Colorectal cancers are biologically and histologically diverse. Two histological types that have a poor clinical outcome are those with extensive mucin production (colloid carcinomas) and those with poor cellular differentiation. A well-characterized patient population will be used to focus on these two unique subsets of colorectal cancers in order to identify markers and mechanisms that may later be applicable to improving diagnosis, staging, and treatment of the broader class of moderately- to well- differentiated adenocarcinomas. Although colloid carcinomas and poorly-differentiated adenocarcinomas are biologically distinct, the same patient population and many of the same methods will be used to study both. The broad goals of this proposal are to identify markers for colon cancers of the colloid carcinoma and poorly-differentiated types and to develop experimental models for studying the biological effects and molecular mechanisms of mucin production.
The specific aims i nclude: 1) Establishment of an adequate data base through close follow-up of analytic colorectal cancer cases; 2) Identification of markers for colloid carcinomas using histochemistry, lectin-binding, and new and existing mucin- reactive antibodies; 3) Establishment of cell lines from colloid and signet ring cell carcinomas and evaluation of the biological behavior of these experimental models; 4) Elucidation of the molecular mechanisms for synthesis and secretion of mucin by identification of precursors, inhibitors, and secretagogues, by structural comparison of colloid carcinoma and adenocarcinoma mucins, by quantitation of glycosyltransferases, and by isolation and characterization of mucin cDNA; 5) Identification of markers and evaluation of models for poorly-differentiated adenocarcinomas by surveying antigen expression immunohistochemically, by producing monoclonal antibodies to poorly-differentiated cells, by examining the biological properties of poorly-differentiated cell lines, and by investigating nuclear and proliferative parameters by flow cytometry and image analysis; 6) Correlation of the results of these laboratory studies with clinical outcome and with histopathological data.
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