Published OnlineFirst March 27, 2013; DOI: 10.1158/1078-0432.CCR-12-3661
Infection and Cancer: Revaluation of the Hygiene Hypothesis
Katerina Oikonomopoulou, Davor Brinc, Kyriacos Kyriacou, et al.
Clin Cancer Res Published OnlineFirst March 27, 2013.
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Clinical
Cancer
Research
Review
Infection and Cancer: Revaluation of the Hygiene Hypothesis
Katerina Oikonomopoulou1, Davor Brinc2, Kyriacos Kyriacou3, and Eleftherios P. Diamandis1,2
Abstract
Several studies have shown that persistent infections and inflammation can favor carcinogenesis. At the
same time, certain types of pathogens and antitumor immune responses can decrease the risk of
tumorigenesis or lead to cancer regression. Infectious agents and their products can orchestrate a wide
range of host immune responses, through which they may positively or negatively modulate cancer
development and/or progression. The factors that direct this dichotomous influence of infection-mediated
immunity on carcinogenesis are not well understood. Even though not universal, several previous reports
have investigated the inverse link of pathogen-induced "benign" inflammation to carcinogenesis and
various other pathologies, ranging from autoimmune diseases to allergy and cancer. Several models and
ideas are discussed in this review, including the impact of decreased exposure to pathogens, as well as the
influence of pathogen load, the timing of infection, and the type of instigated immune response on
carcinogenesis. These phenomena should guide future investigations into identifying novel targets within
the microbial and host proteome, which will assist in the development of cancer therapeutics and vaccine
remedies, analogous to earlier efforts based on helminthic components for the prevention and/or treatment
of several pathologies. Clin Cancer Res; 19(11); 1–8. 2013 AACR.
Introduction
Even though the course of carcinogenesis is undoubtedly
multifactorial, major attention has been attracted on the
role of infectious diseases and the immune system in cancer
development (1–4). Several types of carcinomas are related
to infections (2, 5), whereas inflammation is recognized as
one of the hallmarks of cancer (1, 6), and inclusion of
immunologic assessments in cancer classification and prognosis has been suggested (7, 8). In contrast, immune
responses, including those triggered by microorganisms,
are known to decrease cancer risk or lead to tumor regression. The relationship between infection and tumorigenesis
is not well understood, and both favorable and unfavorable
immune-mediated or direct anticarcinogenic microbial
effects have been observed. This review aims to provide an
update primarily on the inverse association between infections and cancer and provide clues for potential underlying
mechanisms. Attention is drawn to the hygiene hypothesis
that attempts to explain the increased incidence of pathol-
Authors' Affiliations: 1Department of Pathology and Laboratory Medicine,
Mount Sinai Hospital; 2Department of Clinical Biochemistry, University
Health Network, Toronto, Ontario, Canada; and 3Department of EM/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia,
Cyprus
K. Oikonomopoulou and D. Brinc contributed equally to this work.
Corresponding Author: Eleftherios P. Diamandis, Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, 60 Murray Street, Room
L6-201, Toronto, ON M5T 3L9. Phone: 416-586-4800, ext. 8813; Fax: 416619-5521; E-mail: ediamandis@mtsinai.on.ca
doi: 10.1158/1078-0432.CCR-12-3661
2013 American Association for Cancer Research.
ogies such as allergies, autoimmune diseases, and cancer in
the industrial world. Several historical observations and
other theories, such as hormesis (9) and concomitant
immunity (10), are revisited to lend more credence to the
hygiene hypothesis.
The Cancer Hygiene Hypothesis
Several decades ago, the hygiene hypothesis, referring to
the lack of exposure to microbes at childhood, was introduced to explain the higher numbers of allergic and autoimmune diseases in the Western world and urbanized
communities (11–14). More recently, the hygiene hypothesis has been restated to account for the association between
microorganisms and cancer (13). Following the same pattern observed with some immune pathologies, there is
growing evidence of an increased cancer incidence in Westernized economically developed countries (15). Socioeconomic status was also inversely associated with Hodgkin
lymphoma (16), and daycare attendance was associated
with a lower risk of acute lymphoblastic leukemia (17, 18).
