Elsevier

Seminars in Cancer Biology

Volume 14, Issue 6, December 2004, Pages 453-471
Seminars in Cancer Biology

Infectious agents and cancer: criteria for a causal relation

https://doi.org/10.1016/j.semcancer.2004.06.009 Get rights and content

Abstract

Infectious agents, mainly viruses, are among the few known causes of cancer and contribute to a variety of malignancies worldwide. The agents and cancers considered here are human papillomaviruses (cervical carcinoma); human polyomaviruses (mesotheliomas, brain tumors); Epstein-Barr virus (B-cell lymphoproliferative diseases and nasopharyngeal carcinoma); Kaposi’s Sarcoma Herpesvirus (Kaposi’s Sarcoma and primary effusion lymphomas); hepatitis B and hepatitis C viruses (hepatocellular carcinoma); Human T-cell Leukemia Virus-1 (T-cell leukemias); and helicobacter pylori (gastric carcinoma), which account for up to 20% of malignancies around the globe. The criteria most often used in determining causality are consistency of the association, either epidemiologic or on the molecular level, and oncogenicity of the agent in animal models or cell cultures. However use of these generally applied criteria in deciding on causality is selective, and the criteria may be weighted differently. Whereas for most of the tumor viruses the viral genome persists in an integrated or episomal form with a subset of viral genes expressed in the tumor cells, some agents (HBV, HCV, helicobacter) are not inherently oncogenic, but infection leads to transformation of cells by indirect means. For some malignancies the viral agent appears to serve as a cofactor (Burkitt’s lymphoma-EBV; mesothelioma - SV40). For others the association is inconsistent (Hodgkin’s Disease, gastric carcinomas, breast cancer-EBV) and may either define subsets of these malignancies, or the virus may act to modify phenotype of an established tumor, contributing to tumor progression rather than causing the tumor. In these cases and for the human polyomaviruses the association with malignancy is less consistent or still emerging. In contrast despite the potent oncogenic properties of some strains of human adenovirus in tissue culture and animals the virus has not been linked with any human cancers. Finally it is likely that more agents, most likely viruses, both known and unidentified, have yet to be implicated in human cancer. In the meantime study of tumorigenic infectious agents will continue to illuminate molecular oncogenic processes.

Introduction

In the past 25 years revelations on the genesis of human cancer have come at an increasing pace. The contributions of knowledge about oncogenic infectious agents, especially viruses, have been instrumental in that understanding because in transforming cells they mirror, often brilliantly, basic cellular processes that culminate in cancer. Infectious agents, chiefly viruses, are accepted causes or candidates as causes of diverse malignancies of people world-wide. From a universal perspective infectious agents especially viruses account for several of the most common malignancies – up to 20% of all cancers. Some of these cancers are endemic with high incidence in certain geographic locations, but have sporadic low incidence in other parts of the world. The consistency of association of a given virus and a specific malignancy ranges from essentially 100% to as low as 15% depending on the virus, the cancer and the geographic location. The significance of association of a virus and a cancer when less than 100% is generally uncertain and problematic in terms of etiology, but these lesser associations may define subsets of tumors – those infected with a specific virus or those not – as with EBV and gastric carcinoma. In contrast helicobacter is consistently associated with gastric carcinoma. If a given agent is not consistently detected in a malignancy with which it is associated, the question arises whether the agent nevertheless contributes to some phase of oncogenesis.

The agents considered here are human papillomavirus (HPV), human polyomaviruses (JCV, BKV, SV40), Epstein-Barr virus (EBV), Kaposi’s Sarcoma Herpesvirus (KSHV), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell leukemia virus, (HTLV1) and Helicobacter pylori, most of which are believed to cause or contribute in a significant way to the genesis of a variety of malignancies, in particular cervical carcinoma (HPV), mesotheliomas and brain tumors (polyomaviruses), B-cell lymphoproliferative diseases and nasopharyngeal carcinoma (EBV), Kaposi’s Sarcoma and primary effusion lymphomas (KSHV), hepatocellular carcinoma (HBV and HCV), T-cell leukemia (HTLV1) and gastric carcinoma (helicobacter). The human polyomaviruses have not attained the same status as the other agents as probable causative agents, but merit attention because of their compelling oncogenic properties and the increasing strength of their association with specific malignancies. In contrast although strains of human adenoviruses have clearly oncogenic properties including the ability to dysregulate the same tumor suppressor genes targeted by HPV and the human polyomaviruses, there is no known association with human malignancy. In addition to these major associations several of the viruses have lesser associations with other malignancies. Cofactors have been implicated for some of these agents especially in instances where the malignancy has high incidence in certain geographic areas (Table 1).

In the case of DNA-containing tumor viruses, infection is latent, the viral genome persists in some form in the tumor tissue, and a subset of viral genes is expressed in the tissue. If viral genome persists it may do so in either integrated or episomal form. HTLV1 and HBV also persist as integrated genomes. For the hepatitis viruses and helicobacter infection is not latent; rather there is persistent infection and replication of the agent at the site of tumor formation.

