Genetic and cellular basis of multistep carcinogenesis.

Experimental evidence indicates that cancer development is a multistep process, and that multiple genetic changes are required before a normal cell becomes fully neoplastic. These genetic changes involve oncogenes, tumor suppressor genes, and possibly senescence genes. From studies in vivo using several different animal models, the stages are broadly defined as initiation, progression, and clearly involve both genetic and epigenetic events. Studies in vitro using cell culture systems have allowed the multistep process to be dissected in greater detail at both the cellular and molecular genetic level. In the Syrian hamster embryo cell culture model, neoplastic progression requires four heritable changes, involving activation of two oncogenes and loss of two tumor suppressor genes. Like the experimental systems, a limited number of studies of human tumors suggest that the multistep paradigm is also applicable, and that similar genetic events are involved in the development of cancer in humans.