Dose-dependent effects of platelet-derived growth factor-B on glial tumorigenesis.

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Brain-Neoplasms, Cell-Division, Glioma, Mice-Transgenic, NIH-3T3-Cells, Neovascularization-Pathologic, Platelet-Derived-Growth-Factor, Proto-Oncogene-Proteins-c-sis, Receptors-Platelet-Derived-Growth-Factor, Receptors-Vascular-Endothelial-Growth-Factor, Signal-Transduction, Transfection

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Cancer Res 2004 Jul; 64(14):4783-9.


Platelet-derived growth factor (PDGF) is expressed in many different tumors, but its precise roles in tumorigenesis remain to be fully defined. Here, we report on a mouse model that demonstrates dose-dependent effects of PDGF-B on glial tumorigenesis. By removing inhibitory regulatory elements in the PDGFB mRNA, we are able to substantially elevate its expression in tumor cells using a retroviral delivery system. This elevation in PDGF-B production results in tumors with shortened latency, increased cellularity, regions of necrosis, and general high-grade character. In addition, elevated PDGF-B in these tumors also mediates vascular smooth muscle cell recruitment that supports tumor angiogenesis. PDGF receptor (PDGFR) signaling appears to be required for the maintenance of these high-grade characteristics, because treatment of high-grade tumors with a small molecule inhibitor of PDGFR results in reversion to a lower grade tumor histology. Our data show that PDGFR signaling quantitatively regulates tumor grade and is required to sustain high-grade oligodendrogliomas.