte growth transformation, Proc. Natl. Acad. Sci.
USA 90 (1993) 9150–9154.
[91] D. Wang, D. Liebowitz, E. Kieff, An EBV membrane protein expressed in
immortalized lymphocytes transforms established rodent cells, Cell 43
(1985) 831–840.
[92] J.I. Cohen, F. Wang, J. Mannick, E. Kieff, Epstein–Barr virus nuclear protein 2 is
a key determinant of lymphocyte transformation, Proc. Natl. Acad. Sci. USA 86
(1989) 9558–9562.
[93] W. Hammerschmidt, B. Sugden, Genetic analysis of immortalizing functions
of Epstein–Barr virus in human B lymphocytes, Nature 340 (1989) 393–397.
[94] U. Zimber-Strobl, L.J. Strobl, EBNA2 and Notch signalling in Epstein–Barr virus
mediated immortalization of B lymphocytes, Semin. Cancer Biol. 11 (2001)
423–434.
[95] A.G. Eliopoulos, M. Stack, C.W. Dawson, K.M. Kaye, L. Hodgkin, S. Sihota, M.
Rowe, L.S. Young, Epstein–Barr virus-encoded LMP1 and CD40 mediate IL-6
production in epithelial cells via an NF-kappaB pathway involving TNF
receptor-associated factors, Oncogene 14 (1997) 2899–2916.
[96] G. Mosialos, M. Birkenbach, R. Yalamanchili, T. VanArsdale, C. Ware, E. Kieff,
The Epstein–Barr virus transforming protein LMP1 engages signaling proteins
for the tumor necrosis factor receptor family, Cell 80 (1995) 389–399.
[97] M. Hinz, P. Lemke, I. Anagnostopoulos, C. Hacker, D. Krappmann, S. Mathas, B.
Dorken, M. Zenke, H. Stein, C. Scheidereit, Nuclear factor kappaB-dependent
gene expression profiling of Hodgkin’s disease tumor cells, pathogenetic
significance, and link to constitutive signal transducer and activator of
transcription 5a activity, J. Exp. Med. 196 (2002) 605–617.
[98] E. Maggio, A. van den Berg, A. Diepstra, J. Kluiver, L. Visser, S. Poppema,
Chemokines, cytokines and their receptors in Hodgkin’s lymphoma cell lines
and tissues, Ann. Oncol. 13 (Suppl. 1) (2002) 52–56.
[99] U. Kapp, J. Wolf, M. Hummel, M. Pawlita, C. von Kalle, F. Dallenbach, M.
Schwonzen, G.R. Krueger, N. Muller-Lantzsch, C. Fonatsch, et al., Hodgkin’s
lymphoma-derived tissue serially transplanted into severe combined
immunodeficient mice, Blood 82 (1993) 1247–1256.
[100] N. Tedla, P. Palladinetti, D. Wakefield, A. Lloyd, Abundant expression of
chemokines in malignant and infective human lymphadenopathies, Cytokine
11 (1999) 531–540.
[101] H. Hanamoto, T. Nakayama, H. Miyazato, S. Takegawa, K. Hieshima, Y. Tatsumi,
A. Kanamaru, O. Yoshie, Expression of CCL28 by Reed–Sternberg cells defines a
major subtype of classical Hodgkin’s disease with frequent infiltration of
eosinophils and/or plasma cells, Am J Pathol 164 (2004) 997–1006.
[102] M. Samoszuk, L. Nansen, Detection of interleukin-5 messenger RNA in Reed–
Sternberg cells of Hodgkin’s disease with eosinophilia, Blood 75 (1990) 13–16.
[103] H.D. Foss, H. Herbst, E. Oelmann, J. Samol, M. Grebe, T. Blankenstein, J.
Matthes, Z.H. Qin, B. Falini, S. Pileri, et al., Lymphotoxin, tumour necrosis
factor and interleukin-6 gene transcripts are present in Hodgkin and Reed–
Sternberg cells of most Hodgkin’s disease cases, Br. J. Haematol. 84 (1993)
627–635.
