Viral carcinogenesis

Abstract

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 multifactorial 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. © 2006 Springer Science+Business Media, Inc.