The
RNA and DNA tumor viruses have made fundamental contributions to two major areas of
cancer research. Viruses were vital, first, to the discovery and analysis of cellular growth control pathways and the synthesis of current concepts of
cancer biology and, second, to the recognition of the etiology of some human
cancers. Transforming retroviruses carry oncogenes derived from cellular genes that are involved in mitogenic signalling and growth control. DNA tumor viruses encode oncogenes of viral origin that are essential 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
cancer development occurs by the accumulation of multiple cooperating events. Viruses are now accepted as bona fide etiologic factors of human
cancer; these include hepatitis B virus, Epstein-Barr virus, human papillomaviruses, human
T-cell leukemia virus type I and hepatitis C virus, plus several candidate human
cancer viruses. It is estimated that 15% of all human
tumors worldwide are caused by viruses. The infectious nature of viruses distinguishes 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
carcinogens, and the known human
cancer viruses display different roles in transformation. Many years may pass between initial
infection and
tumor appearance and most infected individuals do not develop
cancer, although immunocompromised individuals are at elevated risk of viral-associated
cancers. Variable factors that influence viral
carcinogenesis are reviewed, including possible 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. Future directions for tumor virus studies are considered.