[104] H.D. Foss, M. Hummel, S. Gottstein, K. Ziemann, B. Falini, H. Herbst, H. Stein,
Frequent expression of IL-7 gene transcripts in tumor cells of classical
Hodgkin’s disease, Am. J. Pathol. 146 (1995) 33–39.
[105] H. Herbst, H.D. Foss, J. Samol, I. Araujo, H. Klotzbach, H. Krause, A.
Agathanggelou, G. Niedobitek, H. Stein, Frequent expression of interleukin-
10 by Epstein–Barr virus-harboring tumor cells of Hodgkin’s disease, Blood
87 (1996) 2918–2929.
[106] G.E. Brito-Melo, V. Peruhype-Magalhaes, A. Teixeira-Carvalho, E.F. Barbosa-
Stancioli, A.B. Carneiro-Proietti, B. Catalan-Soares, J.G. Ribas, O.A. Martins-
Filho, IL-10 produced by CD4+ and CD8+ T cells emerge as a putative
immunoregulatory mechanism to counterbalance the monocyte-derived
TNF-alpha and guarantee asymptomatic clinical status during chronic
HTLV-I infection, Clin. Exp. Immunol. 147 (2007) 35–44.
[107] S.I. Yoon, B.C. Jones, N.J. Logsdon, B.D. Harris, S. Kuruganti, M.R. Walter,
Epstein–Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading
to altered signaling properties, J. Biol. Chem. 287 (2012) 26586–26595.
[108] M.T. Bejarano, M.G. Masucci, Interleukin-10 abrogates the inhibition of
Epstein–Barr virus-induced B-cell transformation by memory T-cell
responses, Blood 92 (1998) 4256–4262.
[109] R.F. Jarrett, Viruses and Hodgkin’s lymphoma, Ann. Oncol. 13 (Suppl. 1)
(2002) 23–29.
[110] E. Cahir-McFarland, E. Kieff, NF-kappaB inhibition in EBV-transformed
lymphoblastoid cell lines, Recent Results Cancer Res. 159 (2002) 44–48.
[111] K.H. Shair, K.M. Bendt, R.H. Edwards, E.C. Bedford, J.N. Nielsen, N. Raab-Traub,
EBV latent membrane protein 1 activates Akt, NFkappaB, and Stat3 in B cell
lymphomas, PLoS Pathog. 3 (2007) e166.
[112] I. Penn, Kaposi’s sarcoma in organ transplant recipients: report of 20 cases,
Transplantation 27 (1979) 8–11.
[113] A.E. Friedman-Kien, Disseminated Kaposi’s sarcoma syndrome in young
homosexual men, J. Am. Acad. Dermatol. 5 (1981) 468–471.
[114] Y. Chang, E. Cesarman, M.S. Pessin, F. Lee, J. Culpepper, D.M. Knowles, P.S.
Moore, Identification of herpesvirus-like DNA sequences in AIDS-associated
Kaposi’s sarcoma, Science 266 (1994) 1865–1869.
[115] A. Hansen, C. Boshoff, D. Lagos, Kaposi sarcoma as a model of oncogenesis and
cancer treatment, Expert Rev. Anticancer Ther. 7 (2007) 211–220.
[116] J.N. Martin, Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 and
Kaposi sarcoma, Adv. Dent. Res. 23 (2011) 76–78.
[117] S.C. Verma, E.S. Robertson, Molecular biology and pathogenesis of Kaposi
sarcoma-associated herpesvirus, FEMS Microbiol. Lett. 222 (2003) 155–163.
[118] R. Holzerlandt, C. Orengo, P. Kellam, M.M. Alba, Identification of new
herpesvirus gene homologs in the human genome, Genome Res. 12 (2002)
1739–1748.
[119] I. Guasparri, H. Wu, E. Cesarman, The KSHV oncoprotein vFLIP contains a
TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling, EMBO
Rep. 7 (2006) 114–119.
[120] P. Chugh, H. Matta, S. Schamus, S. Zachariah, A. Kumar, J.A. Richardson, A.L.
Smith, P.M. Chaudhary, Constitutive NF-kappaB activation, normal Fas-induced
apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13
transgenic mice, Proc. Natl. Acad. Sci. USA 102 (2005) 12885–12890.
