Platelet-derived growth factor-B/v-sis confers a tumorigenic and metastatic phenotype to human T98G glioblastoma cells.

Abstract

Autocrine stimulation by platelet-derived growth factor-B (PDGF-B)-like factors has been widely implicated as an important mechanism in the cause and/or maintenance of a variety of human tumors. However, normal human cells appear to be resistant to transformation by PDGF-B-like molecules, and a direct demonstration of the tumor-promoting or tumor-maintaining property of a PDGF-B autocrine system is lacking. T98G human glioblastoma cells are nontumorigenic in athymic mice. We show that these cells express predominantly PDGF-beta type receptors and continuously secrete small amount of PDGF-B/c-sis. Addition of suramin or specific anti-PDGF-B/v-sis antibody inhibits proliferation in culture. Conversely, multiple clonal lines that stably overexpress PDGF-B/v-sis (T98Gsis cells) exhibit a striking 200-250% increased proliferation rate and an enhanced colony-forming frequency in soft agar. Clonal lines with stable expression of PDGF-B/v-sis (T98Gsis cells) reliably (80%) develop tumors in 4-6 weeks, whereas the empty-vector control cells are nontumorigenic. Moreover, in some cases, T98Gsis cells disseminate to form bilateral and multifocal pulmonary metastases. The results show that T98G cells contain functional PDGF receptors that, upon sufficient stimulation, can cause greatly increased mitogenic response, which may account for the development of 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 p53 function of these cells. T98Gsis cells provide a model of growth factor-dependent tumorigenesis and metastases, which may be helpful in elucidating these relationships.