A DOMINANT-NEGATIVE MUTANT OF THE PLATELET-DERIVED GROWTH-FACTOR A-CHAIN INCREASES SURVIVAL OF HAMSTERS IMPLANTED INTRACEREBRALLY WITH THE HIGHLY INVASIVE CXT24-NEO3 GLIOBLASTOMA CELL

Evidence is accumulating to suggest a role for PDGF in stimulating mal ignant growth in astrocytoma, although it has been obtained using mode l systems (growth in 2-dimensional cell culture, athymic nude mice) th at do not assess the complex interactions of these tumors with normal brain tissue. In the current study, the highly invasive hamster gliobl astoma cell line CxT24-neo3 was used as a model to study the role of p latelet-derived growth factor (PD GF) in mediating malignant growth bo th in vitro and in vivo when implanted directly into the right lateral ventricle of the brain. Co-expression of PDGF B-chain mRNA and PD GF alpha-receptors was detected in these cells, indicating potential for autocrine activation of their growth. CxT24-neo3 cells transfected wit h wild-type and receptor binding-deficient forms of the PDGF A- and B- chains displayed alterations in their abilities to grow as three-dimen sional spheroids, with overexpression of wild-type B-chain resulting i n increased spheroid formation, but a decreased rate of spheroid growt h. Influence of these PDGF polypeptides on tumor invasion and survival time in vivo was evaluated following implantation of these spheroids in the brain. While all hamsters implanted with control spheroids died within 21 d (average 17 d), those implanted with cells expressing the receptor binding-deficient A-chain survived for much greater periods of time (average 80 d). Modest increases in survival were also seen in cells stably expressing wild-type A-chain (25 d) and mutant B-chain ( 26 d) proteins. The present study suggests an important role of PDGF i n mediating the malignant growth of the CxT24-neo3 cell line in cerebr al cortex, possibly via paracrine interactions with normal cortical ce ll types (i.e., glia, neurons).