[121] P.M. Chaudhary, A. Jasmin, M.T. Eby, L. Hood, Modulation of the NF-kappa B
pathway by virally encoded death effector domains-containing proteins,
Oncogene 18 (1999) 5738–5746.
[122] I. Guasparri, S.A. Keller, E. Cesarman, KSHV vFLIP is essential for the survival
of infected lymphoma cells, J Exp. Med. 199 (2004) 993–1003.
[123] V. Punj, H. Matta, S. Schamus, T. Yang, Y. Chang, P.M. Chaudhary, Induction of
CCL20 production by Kaposi sarcoma-associated herpesvirus: role of viral
FLICE inhibitory protein K13-induced NF-kappaB activation, Blood 113
(2009) 5660–5668.
[124] B. Ensoli, M. Sturzl, Kaposi’s sarcoma: a result of the interplay among
inflammatory cytokines, angiogenic factors and viral agents, Cytokine
Growth Factor Rev. 9 (1998) 63–83.
[125] S. Sakakibara, G. Tosato, Viral interleukin-6: role in Kaposi’s sarcoma-
associated herpesvirus: associated malignancies, J. Interferon Cytokine Res.
31 (2011) 791–801.
[126] Y. Aoki, E.S. Jaffe, Y. Chang, K. Jones, J. Teruya-Feldstein, P.S. Moore, G. Tosato,
Angiogenesis and hematopoiesis induced by Kaposi’s sarcoma-associated
herpesvirus-encoded interleukin-6, Blood 93 (1999) 4034–4043.
[127] J. An, Y. Sun, R. Sun, M.B. Rettig, Kaposi’s sarcoma-associated herpesvirus
encoded vFLIP induces cellular IL-6 expression: the role of the NF-kappaB and
JNK/AP1 pathways, Oncogene 22 (2003) 3371–3385.
 S.A. Read, M.W. Douglas / Cancer Letters 345 (2014) 174–181
[128] S. Montaner, A. Sodhi, J.M. Servitja, A.K. Ramsdell, A. Barac, E.T. Sawai, J.S.
Gutkind, The small GTPase Rac1 links the Kaposi sarcoma-associated
herpesvirus vGPCR to cytokine secretion and paracrine neoplasia, Blood
104 (2004) 2903–2911.
[129] D.A. Davis, A.S. Rinderknecht, J.P. Zoeteweij, Y. Aoki, E.L. Read-Connole, G.
Tosato, A. Blauvelt, R. Yarchoan, Hypoxia induces lytic replication of Kaposi
sarcoma-associated herpesvirus, Blood 97 (2001) 3244–3250.
[130] Y. Aoki, R. Yarchoan, J. Braun, A. Iwamoto, G. Tosato, Viral and cellular
cytokines in AIDS-related malignant lymphomatous effusions, Blood 96
(2000) 1599–1601.
[131] K.D. Jones, Y. Aoki, Y. Chang, P.S. Moore, R. Yarchoan, G. Tosato, Involvement
of interleukin-10 (IL-10) and viral IL-6 in the spontaneous growth of Kaposi’s
sarcoma herpesvirus-associated infected primary effusion lymphoma cells,
Blood 94 (1999) 2871–2879.
[132] E. Oksenhendler, M. Duarte, J. Soulier, P. Cacoub, Y. Welker, J. Cadranel, D.
Cazals-Hatem, B. Autran, J.P. Clauvel, M. Raphael, Multicentric Castleman’s
disease in HIV infection: a clinical and pathological study of 20 patients, AIDS
10 (1996) 61–67.
[133] A.S. Semeere, N. Busakhala, J.N. Martin, Impact of antiretroviral therapy on
the incidence of Kaposi’s sarcoma in resource-rich and resource-limited
settings, Curr. Opin. Oncol. 24 (2012) 522–530.
[134] S.M. Hosseini-Moghaddam, A. Soleimanirahbar, T. Mazzulli, C. Rotstein, S.
Husain, Post renal transplantation Kaposi’s sarcoma: a review of its
epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy,
Transpl. Infect. Dis. 14 (2012) 338–345.
[135] H.U. Bernard, R.D. Burk, Z. Chen, K. van Doorslaer, H. Hausen, E.M. de Villiers,
Classification of papillomaviruses (PVs) based on 189 PV types and proposal
of taxonomic amendments, Virology 401 (2010) 70–79.
