Neoplastic modulation of extracellular matrix. Colon carcinoma cells release polypeptides that alter proteoglycan metabolism in colon fibroblasts

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. The primary objective of the present study was to test whether human colon carcinoma cells released soluble mediators capable of stimulating the synthesis of proteoglycans in normal colon fibroblasts in vitro. Serum-free medium conditioned by colon carcinoma cells (TCM) was capable of stimulating several-fold the synthesis and secretion of proteoglycans in normal colon fibroblasts without inducing a mitogenic response. This effect was a true stimulation of proteoglycan biosynthesis since the kinetics of turnover were identical in the presence or absence of TCM. Characterization of the proteoglycans synthesized in the absence of TCM revealed that colon fibroblasts synthesized at least three species of proteoglycans including a heparan sulfate proteoglycan which was associated primarily with the cell layer and two populations of proteoglycans which were predominantly released into the medium and contained chondroitin-dermatan sulfate side chains. When fibroblasts were exposed to TCM, they synthesized and released higher amounts of proteoglycans which had overall similar density, molecular weight, and polydispersity but differed from controls in that they contained significantly higher proportions of chondroitin sulfate side chains. Partial characterization of TCM strongly indicated that the stimulatory activity comprised a family of polypeptides, with molecular weight between 5.4 and 6.0 X 10(5), which were heat stable and acid/alkali labile. Neoplastic modulation of proteoglycan metabolism in normal mesenchymal cells may represent an additional mechanism through which tumor cells can alter their surrounding environment.