Colorectal cancer is the second most common cause of cancer deaths in the U.S. yet its pathogenesis is completely understood. The long-term aim of these studies is to test the hypothesis that enzyme-altered foci and/or aberrant crypts in colonic mucosa re putative preneoplastic lesions that will (a) Facilitate our understanding of the pathogenesis of colon cancer in humans and (b) provide new tools for the diagnosis and prevention of this common human disease. Characteristics (oncogene products, enzymes, mucins, and proliferative activity) that may be indicative of a premalignant or malignant condition will be defined in (1) aberrant crypts, (2) enzyme-altered foci, and (3) tumors in the colonic mucosa of F344 rats treated with a single sc injection of 30 mg/kg azoxymethane (AOM) and killed 4, 12, and 36 wk later. Next it be determine if and how would healing and the development of neoplasms are the same or different. To address this question, colonic alterations that occur early (up to 4 weeks) after the injection of (1) AOM or (2) one of several toxic noncarcinogenic substances will be characterized (a) grossly, and (b) in histologic sections. Aberrant crypts, similar to those observed in whole-mount preparations of colon from rodents treated with carcinogen, have been reported recently by us in whole-mount preparations of human colonic mucosa. The frequency of these putative preneoplastic lesions will be quantified in patients at increased risk for colon cancer and those without increased risk. Finally, the same characteristics as listed above will be defined for human (1) aberrant crypts, (2) polyps, and (3) cancers resected from the same patient for therapeutic purposes. These characterizations will be carried out in situ in methacrylate-embedded tissues with (a) antibodies to specific oncogene or supressor gene products (ras, myc, Rb, p53), TGF-B, EGF, and glutathione-s-transferase-P, and with (b) enzyme histochemical procedures for hexosaminidase, alpha-naphthyl butyrate esterase, aldehyde dehydrogenase, and glucose 5-phosphate dehydrogenase. Mucins will be characterized by lectin binding and histochemical procedures; proliferative activity will be determined by (autoradiography after tritiated thymidine injection of rats and (b) immunohistochemistry with antibodies to PUNA/cyclic in human tissues. Dr. Stellate, a surgeon who does many colon resections in our center, does total colonoscopy on our rats that will facilitate the development of in vivo markers for these early lesions. Aberrant crypts provide the earliest identifiable lesion in which to monitor genotypic and/or phenotypic changes that accompany the promotion and progression of cells to malignancy.
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