Cholesterol metabolism and colon cancer

While epidemiologic and concordant experimental data indicate a direct relationship between dietary fat (and presumably caloric) intake and the development of colon cancer, the effect of dietary cholesterol on this disease is still not clear. However, there appears to be a developing literature concerning an inverse relationship between serum and plasma cholesterol levels, and the risk for colon cancer. Findings that low serum cholesterol levels are apparent as early as ten years prior to the detection of colon cancer implies that sub clinical disease is probably not involved initially in this process. The possibility of low serum cholesterol as a bio-marker was considered in epidemiologic studies which focused upon obese men with lower than normal serum cholesterol levels who were found to be at increased risk to colon cancer. While the relationship between low serum cholesterol and colonic or intestinal cholesterol metabolism is presently not understood, current genetic studies provide a promising though as yet unexplored potential association. Alterations which occur during the developmental progression of colonic cancer include changes in chromosome 5, which also carries two genes vital to the biosynthesis and regulation of systemic and cellular cholesterol metabolism, 3-hydroxy-3-methylglutaryl coenzyme A synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA R). Regulation of cholesterol metabolism in intestinal cells in vivo and in vitro varies from that seen in normal fibroblasts or hepatocytes in terms of exogenous sources of cholesterol and how these sources regulate internal synthesis. Colonic cancer cells have been used to assess small bowel enterocyte cholesterol metabolism, which has been possible because of their ability to differentiate in culture, however information regarding true colonic enterocyte cholesterol metabolism is relatively scarce. Colonic cancer cells have been shown to possess a diminished or nonexistent ability to use low density lipoprotein to support cellular growth, unlike normal fibroblasts. Diminished low density lipoprotein (LDL) receptor (LDL-R) activity is a significant alteration in a metabolic pathway with such fundamental ties to cellular growth and activation (via mevalonate effects on isoprenylation of G-proteins for example), that it is selected for in the development of certain tumors--among them human colonic carcinomas. It would be expected that such a loss would provide a growth advantage to the tumor cell. Preliminary investigation of this hypothesis has shown that LDL will inhibit the proliferative capacity of certain human colonic adenocarcinomas, and that these cells possess a high rate of cholesterol synthesis relative to fibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)