Autocrine stimulation by platelet-derived growth factor-B (PDGF-B)

Autocrine stimulation by platelet-derived growth factor-B (PDGF-B) like factors hasbeenwidely Implicated asan important mechanismin the causeand/or maintenanceof a variety of human tumors. However,normal human cells appear to be resistant to transformation by PDGF-B-like molecules,and a direct demonstrationof the tumor-promoting or tumor maintaining property of a PDGF-B autocrine system is lacking. T9SG human glioblastoma cells are nontumorigenic in athymic mice. We show that thesecells expresspredominantly PDGF-fi type receptorsand con tinuously secrete small amount of PDGF-B/c-sis. Addition of suramin or specific anti-PDGF-B/v-sis antibody inhibits proliferation In culture. Con versely, multiple clonal lines that stably overexpress PDGF-B/v-sis (T9SGsis cells) exhibit a striking 200—250%increased proliferation rate and an enhancedcolony-forming frequencyin soft agar. Clonal lines with stableexpressionof PDGF-B/v-sis(T9SGsiscells) reliably (80%) develop tumors in 4—6weeks,whereasthe empty-vector control cells are nontu morigenic. Moreover, in somecases,T9SGsiscells disseminateto form bilateral and multifocal pulmonary metastases.The results show that T98G cellscontain functional PDGF receptorsthat, upon sufficient slim ulation, can causegreatly increasedmitogenic response,which may ac count for the developmentof the malignant phenotype.Metastatic tumor formation In athymic mice by PDGF stimulation has not been reported previously. The mechanism may depend on preexisting changes such as the lost p53function ofthesecells.T9SGsiscellsprovide a modelof growth factor-dependenttumongenesisand metastases, which may be helpful in elucidating theserelationships.