Gastrointestinal cancer: pathogenesis, risk factors and the development of intermediate biomarkers for chemoprevention studies.

Dietary, environmental and genetic factors contribute to the etiology, pathogenesis and risk for gastrointestinal cancers. Measurements of cell proliferation and differentiation further identify abnormal cellular properties associated with increased susceptibility to gastrointestinal cancer. In precancerous esophagus, the proliferative compartment increases in size, increased ploidy and dysplasia develop, and epithelial cells express abnormal cytokeratins and ectopic tumor-associated antigens. In precancerous stomach, increased proliferative activity and metaplasia develop. Intestinal enzymes and mucins are expressed and normal gastric antigens are replaced by intestinal or embryonic antigens. In flat colonic mucosa and in colonic adenomas, expansions of the proliferative compartment occur. Gene expression is modified, gene deletions occur and blood group-related antigens are modified as the cells undergo abnormal differentiation and develop into adenomas and carcinomas. Chemopreventive regimens are now being tested to determine whether they modify such intermediate biomarkers toward normal levels characteristic of lower risk for neoplasia. It is anticipated that the utilization of intermediate biomarkers in chemoprevention studies may permit more novel chemopreventive regimens to be tested in human subjects than heretofore was possible.