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

• Published in: Journal of neuro-oncology 1998-08, Vol.39 (1), p.33-46
• Main Authors: KAETZEL, D. M, REID, J. D, PEDIGO, N, ZIMMER, S. G, BOGHAERT, E. R
• Format: Article
• Language: English
• Subjects: Animals; Astrocytoma; Autocrine signalling; Biological and medical sciences; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - therapy; Brain tumors; Cell culture; Cerebral cortex; Cricetinae; Gene expression; Genes, Dominant; Glioblastoma; Glioblastoma - genetics; Glioblastoma - therapy; Glioma; Growth factors; Injections, Intraventricular; Medical sciences; Mesocricetus; mRNA; Mutants; Neoplasm Invasiveness; Neoplasm Transplantation; Neurology; Neuronal-glial interactions; Organoids; Paracrine signalling; Platelet-derived growth factor; Platelet-Derived Growth Factor - biosynthesis; Platelet-Derived Growth Factor - genetics; Platelet-Derived Growth Factor - physiology; Platelet-derived growth factor A; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Spheroids; Transfection; Tumor Cells, Cultured; Tumors of the nervous system. Phacomatoses; Ventricle; Ventricles (cerebral)
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1023/A:1005905217361

Evidence is accumulating to suggest a role for PDGF in stimulating malignant growth in astrocytoma, although it has been obtained using model systems (growth in 2-dimensional cell culture, athymic nude mice) that do not assess the complex interactions of these tumors with normal brain tissue. In the current study, the highly invasive hamster glioblastoma cell line CxT24-neo3 was used as a model to study the role of platelet-derived growth factor (PDGF) in mediating malignant growth both in vitro and in vivo when implanted directly into the right lateral ventricle of the brain. Co-expression of PDGF B-chain mRNA and PDGF alpha-receptors was detected in these cells, indicating potential for autocrine activation of their growth. CxT24-neo3 cells transfected with wild-type and receptor binding-deficient forms of the PDGF A- and B-chains displayed alterations in their abilities to grow as three-dimensional spheroids, with overexpression of wild-type B-chain resulting in increased spheroid formation, but a decreased rate of spheroid growth. 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 in mediating the malignant growth of the CxT24-neo3 cell line in cerebral cortex, possibly via paracrine interactions with normal cortical cell types (i.e., glia, neurons).