The development of successful models for the initiation and characterization of in vitro transformed epithelial cells is needed since the majority of cancers are of epithelial cell origin. The choice of colon epithelium is based on a number of factors. Large bowel cancer currently represents the highest incidence of all visceral human neoplastic diseases in the United States. However, few in vitro studies have been done using colon or other gastrointestinal epithelia, since no good method to culture these cells has been available. Our recent success in culturing human colon epithelium now allows us to pursue the much-needed in vitro transformation experiments which may help elucidate the mechanism(s) of oncogenesis. This revised application, which has been modified in response to reviewers' suggestions made following a site visit on November 28, 1983, addresses that need. The major objective of this proposed research is to culture and characterize normal and malignant human colon cells. Key questions to be addressed by these studies are as follows: (1) What specific phenotypic or genotypic differences exist between normal and tumor cells? (2) Can culture conditions be optimized for long-term cultures particularly those from normal colon epithelium? (3) If conditions for development of a normal cell line are found, are the culture characteristics stable and do the cells display a """"""""normal"""""""" cellular phenotype? and (4) Do cells transformed in vitro display some characteristics in common with tumor cells? Features of normal and tumor cells to be compared include morphology, growth, cytogenetics, viral oncogene expression and cell surface and ionic changes. These analyses should determine if specific features associated with colon cancer (e.g., induction of embryonic antigens such as CEA, changes in lectin binding, or expression of antigens directed by specific monoclonal antibodies) may occur upon cell transformation. In addition various culture media, supplemental growth factors, and dissociation methods will be tried in an attempt to optimize culture conditions and ultimately select for established, continuous cell lines, particularly from normal colon mucosa and normal tumor cell culture """"""""pairs"""""""" initiated from tissues of the same patient. The proposed research will contribute to a better understanding of growth regulation and differentiation of human colon epithelial cells, and will provide a foundation for designing biologically relevant approaches to colon cancer diagnosis and therapy. (S)
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