PDGF-C induces maturation of blood vessels in a model of glioblastoma and attenuates the response to anti-VEGF treatment.

Abstract

BACKGROUND:

Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). However, the survival benefit is usually short-lived as tumors escape anti-VEGF therapies. Here we tested the hypothesis that Platelet Derived Growth Factor-C (PDGF-C), an isoform of the PDGF family, affects GBM progression independent of VEGF pathway and hinders anti-VEGF therapy.

PRINCIPAL FINDINGS:

We first showed that PDGF-C is present in human GBMs. Then, we overexpressed or downregulated PDGF-C in a human GBM cell line, U87MG, and grew them in cranial windows in nude mice to assess vessel structure and function using intravital microscopy. PDGF-C overexpressing tumors had smaller vessel diameters and lower vascular permeability compared to the parental or siRNA-transfected tumors. Furthermore, vessels in PDGF-C overexpressing tumors had more extensive coverage with NG2 positive perivascular cells and a thicker collagen IV basement membrane than the controls. Treatment with DC101, an anti-VEGFR-2 antibody, induced decreases in vessel density in the parental tumors, but had no effect on the PDGF-C overexpressing tumors.

CONCLUSION:

These results suggest that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization.

• Authors: Emmanuelle di Tomaso, Nyall London, Daniel Fuja, James Logie, James A Tyrrell, Walid Kamoun, Lance L Munn, Rakesh K Jain
• Journal: PloS one (PLoS One) Vol. 4 Issue 4 Pg. e5123 ( 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 19352490 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• DC101 monoclonal antibody
• Lymphokines
• Platelet-Derived Growth Factor
• Vascular Endothelial Growth Factor A
• platelet-derived growth factor C

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Capillary Permeability
• Cell Line, Tumor
• Glioblastoma (blood supply, drug therapy)
• Humans
• Lymphokines (metabolism, physiology)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Platelet-Derived Growth Factor (metabolism, physiology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)