Progression Markers during the Intestinal Carcinogenesis Intermediate Biomarkers

Colon carcinogenesis is a multistep process in which an accumulation of genetic events within a single cell line leads to a progressively dysplastic cellular appearance, deregulated cell growth, and, finally, carcinoma. The "adenoma-carcinoma sequence" occurs through a series of mutations in cancer-causing genes and usually takes about 11 years. These genes (oncogenes, tumour suppressor genes, DNA mismatch repair genes) encode proteins that control vital cell functions such as growth and survival. Development of intermediate markers for chemopre-vention trials is important. Premalignant lesions are a potential source of intermediate markers. Monitoring intermediate markers that correlate with a reduction in cancer incidence would allow a more expeditious evaluation of potentially active chemopreven-tive agents. If a disappearance of these lesions can be correlated with a reduction in cancer incidence, then markers of premalignancy may serve as intermediate endpoints for chemoprevention trials.

Intermediate biomarkers of abnormal cell growth and development have recently been used in chemo-prevention trials in attempts to identify the efficacy of chemopreventive agents in human subjects. Measurements carried out include those related to cell proliferation, differentiation, and gene structure and expression in the colon. Among the modified patterns of cell proliferation identified by microautoradiographic or immunoperoxidase assays, a characteristic expansion in the size of the proliferative compartment has been observed in normal-appearing colorectal mucosa of human subjects with disease increasing cancer risk; the same patterns have been induced by chemical carcinogens in rodents. Moreover, this intermediate biomarker has been modulated by chemopreventive agents in both rodents and humans. Newer intermediate biomarkers being studied for application to human chemopreventive programs include normal and abnormal patterns of expression of mucins, intermediate filaments and cytoskeletal proteins, and the structure and expression of a variety of genes associated with normal and abnormal cell development. The application of these various intermediate biomarkers to chemopreven-tion studies is increasing the ability of investigators to analyse the effects of novel chemopreventive agents in the colon and in other organs.

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