INHIBITION OF GLIOMA CELL-GROWTH BY A TRUNCATED PLATELET-DERIVED GROWTH-FACTOR-BETA RECEPTOR

Abnormal expression of platelet-derived growth factor (PDGF) receptors has been observed in malignant glioma and other tumors such as osteos arcomas and malignant melanomas. However, their role in the developmen t and maintenance of the tumors is not understood. Signaling through t he PDGF receptors is activated by ligand-induced dimerization. Thus, i ntroduction of mutant receptors that are kinase deficient but still di merization competent is one strategy to study the importance of PDGF r eceptors in glioma cell growth. A truncated PDGF-beta receptor was int roduced into C6 rat glioma cells and the PDGF-mediated signaling and s ubsequent cell growth studied. In clones expressing the mutant recepto r, PDGF-BB-induced tyrosine phosphorylation of the endogenous receptor was significantly reduced. In addition, these cells grew to lower den sity in culture and formed smaller colonies in soft agar than the C6 p arental cells. Furthermore, the ability of cells expressing the trunca ted receptor to grow as xenografts in nude mice was significantly impa ired. These results support the important role for the PDGF-beta recep tor in C6 glioma cell growth. They also demonstrate the usefulness of dominant-negative mutants of the PDGF receptor for the evaluation of t he role of the receptor in tumorigenesis.