Giuseppe Barbanti Brodano

Important causes of human tumors are biologic and environmental agents, mostly of a chemical and physical nature, that act by genotoxic mechanisms which induce alterations in the cell genome such as chromosomal deletions, rearrangements, and mutations. In the complex multi-factorial pathogenesis of cancer, viruses often participate as biologic cofactors that cooperate with chemical and physical agents in both the initiation and progression of tumors. Thus, the detection of a tumor virus in a given tumor does not establish causation. Moreover, the genetic background of an individual and his/her immune status at the time of infection or during viral latency may influence susceptibility to various carcinogens, especially viral carcinogens. Often, it appears that oncogenic viruses act at the beginning of tumor development, inducing in the host cell a number of genetic alterations and immortalizations that can lead to tumor growth. Viruses at other times can be oncogenic only upon infection of cells that already contain genetic alterations. For example, BKV can transform human mesothelial cells that overexpress Notch-1 and which express telomerase activity, whereas in the absence of these alterations, mesothelial cells were not transformed. Oncogenic viruses may act directly, as the combined effects of viral sequences or gene products within the target cell lead to transformation. In other circumstances, the role of viruses may be more subtle, that is, predominantly indirect. Examples of this condition are liver cancer, arising during hepatocyte regeneration that follows hepatitis B and C virus infection, and acquired immunodeficiency syndrome (AIDS)-associated neoplasms, favored by loss of antitumor immune surveillance as a result of human immunodeficiency virus (HIV) infection of the immune system and consequent immunosuppression. HIV-induced immunosuppression allows the emergence of oncogenic viruses such as Epstein-Barr virus (EBV), which causes B-cell lymphomas in AIDS patients. Thus, in AIDS, two viruses cooperate independently to cause human cancer. It is also argued that the regenerative process associated with liver cirrhosis, which is caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and the release of cytokines by the inflammatory infiltrate in the regenerating liver favor tumor development. In this latter scenario, the role of HBV and HCV in causing hepatocellular carcinoma would be indirect yet critical.

Viruses are important causes of cancer in several animal species, and they are increasingly implicated in human neo-

plasia. Because oncogenic viruses are generally involved in the initial phases of tumor development, control of viral infection should prevent or reduce the incidence of those tumors linked to viral infection. Cancer-associated viruses belong to several families of deoxyriboviruses and riboviruses (Table 17.1). The International Agency for Research on Cancer (IARC) so far has identified six viruses—human papillomavirus (types 16 and 18), Epstein-Barr virus, hepatitis B virus, hepatitis C virus, human T-cell lymphotropic virus type I, and human immunodeficiency virus type 1 (also, KSHV is a likely candidate)—as group 1 carcinogens, that is, agents that have been shown to be carcinogenic in humans. Together, these viruses may cause or contribute to about 15% of human malignancies.1 However, if other viruses for which the evidence is suggestive but not definitive, and the group 2 carcinogens are included, this value would almost double.1 Ment in SV-40 as an emerging carcinogenic agent.

The classic Koch's postulates, formulated to demonstrate the etiologic role of microorganisms in infectious diseases, cannot be applied directly to prove the viral etiology of human tumors for various reasons: (1) several tumor-associated viruses are ubiquitous in humans, and (2) they produce a persistent or latent infection in many human tissues, making epidemiologic studies difficult. Viruses are seldom complete carcinogens, and their carcinogenic potential becomes apparent only when studied together with those carcinogens associated with a specific tumor type. For example, skin carcinomas in patients infected with cutaneous human papillomavirus (HPV) develop in sun-exposed areas because of the cocarcinogenicity of UV light; SV-40 infection may carry a higher risk of mesothelioma development in individuals exposed to asbestos, etc. Furthermore, cooperation among different viruses may be required for cocarcinogene-sis, such as HIV-1 and EBV in lymphomas that develop in AIDS patients. In this case, HIV causes immunosuppression that facilitates EBV lymphomagenesis. Thus, because Koch's postulates do not address these issues, new rules should be considered to establish the oncogenic role of viruses in humans.2-4 To address this problem, the National Cancer Institute (NCI) organized (December 11-12, 2003), an international workshop with some of the leading experts in various disciplines. The recommendations of this workshop concerning the identification of human cocarcinogens appeared in an issue of Seminars in Cancer Biology in 2004, edited by M. Carbone and M. Wong.

TABLE 17.1. Human tumor viruses.

Virus family

Virus

Genome type

Associated tumors

Herpesviridae

Papovaviridae

Hepadnaviridae Flaviviridae

Retroviridae

Epstein-Barr virus

Human herpesvirus 8

BK virus

JC virus

Simian virus 40

Human papillomavirus

Hepatitis B virus

Hepatitis C virus

Human T-cell lymphotropic virus I

Human T-cell lymphotropic virus II

Human immunodeficiency virus 1

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