The resemblance of the hygiene–immunopathology relationship to the one exhibited by hygiene and cancer is not
surprising, given that preliminary observations have associated tumorigenesis with chronic immune-mediated disorders (Table 1); for example, an increased risk of cancer
has been observed in patients with autoimmune disease
(19, 20), chronic allergic disorders have been connected to
pro- and antitumor effects (21–24), and allergic patients
with cancer have been suggested to exhibit higher cure rates
and more favorable disease progression (25). Some experimental evidence may also support the cancer hygiene
hypothesis, that is, the antitumorigenic role of several
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Table 1. Association between different
pathologies and cancer, based on
epidemiologic and experimental studies
Condition
Infections
Helminths and
protozoa
Viruses
Bacteria
Allergy
Autoimmune
diseases
Association
with cancer
References
Negativea
(13, 58, 80, 93–95)
Positiveb
Negativea
Positiveb
Negativea
Positiveb
Negativea
Positiveb
Positiveb
(43, 96, 97)
(57)
(2, 5, 13, 98)
(13, 26, 28, 47, 54–56)
(2, 5, 13, 27, 37, 98)
(21–24)
(21, 24)
(19, 20)
a
Negative: cancer prevention, cancer regression, decreased
cancer risk.
b
Positive: cancer promotion, increased cancer risk.
inflammatory components, the ability of some commensals
and benign gastrointestinal parasites like helminths to
downregulate inflammation, as well as the ability of pathogens and their products to stimulate anticancer immunity
(see sections below). However, the hygiene hypothesis, as
it stands, cannot rationalize why specific infectious agents
(e.g., Helicobacter pylori; refs. 26, 27) or microbial products
[e.g., lipopolysaccharide (LPS); refs. 28, 29] can exhibit
both pro- and anticarcinogenic functions and, therefore,
many questions remain unresolved.
Immune Responses to Infection and Cancer
Host immune response to pathogens generally involves
effectors preexisting locally in mucus (e.g., immunoglobulin A, antimicrobial peptides, lysozyme) or plasma (natural immunoglobulin M, complement), followed by activation of more specialized innate (e.g., macrophages,
granulocytes, dendritic, mast, natural killer cells) and
adaptive (T cells, B cells) immune processes, to facilitate
clearance of pathogens or reduction of their impact (30).
Innate immune cell activation can trigger phagocytosis,
release of antimicrobial compounds and proinflammatory cytokines, as well as lead to immune suppression,
fibrosis, angiogenesis, and wound healing (31). T cells,
following pathogen recognition and depending on the
antigen and local environment, develop into CTL or Thelper cells (TH), namely TH1, TH17, or TH2 cells, mediating different cytokine expression patterns, known as
classical (TH1, TH17) or alternative (TH2) inflammation
(32). TH cells also stimulate production of antibodies
from antigen-activated B cells. Another distinct cell subtype, regulatory T cells (Treg), particularly observed in
chronic parasitic infections (e.g., helminths), have a role
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Clin Cancer Res; 19(11) June 1, 2013
in preventing immune-mediated damage (33, 34). Notably, the immune response pattern can vary during the
infection course; in helminth infections, a TH1 to TH2
shift is commonly observed in parallel with infection
progression, and may also signal the reduced effectiveness
of a drug therapy (35, 36).
The various immune processes induced during infection
may also be implicated in cancer. In 1863, it was Rudolf
Virchow who showed the presence of leukocytes in neoplastic tissue (reviewed in ref. 37). Paul Ehrlich later suggested that the immune system continuously destroys spontaneously arising tumors (immune surveillance hypothesis), work that was updated by the cancer immunoediting
hypothesis, stating that the immune system has a significant
role in shaping the properties of an emerging tumor (38,
39). Both innate and adaptive immune cells are now known
to localize at tumor sites, with specific cell subsets, densities,
and intratumor locations being associated with cancer risk
or survival (8). Antibodies against tumor-associated antigens have also been detected in cancer patients’ sera (International SEREX Program, The Ludwig Institute for Cancer
Research, Uppsala, Sweden). However, although several
studies have considered the role of immunity in cancer
survival/progression, the idea that an existing infection may
further modulate the pro-/antitumorigenic immune effect
has been overlooked.
