The development from a normal cell to a cancerous cell is usually a multistep process of clonal evolution driven by a series of somatic mutations that progressively convert the cell from normal growth to a precancerous state and finally a cancerous state.
The presence of myriad chromosomal abnormalities in precancerous and cancerous cells lends support to the role of multiple mutations in the development of cancer. This has been demonstrated in human colon cancer, which progresses in a series of well-defined morphologic stages (Figure 22-4). Colon cancer begins as small, benign tumors called adenomas in the colorectal epithelium. These precancerous tumors grow, gradually becoming increasingly disorganized in their intracellular organization until they acquire the malignant phenotype. These well-defined morphologic stages of colon cancer have been correlated with a sequence of gene changes involving inactivation or loss of three tumor-suppressor genes (APC, DCC, and p53) and activation of one cellular proliferation oncogene (K-ras).
Studies with transgenic mice also support the role of multiple steps in the induction of cancer. Transgenic mice expressing high levels of Bcl-2 develop a population of small resting B cells, derived from secondary lymphoid follicles, that have greatly extended life spans. Gradually these transgenic mice develop lymphomas. Analysis of lymphomas from these mice has shown that approximately half have a c-myc translocation to the immunoglobulin H-chain locus. The synergism of Myc and Bcl-2 is highlighted in double-transgenic mice produced by mating the bcl-2+ transgenic mice with myc+ transgenic mice. These mice develop leukemia very rapidly.
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