TUMOR-CELLS SECRETE AN ANGIOGENIC FACTOR THAT STIMULATES BASIC FIBROBLAST GROWTH-FACTOR AND UROKINASE EXPRESSION IN VASCULAR ENDOTHELIAL-CELLS

Culture medium conditioned by human SK-Hep1 hepatoma cells or mouse S1 80 sarcoma cells rapidly up-regulates endothelial cell expression of b asic fibroblast growth factor (bFGF) and induces formation of capillar y-like structures by vascular endothelial cells grown on three-dimensi onal fibrin gels (in vitro angiogenesis). Incubation of endothelial ce lls with the tumor cell-conditioned media also results in increased ex pression of urokinase plasminogen activator (uPA), a key component of the proteolytic system required for cell invasion and capillary format ion. Although the tumor cell-conditioned media contain no bFGF, additi on of anti-recombinant bFGF Ige abolishes the up-regulation of uPA and blocks in vitro angiogenesis. This indicates that both the increase i n uPA production and formation of capillary-like structures are mediat ed by endogenous bFGF expressed by the endothelial cells. Both the bFG F/uPA-inducing activity and the angiogenic activity of SK-Hep1 cell-co nditioned medium copurify with a relatively acid-resistant peptide tha t has moderate affinity for heparin and M(r) < 18 kDa > 3.5 kDa. Known cytokines with similar biochemical features do not possess the same b iological activity. These findings indicate that angiogenesis can be m ediated by endothelial cell bFGF through an autocrine mechanism and th at the bFGF-inducing peptide may represent a novel tumor-derived angio genic factor that modulates in endothelial cells the concerted express ion of cytokines and proteolytic enzymes required for capillary format ion. (C) 1994 Wiley-Liss, Inc.