The goal of this article is to come to grips with the criteria that establish a given infectious agent as oncogenic. In the context of the many associations between a virus or microbial agent and a given malignancy, the distinction between associated versus causative agent frequently arises and may be difficult to decide. However, since some of the associations are considered to be causal or probably causal and others are not, it is instructive to consider by specific cases what evidence is generally accepted as sufficient to establish a causal relation, and which factors may be dispensable. The approach taken here will be to review briefly the salient associations for each of the commonly accepted agents in terms of consistency of disease association, oncogenic properties, nature of the association, mechanism of oncogenesis and essential or suspected cofactors. Alternatively it is possible that an infectious agent may establish a noncausal relation with a tumor, that is, it may modify the phenotype of a tumor cell. Based on this information inferences can be made and provide an additional perspective on issues of causality.

Section snippets

EBV

The Epstein-Barr virus was originally isolated from biopsy tissue samples of the childhood malignancy, African Burkitt’s lymphoma [1]. This unusual cancer occurs with high incidence in an endemic region that is also holoendemic for malaria. An association with EBV was subsequently discovered in nasopharyngeal carcinoma, a cancer that develops with extraordinarily high incidence among the Cantonese Chinese and with elevated incidence among Alaskan Inuits and in Mediterranean Africa. EBV is

Malignancies

Kaposi’s sarcoma-associated herpesvirus (KSHV) has been linked to several malignancies in the human population: Kaposi’s sarcoma (KS), primary effusion lymphomas (PELs) and multicentric Castleman’s disease (MCD).

KS is a multifocal vascular tumor of mixed cellular composition manifested most often as a cutaneous lesion. KSHV is always detected in the spindle cells of the KS lesion, which are thought to be endothelial in origin. There are four major forms: (i) Classic KS is seen in men of

HPV

Human papillomaviruses are consistently associated with cancer of the cervix. Virtually 100% of cervical cancers contain HPV (317-Fp 2264). However, only some types of HPV regularly have this relation. Of the approximately 130 HPV types so far distinguished, 30 are so-called anogenital types. A subset of these 30 types is considered “high risk” virus (types 16 and 18) based on the consistency of the association with cervical (and anal) cancer. HPV31 and 45 are also found in these cancers and

Polyomaviruses

There are three primate polyomaviruses: JCV, BKV and SV40. There is evidence of a role in neoplasia for each [42], [43].

HBV and HCV

Hepatocellular carcinoma (HCC) is among the most common cancers in the world. Most HCC cases are due to hepatitis B virus (HBV), but the number of hepatitis C virus (HCV)-associated cases is still growing in many countries. The role of HBV as a major etiological agent of HCC has been firmly established; the lifetime risk of developing HCC is estimated to be 10- to 25-fold greater for chronic HBV carriers compared with noninfected populations, placing HBV in the first rank among known human

Helicobacter pylori

Once established in a host, H. pylori colonizes the stomach for decades, most often for the individual’s entire lifespan, unless removed by antimicrobial treatment [75]. Helicobacter pylori has colonized the human stomach since time immemorial [76]. Colonized hosts have an extensive and complex response to the organism that enhances risk for adenocarcinoma of the (non-cardia) stomach [77], as well as for gastric non-Hodgkin’s (MALT) lymphoma.

HTVL-1

HTLVI is the first and still the only human retrovirus discovered in the context of malignancy, namely, certain acute T-cell leukemias (ATL) that are endemic in southern Japan where HTLV1 causes ATL in 3–5% of infected persons over their life-time [82]. Curiously, unlike the many animal retroviruses that cause cancers in animals and gave rise to the discovery of oncogenes and the concept of protooncogenes, HLTV1 does not contain a classical oncogene. However, the virus can induce expression of

Discussion

Best established as human oncogenic agents are HPV (cervical cancer), EBV (B-cell lymphoproliferative diseases), KSHV (Kaposi’s sarcoma and primary effusion lymphoma PEL), HTLV1 (T-cell leukemia), HCV and HBV (hepatocellular carcinoma) and H. pylori (gastric cancer). However, the criteria accepted as establishing causality differ in degree of completeness for the various malignancies. For HPV and cervical cancer, although the epidemiologic evidence was mustered later than the molecular, all

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      Citation Excerpt :

      Some viruses are acknowledged for triggering different types of cancers, several of them are adequately common in people and supposed to be active components of the human virome. Some of the known cancer causing viral families include hepatitis B (HBV), human papillomaviruses (HPV) triggering cervical cancer, human T-cell leukemia virus-1 (HTLV) and C viruses (HCV) that lead to liver cancer, Epstein–Barr virus (EBV) leads to B-cell lympho-proliferative illnesses and nasopharyngeal carcinoma, Kaposi sarcoma–associated herpesvirus (KSHV) leads to Kaposi sarcoma, primary effusion lymphomas [19–21], Simian Virus 40 (SV40) and Merkel cell polyomavirus (MCV) are causative agents for mesothelioma and Merkel cell carcinoma (MCC), respectively [19,20]. Additionally, MCV which is very common in people gives rise to skin cancer in old and immunocompromised people [22].

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