others 1997) and c-myc, which interacts with Bc1-2 (Bissonnette and others 1992; Evan and others 1992; Fanidi and others 1992). The level of ATP also influences apoptosis (Eguchi and others 1997), and one of the early targets for caspases, PARP, can drain the cell of NAD and ATP in the presence of excess DNA breakage (Shah and others 1996).

Apoptosis is a normal process of cell elimination that can clear abnormal cells from the population. If apoptosis is no longer functional, abnormal cells can persist and expand in the population. The loss of apoptosis can therefore play an important role in clonal expansion during carcinogenesis. Additional genetic changes can then occur, moving a cell population through multiple stages required for the emergence of a fully malignant phenotype. Along the way, irradiated cell populations and tumor cells develop instabilities and mutator phenotypes that favor further diversity.

Initial Genetic Changes in Carcinogenesis—The Gatekeeper Genes

Investigation of rare cancers with strong hereditary factors—such as subsets of colon, breast, retina, and skin cancers—has suggested that genetic alterations are involved in carcinogenesis (Fearon 1997). In general, tissue-specific alterations in a small number of genes act as critical rate-limiting steps that allow cells to escape from normal controls on growth and function and to develop into autonomous populations. The genes that normally exercise these tissue-specific controls have been figuratively called gatekeepers (Kinzler and Vogelstein 1997). The autonomous cell populations acquire functions that include the suppression of apoptosis, independence from extracellular matrix signals, invasive behavior, genomic instability, the activation of oncogenes, and the inactivation of tumor suppressors. Oncogenes, such as ras, are genes that are activated by mutation or translocation and act as dominantly acting genes that induce malignant properties. Tumor suppressors, such as Rb, are genes that maintain normal cell and tissue homeostasis and whose loss permits unregulated cell proliferation to begin.

The ordered progression of genetic changes involved in carcinogenesis is most clearly understood in colon carcinogenesis (Kinzler and Vogelstein 1996). One of the earliest genes to be affected is the APC gene; it is followed by changes in DCC, p53, ras, and others. Error generation in this process is enhanced by mutations in mismatch-repair genes (Arnheim and Shibata 1997). In colon carcinogenesis, APC mutation seems to be required early, before ras mutation; when ras mutations are observed first in colon polyps, the growths are usually benign and regress; when APC mutations occur before ras mutations the tissue usually progresses to other changes that result in malignancy (Jen and others 1994). It is unlikely that such an ordered sequence of mutations or gene loss will be as clear and precise in most tissues, but the principle of an approximate sequential order to the earlier genetic changes involved in carcinogenesis seems reasonable.



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