Infection as a Carcinogenic Factor
Some infectious agents can directly influence carcinogenesis; for instance, human papillomavirus protein E7 can
bind the retinoblastoma tumor suppressor and the cyclindependent kinase inhibitor p21 in infected cells, promoting
DNA replication and cell proliferation (40), whereas Hepatitis B virus can induce hypoxia-inducible factor-1a, stimulating angiogenesis (41). Pathogens may also promote
tumorigenesis indirectly (Table 1; refs. 3, 4), by activating
cancer-mediating host inflammatory pathways. The helminth Schistosoma haematobium can induce urothelial dysplasia and inflammation upon intravesical administration
in mice (42) and has been linked to bladder cancer (43). In
another example, Propionibacterium acnes, found in prostate
cancer and benign hyperplasia samples, when cocultured
with prostate epithelial cells results in production of proinflammatory cytokines, prostaglandins, and activated
matrix metalloproteinases, whereas long-term infection
leads to anchorage-independent cancer cell growth (44).
Inflammation induced by chronic infections may be able to
trigger mutations, epigenetic changes, and protein modifications that may lead to oncogene activation and tumor
suppressor inhibition (3). Apart from the typical infectious
agents, altered intestinal microbiota may also promote
carcinogenesis, DNA damage, and cell proliferation via
chronic inflammatory processes (45). Secretion of pathogen-induced cytokines may also have a dual role depending
on the settings; for example, TNFa can mediate tumor
hemorrhagic necrosis and regression (46, 47), whereas, on
the other hand, it can promote carcinogenesis if present in
a chronic fashion (48).
Clinical Cancer Research
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Infection and Cancer
In addition to giving rise to the inflammation-mediated
detrimental effects, pathogens may also promote tumorigenesis by inhibiting host anticancer immunity, for
instance, by stimulating production of immunosuppressive
cytokines [e.g., interleukin (IL)-10], causing T-cell apoptosis, promoting T-cell subtypes with attenuated antitumor
activity (e.g., TH2), or triggering recruitment of myeloid
suppressor cells and Tregs (49–52). Another potential effect
on antitumor immunity triggered by chronic infections,
also observed in cancer, is the dysfunction and subsequent
elimination of antigen-specific T cells, a phenomenon
called T-cell exhaustion (53).
Infection in Cancer Prevention
Several observations, reported as early as the 1700s,
support the link between infection-mediated inflammation
and cancer prevention or regression (Table 1); most notable are the efforts by William Coley in early 19th century to
vaccinate his patients with cancer with an attenuated bacterial mixture (Streptococcus pyogenes and Serratia marcescens)
that accomplished significant cure and favorable progression rates (47, 54). There is also evidence of the antitumor
effect of certain microbial products (e.g., LPS) and attenuated pathogen forms [e.g., Bacillus Calmette-Guerin (BCG)
vaccine; refs. 13, 28, 55]; more specifically, BCG, vaccinia,
or yellow fever virus vaccinations have been linked to melanoma protection (56, 57). In addition, infectious agents
have also been inversely associated with cancer (Table 1), as
in the case of Trypanosoma cruzi, which can result in lower
incidence of experimentally induced rodent colon cancer
(58). These observations support the protective action of
infections, as proposed by the hygiene hypothesis (11–14).
In the subsequent sections, we will expand on this discussion by suggesting potential mechanisms that are often
underestimated but may likely explain the favorable association of infection to carcinogenesis (Fig. 1).
