PLEIOTROPIC EFFECTS OF PDGF SUGGEST NEW TARGETS FOR CANCER-THERAPY

The platelet-derived growth factor (PDGF) is a potent mitogen and chem otactic factor. Because the B chain of PDGF is a proto-oncogene, it is important in transformation and believed to transform cells by an aut ocrine mechanism. Both PDGF A and PDGF B are often highly expressed in tumor cell lines and thus PDGF may be important in other ways in huma n malignancies. We now show that the autocrine mechanism of transforma tion by PDGF is required but not sufficient for transformation of cell s by PDGF and that PDGF requires a second, genetically stable abnormal ity with which to cooperate with endogenous overexpression of the bcl- 2 gene to induce transformation of normal rat kidney (NRK) cells, thus identifying one pathway with which PDGF can cooperate in a multi-step pathway of transformation. We also have identified a new property of PDGF. Under conditions of growth arrest by culture in 0.1% serum, PDGF induces apoptosis in NRK cells. The apoptotic response is seen with b oth PDGF A and B. It is not blocked by endogenous expression of the bc l-2 gene product but insulin rescues NRK cells from apoptotic cell dea th. The PDGF isoforms appear to be highly relevant targets for therape utic intervention at multiple levels.