Long term objectives are to identify nutritional factors which 1) contribute to, or reduce the risk for the high incidence of colon cancer in Western culture or 2) could be useful as adjunctive therapy in the management of bowel cancer. Dietary cholesterol contributes to risk for colon cancer epidemiologically and experimentally, but little is known of cholesterol dynamics in colonic mucosal epithelium or in tumors arising from it. Based upon preliminary evidence, the following is hypothesized: The large bowel mucosal epithelium exhibits membrane low density lipoprotein (LDL) receptors. During tumor development and alterations in the state of differentiation, in the bowel, there is a loss in the ability of epithelial derived tumors to express membrane LDL-cholesterol receptors. This implies that colon tumor cells and derived hepatic or other metastases obtain their cholesterol-requirements for cellular maintenance and replication from internal cholesterol pools. An inability of colon tumor cells to obtain exogenous LDL cholesterol points to a selective strategy which may have chemotherapeutic, or radiodiagnostic, implications. This will be evaluated in 1) colon tumor cell lines for the presence or absence of LDL receptors using meyinolin as an inhibitor, an ELISA that measures binding of monoclonal bovine/human antibody to the receptor with an immunoperoxidase stain for LDL binding, utilizing 2 I-LDL and methylated LDL to assess receptor dependent and independent LDL uptake; 2) by preparing murine monoclonal antibodies specific for human LDL receptors and comparing this with bovine LDL receptor antibody in histochemical preparations of human normal colon, """"""""uninvolved' colon adjacent to colonic tumors and colonic tumors; 3) by ascertaining if bowel tumors removed at surgery, and metastatic lesions possess LDL receptors as defined by histochemical techniques; 4) by assessing colon polyps for LDL receptors histochemically and usefulness in polyp classification; and 5) by defining the distribution and density of LDL receptors throughout the entire normal human colon using LDL receptor antibody coupled to histochemical stains.
|Broitman, S A; Cerda, S; Wilkinson 4th, J (1993) Cholesterol metabolism and colon cancer. Prog Food Nutr Sci 17:1-40|
|Fabricant, M; Broitman, S A (1990) Evidence for deficiency of low density lipoprotein receptor on human colonic carcinoma cell lines. Cancer Res 50:632-6|
|Fox, E S; Broitman, S A; Thomas, P (1990) Bacterial endotoxins and the liver. Lab Invest 63:733-41|