PDGF-C Induces Maturation of Blood Vessels in a Model of Glioblastoma and Attenuates the Response to anti-VEGF Treatment

PLoS One. 2009;4(4):e5123. doi: 10.1371/journal.pone.0005123. Epub 2009 Apr 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

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