Inlammation/Immunity
Suppression
Activation
Antigen cross-reactivity
Angiogenesis inhibition
Immune
cells
STOP
STOP
Pathogens
Carcinogen removal
Tumor
cells
Preexisting immunity
Low-dose High-dose
effects
effects
Pathogen-induced
antitumor
mechanisms
Hormetic effects
Tumor microenvironment
Threshold
© 2013 American Association for Cancer Research
Figure 1. Potential pathogen-mediated antitumor mechanisms. A microorganism may influence the fine balance between immunosuppression and
immunity against a concurrent or subsequent tumor by modulating the availability and presentation of cross-reactive antigens, by influencing induction of
preexisting immunity, and by shaping the components of the tumor microenvironment. The levels of microbe-triggered stimuli are also decisive factors on
the biphasic influence (pro- or anti-inflammatory) that a microorganism can have on immune functions. Several other mechanisms, such as removal of
carcinogens and restriction of tumor vascularization may also facilitate the beneficial antitumor effects of microbes on their host.
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Suppression of inflammation
Several microbial products (e.g., lysophosphatidylserine)
can have anti-inflammatory effects (34, 59); for instance,
they can suppress toll-like receptor signaling, inflammatory
cytokine and nitric oxide production, as well as inhibit
innate immune cell activation and stimulate production
of immunosuppressive cytokines and recruitment of Tregs.
In this regard, TH1 or TH2 responses to some helminth
infections rarely result in severe pathology (36) and can,
in fact, downregulate allergic or autoimmune pathology
(e.g., see ref. 60). However, immunosuppressive cytokines,
specifically, have pleiotropic effects on tumorigenesis either
by inhibiting inflammation-associated tumorigenesis or
by restricting antitumor immunity; for example, IL-10 is
known to either inhibit or promote tumor growth, as well
as facilitate tumor rejection in mice (61).
Promotion of antitumor immunity
Microorganisms may provide specific triggers (e.g., lowlevel endotoxin, commonly produced by many pathogens)
that increase antigenicity of nascent tumor cells, or keep
the immune cells in an "alerted" immunosurveillance state
(13). This phenomenon resembles the infection-mediated
stimulation of autoimmunity as a result of molecular mimicry, epitope spreading, exposure of cryptic antigens, or
bystander activation (62). Epitope spreading has been
observed in few cancer vaccine studies, i.e., following injection of dendritic cells in patients with melanoma (63). An
infection can also lead to tumor cell destruction, subsequent
release of tumor antigens, and activation of antigen-presenting cells. This could potentially trigger T-cell responses with
antitumor activities, like the ones that may be responsible
for the protective action of BCG (64). Moreover, potential
increases in tumor vascular permeability may also facilitate
the local recruitment of anticancer T cells (47). Heat shock
proteins expressed by stressed cells and found upregulated
in virus-infected and several cancer cells can also be immunogenic, thus influencing antitumor responses (65).
Presentation of cross-reactive antigens
Several pathogens contain antigens, mainly glycoproteins, that cross-react with tumor-associated antigens. As
an example of such glycoprotein cross-reactivity, the Thomsen–Friedenreich T and Tn parasitic antigens can be
detected in more than 80% of patients with cancer and
have been under experimental and clinical investigations as
markers and therapeutic targets for cancer (66, 67). Furthermore, sera from patients suffering from parasitic infections (e.g., Echinococcus) are commonly found to crossreact (contain similar immunogenic epitopes) with sera
from patients with cancer (68). Interestingly, it has been
observed that such sera are more frequent in patients with
less extensive malignancy. Antibodies against these shared
parasite/tumor-associated antigens can potentially target
tumor cells for destruction or promote antigen presentation
to T cells and induce antitumor responses; this antibodymediated immune enhancement has been observed for
nontumor antigens in experimental models (69).
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Induction of preimmunity
The "concomitant immunity hypothesis" was originally
suggested to explain resistance to secondary tumors or
infections, particularly in animal models (10, 70). As an
ongoing persistent infection can protect the host from the
same infection, similarly, in animal models, immunity to
the original tumor can prevent growth of a comparable
mass (10, 71). Concomitant immunity was considered the
result of either immunogenic factors, for example common
antigenic epitopes, or nonimmunogenic factors, such as
putative antimitotic components (10). The concomitant
effect may be abrogated once the original tumor is removed.
