Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease

The RNA and DNA tumor viruses have made fundamental contributions to two ma jor areas of cancer research. Viruses were vital, first, to the discovery a nd analysis of cellular growth control pathways and the synthesis of curren t concepts of cancer biology and, second, to the recognition of the etiolog y of some human cancers. Transforming retroviruses carry oncogenes derived from cellular genes that are involved in mitogenic signalling and growth co ntrol. DNA tumor viruses encode oncogenes of viral origin that are essentia l for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression and led to the discovery of tumor suppressors. Viral systems support the concept that canc er development occurs by the accumulation of multiple cooperating events, V iruses are now accepted as bona fide etiologic factors of human cancer; the se include hepatitis B virus, Epstein-Barr virus, human papillomaviruses, h uman T-cell leukemia virus type I and hepatitis C virus, plus several candi date human cancer viruses. It is estimated that 15% of all human tumors wor ldwide are caused by viruses. The infectious nature of viruses distinguishe s them from all other cancer-causing factors; tumor viruses establish long- term persistent infections in humans, with cancer an accidental side effect of viral replication strategies. Viruses are usually not complete carcinog ens, and the known human cancer viruses display different roles in transfor mation. Many years may pass between initial infection and tumor appearance and most infected individuals do not develop cancer, although immunocomprom ised individuals are at elevated risk of viral-associated cancers. Variable factors that influence viral carcinogenesis are reviewed, including possib le synergy between viruses and environmental cofactors. The difficulties in establishing an etiologic role for a virus in human cancer are discussed, as well as the different approaches that proved viral links to cancer, Futu re directions for tumor virus studies are considered.