[136] D.M. Parkin, F. Bray, Chapter 2: The burden of HPV-related cancers, Vaccine
24 (Suppl. 3) (2006). S3/11-25.
[137] K. Munger, B.A. Werness, N. Dyson, W.C. Phelps, E. Harlow, P.M. Howley,
Complex formation of human papillomavirus E7 proteins with the
retinoblastoma tumor suppressor gene product, EMBO J. 8 (1989) 4099–
4105.
[138] D.J. McCance, R. Kopan, E. Fuchs, L.A. Laimins, Human papillomavirus type 16
alters human epithelial cell differentiation in vitro, Proc. Natl. Acad. Sci. USA
85 (1988) 7169–7173.
[139] M. Scheffner, B.A. Werness, J.M. Huibregtse, A.J. Levine, P.M. Howley, The E6
oncoprotein encoded by human papillomavirus types 16 and 18 promotes
the degradation of p53, Cell 63 (1990) 1129–1136.
[140] C.L. Halbert, G.W. Demers, D.A. Galloway, The E7 gene of human
papillomavirus type 16 is sufficient for immortalization of human epithelial
cells, J. Virol. 65 (1991) 473–478.
[141] K. Munger, W.C. Phelps, V. Bubb, P.M. Howley, R. Schlegel, The E6 and E7
genes of the human papillomavirus type 16 together are necessary and
sufficient for transformation of primary human keratinocytes, J. Virol. 63
(1989) 4417–4421.
[142] J.M. Arbeit, P.M. Howley, D. Hanahan, Chronic estrogen-induced cervical and
vaginal squamous carcinogenesis in human papillomavirus type 16
transgenic mice, Proc. Natl. Acad. Sci. USA 93 (1996) 2930–2935.
[143] A. Saha, R. Kaul, M. Murakami, E.S. Robertson, Tumor viruses and cancer
biology: modulating signaling pathways for therapeutic intervention, Cancer
Biol. Ther. 10 (2010) 961–978.
[144] J.M. Oh, S.H. Kim, E.A. Cho, Y.S. Song, W.H. Kim, Y.S. Juhnn, Human
papillomavirus type 16 E5 protein inhibits hydrogen-peroxide-induced
apoptosis by stimulating ubiquitin-proteasome-mediated degradation of
Bax in human cervical cancer cells, Carcinogenesis 31 (2010) 402–410.
[145] J.M. Oh, S.H. Kim, Y.I. Lee, M. Seo, S.Y. Kim, Y.S. Song, W.H. Kim, Y.S. Juhnn,
Human papillomavirus E5 protein induces expression of the EP4 subtype of
prostaglandin E2 receptor in cyclic AMP response element-dependent
pathways in cervical cancer cells, Carcinogenesis 30 (2009) 141–149.
[146] K. Subbaramaiah, A.J. Dannenberg, Cyclooxygenase-2 transcription is
regulated by human papillomavirus 16 E6 and E7 oncoproteins: evidence
of a corepressor/coactivator exchange, Cancer Res. 67 (2007) 3976–3985.
[147] D. Wang, R.N. Dubois, Prostaglandins and cancer, Gut 55 (2006) 115–122.
[148] P. Bhat, S.R. Mattarollo, C. Gosmann, I.H. Frazer, G.R. Leggatt, Regulation of
immune responses to HPV infection and during HPV-directed
immunotherapy, Immunol. Rev. 239 (2011) 85–98.
[149] P. Delvenne, W. al-Saleh, C. Gilles, A. Thiry, J. Boniver, Inhibition of growth of
normal and human papillomavirus-transformed keratinocytes in monolayer
and organotypic cultures by interferon-gamma and tumor necrosis factor-
alpha, Am. J. Pathol. 146 (1995) 589–598.
[150] S. Kyo, M. Inoue, N. Hayasaka, T. Inoue, M. Yutsudo, O. Tanizawa, A. Hakura,
Regulation of early gene expression of human papillomavirus type 16 by
inflammatory cytokines, Virology 200 (1994) 130–139.
