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

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 th...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2004-07, Vol.64 (14), p.4783-4789
Main Authors: SHIH, Alan H, CHENGKAI DAI, XIAOYI HU, ROSENBLUM, Marc K, KOUTCHER, Jason A, HOLLAND, Eric C
Format: Article
Language:English
Subjects:
5' Untranslated Regions
Animals
Antineoplastic agents
Biological and medical sciences
Brain Neoplasms - blood supply
Brain Neoplasms - genetics
Brain Neoplasms - metabolism
Brain Neoplasms - pathology
Cell Division - physiology
Glioma - blood supply
Glioma - genetics
Glioma - metabolism
Glioma - pathology
Medical sciences
Mice
Mice, Transgenic
Neovascularization, Pathologic - genetics
Neovascularization, Pathologic - metabolism
Neovascularization, Pathologic - pathology
NIH 3T3 Cells
Pharmacology. Drug treatments
Platelet-Derived Growth Factor - physiology
Proto-Oncogene Proteins c-sis - biosynthesis
Proto-Oncogene Proteins c-sis - genetics
Proto-Oncogene Proteins c-sis - physiology
Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors
Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors
Signal Transduction - physiology
Transfection
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-03-3831