Despite the growing evidence implicating proteoglycans in the control of cell proliferation and differentiation, little is known about the factors that control their metabolism in neoplasia or the mechanisms through which these macromolecules may influence neoplastic growth. This project is based upon our previous in vivo observation that proteoglycans are markedly increased in human colon carcinoma, and that the connective tissue stroma surrounding the neoplastic cells is the major site of synthesis and accumulation of sulfated proteoglycans. This research will study the interaction between human neoplastic and mesenchymal cells in an in vitro system using human colon carcinoma cells and the two major mesenchymal cells of colon, i.e., colon fibroblasts and smooth muscle cells. The primary goal is to determine whether these tumor cells influence the levels of proteoglycans synthesized by normal human colon fibroblasts and smooth muscle cells in vitro, and to determine whether these effects reflect alteration in the rates of synthesis and/or degradation of the various proteoglycans in these two normal cell types. Experiments will be performed to analyze the biochemical and structural characteristics of the proteoglycans synthesized by colon fibroblasts and smooth muscle cells when cultured in the presence or absence of tumor metabolites. We will determine whether the postulated effects occur via a direct neoplastic-mesenchymal cell interaction or via the release of diffusable metabolites produced by the tumor cells. Additional studies are planned to investigate the nature of the modulation of proteoglycan metabolism and whether this effect is coupled to a stimulation of cell proliferation. (S)
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