MULTISTEP TUMORIGENESIS: MOLECULAR EVENTS ASSOCIATED WITH THE GENESIS OF COLON CANCER

     Colon cancer is unusual in that the precancerous lesions can be identified early via colonoscopy. Molecular analysis of the various stages of colon cancer is therefore possible. These studies have identified a rough sequence of molecular events that characterize tumor development in colorectal cancer. Because we now know the molecular function many tumor suppressor genes and oncogenes,
we are beginning to understand the genetic changes that occur during cancer formation.The earliest stage of colon cancer formation is the appearance of a hyperproliferative epithelium. This is associated with the loss of the APC tumor suppressor. Recall that APC limits Wnt signaling in the gut epithelium where it is expressed at high levels in non-dividing cells and low levels in the stem cells of the crypts.

     Loss of the APC gene results in hyperactive Wnt signaling and proliferation of cells beyond the crypts. Subsequent to loss of APC, there appears to be a period of genomic instability, which permits the cells to acquire mutations more rapidly. Progression of adenomas is associated with activation of the mitogenic Ras-MAPK pathway through the acquisition of activating mutations in the K-ras oncogene. Later, a further blow to growth control occurs via the loss of a SMAD gene required for signaling through the growth inhibitory TGF-beta signaling pathway. Finally, the progression from late ademonas to malignant carcinoms is associated with the loss of the p53 tumor suppressor, which releases the cells from DNA damage and stress induced apoptosis and cell cycle arrest. (For description of cancer nomenclature, see the Introduction to Cancer Pathology lecture.)

     There are additional changes in tumor suppressor genes and oncogenes that occur during tumor progression that are different in different colon cancers, some of which have yet to be identified. Nonetheless, the study of the molecular basis of colon cancer has given us a picture of the multi-step evolution of a tumor and the genetic changes that drive them. Importantly, an understanding of the specific genetic changes that occur during this multi-step process allows for the identification of key steps for intervention and the development of specific therapeutic strategies.



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