It has also been observed that anticancer immunity can
be present after the removal of the original malignant mass,
a phenomenon termed sinecomitant immunity (10, 71)
that can potentially be attributed to the parallel removal of
tumor-induced immunosuppression.
Formulation of the tumor microenvironment
In principle, any agent that modulates antigen expression
and cell populations in the tumor microenvironment can
determine the quality and level of anticancer immunity. For
instance, the previously observed effect of Coley’s toxin on
cancer regression may be the result of TNFa affecting local
vascular permeability and enhancing leukocyte recruitment
(47, 54). Microorganisms, such as helminthes and commensals, may also contribute to a cancer inhibitory microenvironment by affecting TH1/TH2 responses and Tregs
recruitment (36, 72). Infection-mediated antitumor immunity can also be restricted by the immunosuppressive microenvironment that is often associated with developed tumors
and characterized by TH2 responses and the presence of
myeloid-derived suppressor cells and Tregs (73). Tumorassociated macrophages can also promote angiogenesis,
tumor cell invasion, metastasis, and T-cell inhibition.
Angiogenesis itself has been related to immune suppression; for example, VEGF may lead to decreased antigen
presentation to T cells, due to inhibition of dendritic cells
maturation (74). The role of microbial infections in forming the local versus systemic or "secondary" (noninfected
site) pro- or anticarcinogenic immune milieu in competition with the immunosuppressive tumor microenvironment remains to be discovered.
Production of low-level "danger" signals
A phenomenon termed hormesis has been coined to
describe a biphasic dose-dependent response to an agent
characterized by a low-dose beneficial effect and a highdose inhibitory or toxic effect (9). It can be speculated
that microbes, and specifically relatively benign microorganisms and commensals, embody this pleiotropic
response by stimulating DNA and tissue repair processes
at low infectious agent loads while resulting in extensive
inflammatory and genomic changes that can subsequently foster procarcinogenic processes at higher pathogen
loads. Interestingly, it has been postulated that the
hygiene hypothesis describes this beneficial low-level
exposure phenomenon (75). As the hormetic effect would
Clinical Cancer Research
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Infection and Cancer
be highly dependent on spatial and temporal factors,
in the case of carcinogenesis, both tumor stage and location at the time of infection may be of paramount importance; the beneficial effects of pathogen-triggered stress
repair processes at tumor initiation may, therefore, be
replaced by detrimental effects in later stages, when repair may be accompanied by a more immunosuppressive
microenvironment.
Removal of carcinogens
The health benefits of bacterially enriched food (probiotics) and certain ingredients that can stimulate growth of
indigenous commensal bacteria (prebiotics) have been
widely discussed in several settings, including inflammation
(76). Although the evidence for the ability of probiotics to
reduce risk of colorectal cancer is still controversial, probiotics, particularly containing bifidobacteria and lactobacilli, have been suggested to reduce the production of
carcinogens by other gastrointestinal bacteria like clostridia
and bacteroides (77).
Inhibition of angiogenesis
It has been suggested that infection can prevent angiogenesis, an effect that may subsequently lead to restriction
of tumor growth. For example, despite its potential role in
induction of tumor-promoting myeloid suppressor cells
(78, 79), Toxoplasma gondii infection is also known to
suppress vascularization in a mouse melanoma model, an
effect that may be attributed in part to secretion of antiangiogenic cytokines (80).
Cancer Immunotherapy and Pathogen-Based
Therapeutics
The concept of using anti-inflammatory agents to regulate
not only immune processes but also the tumor load is not
new, with the most widely discussed recent example being
the benefits of aspirin in carcinogenesis risk reduction (81).
