Abstract
BackgroundRecent 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 FindingsWe 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.ConclusionThese 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.
Highlights
Glioblastoma Multiforme (GBM) is a uniformly fatal tumor afflicting approximately 9,000 persons each year in the United States, and there is currently no efficacious therapy
These results suggest that Platelet Derived Growth Factor-C (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
Human gliomas express significant levels of Platelet-derived growth factors (PDGF)-C To assess whether PDGF-C is expressed in human glioblastomas, we first examined a series of 27 surgical specimens of human glioblastomas from MGH patients
Summary
Glioblastoma Multiforme (GBM) is a uniformly fatal tumor afflicting approximately 9,000 persons each year in the United States, and there is currently no efficacious therapy. Anti-VEGF treatment of recurrent tumors has shown some promise, but these tumors invariably escape VEGF-blockade [2,3,4]. Platelet-derived growth factors (PDGF) are a pleiotropic family of peptides that signal through cell surface, tyrosine kinase receptors (PDGFR) and stimulate cellular functions including growth, proliferation and differentiation [5]. Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). The survival benefit is usually short-lived as tumors escape anti-VEGF therapies. 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
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