GROWTH-FACTOR PDGF-B V-SIS CONFERS A TUMORIGENIC PHENOTYPE TO HUMAN TUMOR-CELLS BEARING PDGF RECEPTORS BUT NOT TO CELLS DEVOID OF RECEPTORS- EVIDENCE FOR AN AUTOCRINE, BUT NOT A PARACRINE, MECHANISM/

Numerous established human tumor lines co-express platelet-derived gro wth factor (PDGF) and cognate receptors, suggesting that an autocrine and/or paracrine growth mechanism may be a causal or contributing mech anism to their transformed phenotype. Indeed, it is known that a PDGF- autocrine system is functional in several established tumor lines, esp ecially in human gliomas, and a model for a functional paracrine mecha nism has been established in a human melanoma line. However, at least 168 human cell lines representing 26 different human tumor types have been reported to continuously express PDGF-A and/or -B chains, and 55 of these also express PDGF receptors. For the majority of these cases, the significance of co-expression and the relative roles of autocrine and paracrine mechanisms in transformation remains unclear. Here, we show that human glioblastoma T98G cells co-express PDGF-B/c-sis and mo derate levels of the cognate beta-type PDGF receptor (PR-beta) but are not tumorigenic in athymic mice. In contrast, human breast carcinoma MCF-7 cells do not express PR-beta and are tumorigenic. Clonal lines o f each cell type with greatly increased secretion of p16(v-sis) (T98Gs is and MCF-7sis cells) were characterized. T98Gsis cells are 85% tumor igenic and occasionally develop pulmonary metastases, showing that end ogenous PR-beta can mediate complete transformation upon sufficient st imulation. In contrast, MCF-7sis cells exhibit some growth slowing in vitro and an exactly proportional decrease in tumor growth rate. We co nclude that a PDGF-autocrine, and not a paracrine, mechanism best acco unts for the acquired tumorigenicity of T98Gsis cells, thereby emphasi zing the potential significance of expression of even moderate levels of PR-beta by human tumor cells. (C) 1996 Wiley-Liss, Inc.