The latest approach in immune-related cancer therapy is to
promote targeting of specific tumor antigens or stimulate
the host immune response to growing tumors using a
number of different approaches (82, 83). Several tumor
cell antigens, that is, cancer specific, differentiation, viral,
and carbohydrate, as well as mutated and overexpressed
proteins have been considered as potential vaccine candidates (e.g., see ref. 84). In addition, antibody-based therapeutic agents with reduced immunogenicity have been
designed to specifically recognize and destroy tumor cells
directly or via their specific stromal or immunomodulatory
effects (82). T cells have also been investigated in cancer
treatment, for example, in patients with leukemia and
melanoma (85). In addition, Tregs from mice infected by
selected pathogens (e.g., Helicobacter hepaticus) have exhibited anticancer activity (86).
In a more microbe-based approach, pathogens and
their toxins have been tested as antitumor agents or as
carriers for tumor-targeting therapies (87). The concept
behind this approach is to use the infectious agent or
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its selected components as means to treat/prevent cancer. In this regard, the BCG vaccine, an attenuated form
of Mycobacterium bovis, is now an U.S. Food and Drug
Administration–approved agent for the first-line intravesical treatment of bladder cancer (55). BCG in this
context may have a role in stimulating the body’s own
anticancer immunity via enhancing TH1 cytokine production (e.g., IFN-g, TNFa; refs. 88, 89). Microbial components may also find applicability in preventing cancer,
as in the case of the tumor-pathogen T/Tn antigen (90)
and the bacterial endotoxin LPS (28). More specifically
for the T/Tn antigen, vaccination regimens based on
this common microbe–tumor glycoprotein (66, 67) have
been previously evaluated in breast cancer prevention
(90). Vaccination was accompanied by an increase of
helper T lymphocytes and decrease of T-suppressor/cytotoxic cell ratio, possibly leading to regulation of antitumor immune responses and subsequent prevention of
breast cancer recurrence.
More recently, the helminth Trichuris suis has been
under clinical and experimental investigation for its ability to alleviate diseases, such as inflammatory bowel
disease (ulcerative colitis, Crohn disease), multiple sclerosis, and allergy (e.g., see ref. 91, 92). Its applicability to
cancer pathology, and more specifically to tumors of
the gastrointestinal system, is a question open to future
investigations.
Conclusion and Future Perspectives
Both protective and detrimental effects of microorganisms have been observed, many of them linked to various
immune components. Overall, their effect may depend
on the fine orchestration between induction and suppression of cancer-promoting or antitumorigenic immunity
as well as on the level of pathogen load and the timing
between infection and cancer initiation. In this regard,
cancer may be associated with the increased hygiene/
decreased exposure to specific microorganisms, similar
to what is known for autoimmune diseases and allergies.
That said, it should be noted that not all types of
microorganisms are expected to have the same anticarcinogenic effect; for example, viral infections seem to be
mainly procarcinogenic, in contrast to bacteria or parasitic worms that have a longer coevolution history with
human species and may have, therefore, adapted to
exhibit more antitumorigenic effects. Novel clinical studies are therefore needed to delineate the specific role of
these relatively benign organisms in modulating the host
immune response toward cancer prevention. The adjuvant and cross-reactive effects of parasites and commensals should be investigated in more detail to identify
potential novel therapeutic targets. Exploration of the
immunogenic epitope availability orchestrated by these
agents may also, in the future, assist in the development
of personalized treatments and immunization strategies
that can be used to prevent, regress, or slow down cancer
progression.
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Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: K. Oikonomopoulou, D. Brinc, K. Kyriacou, E.P.
Diamandis
Writing, review, and/or revision of the manuscript: K. Oikonomopoulou, D. Brinc, K. Kyriacou, E.P. Diamandis
Study supervision: K. Oikonomopoulou, K. Kyriacou, E.P. Diamandis
Acknowledgments
The authors apologize for not citing more reviews and original papers
related to this topic due to space limitations.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
this fact.
Received November 28, 2012; revised March 20, 2013; accepted March 21,
2013; published OnlineFirst March 27, 2013.
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