[151] K.Y. Kim, L. Blatt, M.W. Taylor, The effects of interferon on the expression of
human papillomavirus oncogenes, J. Gen. Virol. 81 (2000) 695–700.
[152] R.W. Tindle, Immune evasion in human papillomavirus-associated cervical
cancer, Nat. Rev. Cancer 2 (2002) 59–65.
[153] E.R. Vandermark, K.A. Deluca, C.R. Gardner, D.F. Marker, C.N. Schreiner, D.A.
Strickland, K.M. Wilton, S. Mondal, C.D. Woodworth, Human papillomavirus
type 16 E6 and E 7 proteins alter NF-kB in cultured cervical epithelial cells
and inhibition of NF-kB promotes cell growth and immortalization, Virology
425 (2012) 53–60.
[154] J.R. Basile, V. Zacny, K. Munger, The cytokines tumor necrosis factor-alpha
(TNF-alpha) and TNF-related apoptosis-inducing ligand differentially
181
modulate proliferation and apoptotic pathways in human keratinocytes
expressing the human papillomavirus-16 E7 oncoprotein, J. Biol. Chem. 276
(2001) 22522–22528.
[155] P.J. Duerksen-Hughes, J. Yang, S.B. Schwartz, HPV 16 E6 blocks TNF-mediated
apoptosis in mouse fibroblast LM cells, Virology 264 (1999) 55–65.
[156] L.L. Villa, K.B. Vieira, X.F. Pei, R. Schlegel, Differential effect of tumor necrosis
factor on proliferation of primary human keratinocytes and cell lines containing
human papillomavirus types 16 and 18, Mol. Carcinog. 6 (1992) 5–9.
[157] K.B. Vieira, D.J. Goldstein, L.L. Villa, Tumor necrosis factor alpha interferes
with the cell cycle of normal and papillomavirus-immortalized human
keratinocytes, Cancer Res. 56 (1996) 2452–2457.
[158] C.D. Woodworth, E. McMullin, M. Iglesias, G.D. Plowman, Interleukin 1 alpha
and tumor necrosis factor alpha stimulate autocrine amphiregulin expression
and proliferation of human papillomavirus-immortalized and carcinoma-
derived cervical epithelial cells, Proc. Natl. Acad. Sci. USA 92 (1995) 2840–
2844.
[159] D. Gaiotti, J. Chung, M. Iglesias, M. Nees, P.D. Baker, C.H. Evans, C.D.
Woodworth, Tumor necrosis factor-alpha promotes human papillomavirus
(HPV) E6/E7 RNA expression and cyclin-dependent kinase activity in HPV-
immortalized keratinocytes by a ras-dependent pathway, Mol. Carcinog. 27
(2000) 97–109.
[160] S. Hess, H. Smola, U. Sandaradura De Silva, D. Hadaschik, D. Kube, S.E. Baldus,
U. Flucke, H. Pfister, Loss of IL-6 receptor expression in cervical carcinoma
cells inhibits autocrine IL-6 stimulation: abrogation of constitutive monocyte
chemoattractant protein-1 production, J. Immunol. 165 (2000) 1939–1948.
[161] K. Kleine-Lowinski, J.G. Rheinwald, R.N. Fichorova, D.J. Anderson, J. Basile, K.
Munger, C.M. Daly, F. Rosl, B.J. Rollins, Selective suppression of monocyte
chemoattractant protein-1 expression by human papillomavirus E6 and E7
oncoproteins in human cervical epithelial and epidermal cells, Int. J. Cancer
107 (2003) 407–415.
[162] E. Boccardo, A.P. Lepique, L.L. Villa, The role of inflammation in HPV
carcinogenesis, Carcinogenesis 31 (2010) 1905–1912.
[163] P.E. Castle, S.L. Hillier, L.K. Rabe, A. Hildesheim, R. Herrero, M.C. Bratti, M.E.
Sherman, R.D. Burk, A.C. Rodriguez, M. Alfaro, M.L. Hutchinson, J. Morales, M.
Schiffman, An association of cervical inflammation with high-grade cervical
neoplasia in women infected with oncogenic human papillomavirus (HPV),
Cancer Epidemiol. Biomarkers Prev. 10 (2001) 1021–1027.
