THE CELL-SURFACE HEPARAN-SULFATE PROTEOGLYCAN GLYPICAN-1 REGULATES GROWTH-FACTOR ACTION IN PANCREATIC-CARCINOMA CELLS AND IS OVEREXPRESSED IN HUMAN PANCREATIC-CANCER

Heparan sulfate proteoglycans (HSPGs) play diverse roles in cell recog nition, growth, and adhesion. In vitro studies suggest that cell-surfa ce HSPGs act as coreceptors for heparin-binding mitogenic growth facto rs, Here we show that the glycosylphosphatidylinositol- (GPI-) anchore d HSPG glypican-1 is strongly expressed in human pancreatic cancer, bo th by the cancer cells and the adjacent fibroblasts, whereas expressio n of glypican-1 is low in the normal pancreas and in chronic pancreati tis. Treatment of two pancreatic cancer cell lines, which express glyp ican-1, with the enzyme phosphoinositide-specific phospholipase-C (PI- PLC) abrogated their mitogenic responses to two heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibrobl ast growth factor 2 (FGF2) and heparin-binding EGF-like growth factor (HB-EGF). PI-PLC did not alter the response to the non-heparin-binding growth factors EGF and IGF-1, Stable expression of a form of glypican -1 engineered to possess a transmembrane domain instead of a GPI ancho r conferred resistance to the inhibitory effects of PI-PLC on growth f actor responsiveness. Furthermore, transfection of a glypican-1 antise nse construct attenuated glypican-1 protein levels and the mitogenic r esponse to FGF2 and HB-ECF. We propose that glypican-1 plays an essent ial role in the responses of pancreatic cancer cells to certain mitoge nic stimuli, that it is relatively unique in relation to other HSPGs, and that its expression by pancreatic cancer cells may be of importanc e in the pathobiology of this disorder.