Genomic components of carcinogenesis

Abstract

Abstract Many of the genes encoding growth factors, growth factor receptors, enzymes, and other effector molecules that regulate normal cell growth are designated protooncogenes. Oncogenes, those genes associated with cellular transformation, differ from their protooncogenic progenitors by being mutated, overexpressed, or expressed at inappropriate times or locations in the cell. One of the activities of growth factors is to prime cells to undergo programmed cell death, which is characterized by a series of morphologic changes called apoptosis. In normal cells, specific mediators must be activated or suppressed to bypass programmed cell death. In tumor cells, either the pathways leading to apoptosis are not functional or the mediators that normally "rescue" cells from this fate are overexpressed or constitutively activated. In addition to the biochemical pathways that drive cell division, there are others that limit cell proliferation; these, designated tumor suppressors, anti-oncogenes, or recessive oncogenes, must be inactivated in normal cells to allow passage through the cell cycle and cell proliferation. In contrast to oncogenes, which are overexpressed or activated in tumors, tumor-suppressor genes are frequently inactivated in tumor cells, either by mutation or deletion. Thus, in normal cells a series of checks and balances must be overcome to allow initiation and continuation of cell division. In tumors, these processes are aberrant, resulting in increased rates of cell division, increases in the proportion of cells in the cell cycle, or increased survival of activated cells. Therefore, tumor cells frequently accumulate genomic alterations, which may result in the activation of a particular array of oncogenes, the inactivation of specific tumor-suppressor genes, and the bypassing of programmed cell death. Trials of antitumor agents that act by exploiting the overexpression of oncogenes in tumors and of the biochemical pathways by which they mediate cell proliferation are currently underway.