[164] G. Castrilli, D. Tatone, M.G. Diodoro, S. Rosini, M. Piantelli, P. Musiani, Interleukin
1alpha and interleukin 6 promote the in vitro growth of both normal and
neoplastic human cervical epithelial cells, Br. J. Cancer 75 (1997) 855–859.
[165] E. Tartour, A. Gey, X. Sastre-Garau, C. Pannetier, V. Mosseri, P. Kourilsky, W.H.
Fridman, Analysis of interleukin 6 gene expression in cervical neoplasia using
a quantitative polymerase chain reaction assay: evidence for enhanced
interleukin 6 gene expression in invasive carcinoma, Cancer Res. 54 (1994)
6243–6248.
[166] V.M. Williams, M. Filippova, U. Soto, P.J. Duerksen-Hughes, HPV-DNA
integration and carcinogenesis: putative roles for inflammation and
oxidative stress, Future Virol. 6 (2011) 45–57.
[167] M.E. Spurgeon, P.F. Lambert, Merkel cell polyomavirus: a newly discovered
human virus with oncogenic potential, Virology 435 (2013) 118–130.
[168] R. Arora, Y. Chang, P.S. Moore, MCV and Merkel cell carcinoma: a molecular
success story, Curr. Opin. Virol. 2 (2012) 489–498.
[169] M.E. McLaughlin-Drubin, K. Munger, Viruses associated with human cancer,
Biochim. Biophys. Acta 1782 (2008) 127–150.
[170] A.C. Tricco, C.H. Ng, V. Gilca, A. Anonychuk, B. Pham, S. Berliner, Canadian
oncogenic human papillomavirus cervical infection prevalence: systematic
review and meta-analysis, BMC Infect. Dis. 11 (2011) 235.
[171] C.Y. Wu, Y.J. Chen, H.J. Ho, Y.C. Hsu, K.N. Kuo, M.S. Wu, J.T. Lin, Association
between nucleoside analogues and risk of hepatitis B virus-related
hepatocellular carcinoma recurrence following liver resection, JAMA 308
(2012) 1906–1914.
[172] Y.F. Liaw, J.J. Sung, W.C. Chow, G. Farrell, C.Z. Lee, H. Yuen, T. Tanwandee, Q.M.
Tao, K. Shue, O.N. Keene, J.S. Dixon, D.F. Gray, J. Sabbat, Lamivudine for
patients with chronic hepatitis B and advanced liver disease, N. Engl. J. Med.
351 (2004) 1521–1531.
[173] C.J. Chen, H.I. Yang, J. Su, C.L. Jen, S.L. You, S.N. Lu, G.T. Huang, U.H. Iloeje, Risk
of hepatocellular carcinoma across a biological gradient of serum hepatitis B
virus DNA level, JAMA 295 (2006) 65–73.
[174] P.M. Rothwell, F.G. Fowkes, J.F. Belch, H. Ogawa, C.P. Warlow, T.W. Meade,
Effect of daily aspirin on long-term risk of death due to cancer: analysis of
individual patient data from randomised trials, Lancet 377 (2011) 31–41.
[175] X. Wang, P.J. Crowe, D. Goldstein, J.L. Yang, STAT3 inhibition, a novel
approach to enhancing targeted therapy in human cancers (review), Int. J.
Oncol. (2012).
[176] A.M. Algra, P.M. Rothwell, Effects of regular aspirin on long-term cancer
incidence and metastasis: a systematic comparison of evidence from
observational studies versus randomised trials, Lancet Oncol. 13 (2012)
518–527.
[177] M. Jang, L. Cai, G.O. Udeani, K.V. Slowing, C.F. Thomas, C.W. Beecher, H.H.
Fong, N.R. Farnsworth, A.D. Kinghorn, R.G. Mehta, R.C. Moon, J.M. Pezzuto,
Cancer chemopreventive activity of resveratrol, a natural product derived
from grapes, Science 275 (1997) 218–220.
[178] S. Bengmark, Curcumin, an atoxic antioxidant and natural NFkappaB,
cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase
inhibitor: a shield against acute and chronic diseases, JPEN J. Parenter
Enteral Nutr. 30 (2006) 45–51.