A multidisciplinary group will characterize growth regulation in human colon neoplasms to identify growth regulatory targets for development of anticolon cancer therapeutic agents. The in vitro model system will consist of the types of cells found in normal colon; hyperplastic polyps, adenomatous polyps and carcinomas. Comparative analysis of the biological characteristics of each type of cell will be made and include tumorigenicity, ability to grow with anchorage independence, metastatic capability and analysis of differentiation markers. A profile of expression of growth regulatory mechanisms will be established for each growth phenotype. This profile will provide for the characterization of the dependence of the growth of cellular phenotypes on specific autocrine growth factors, exogenous growth factors and oncogenes. Cellular phenotype specific interrelationships among these three types of molecules will also be characterized. These characterizations will identify autocrine factors which if uncoupled (either by antibodies or analogues) could lead to a significant change in the dependent cell's biological characteristics toward a more benign phenotype or perhaps cell death. Uncoupling of synergistic inter- relationships among these types of molecules could also produce the same result. It will be determined whether modulation of the growth regulatory phenotype associated with a cellular phenotype will also result in the modulation of the biological properties associated with the phenotype. This will be accomplished by developing appropriate transfection vectors for the overexpression of growth regulatory associated autocrine factors and oncogenes in benign cells. Successfully transfected cells will be tested for alterations in biological and growth regulatory phenotypes. Some oncogenes have been associated with the expression of differentiated functions in colon and other systems. These will also be tested in transfection systems to determine whether their overexpression will modulate malignant phenotypes to more benign states. It will also be determined whether a series of putative differentiation or inhibitory agents can affect the biological and growth regulatory phenotypes in a similar manner. Of particular interest will be the effects of differentiation promoting transfections and the inhibitory agents on the expression of growth regulatory molecules and their relationships since the development of agents to mimic these effects could allow for effective therapeutic intervention.
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