RRC ID 43254
Author Kadenhe-Chiweshe A, Papa J, McCrudden KW, Frischer J, Bae JO, Huang J, Fisher J, Lefkowitch JH, Feirt N, Rudge J, Holash J, Yancopoulos GD, Kandel JJ, Yamashiro DJ.
Title Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation.
Journal Mol. Cancer Res.
Abstract Vascular endothelial growth factor (VEGF) blockade has been validated clinically as a treatment for human cancers, yet virtually all patients eventually develop progressive disease during therapy. In order to dissect this phenomenon, we examined the effect of sustained VEGF blockade in a model of advanced pediatric cancer. Treatment of late-stage hepatoblastoma xenografts resulted in the initial collapse of the vasculature and significant tumor regression. However, during sustained treatment, vessels recovered, concurrent with a striking increase in tumor expression of perlecan, a heparan sulfate proteoglycan. Whereas VEGF mRNA was expressed at the periphery of surviving clusters of tumor cells, both secreted VEGF and perlecan accumulated circumferential to central vessels. Vascular expression of heparanase, VEGF receptor-2 ligand binding, and receptor activation were concurrently maintained despite circulating unbound VEGF Trap. Endothelial survival signaling via Akt persisted. These findings provide a novel mechanism for vascular survival during sustained VEGF blockade and indicate a role for extracellular matrix molecules that sequester and release biologically active VEGF.
Volume 6(1)
Pages 1-9
Published 2008-1
DOI 10.1158/1541-7786.MCR-07-0101
PII 6/1/1
PMID 18234958
MeSH Animals Collagen / metabolism Endothelial Cells / enzymology Endothelial Cells / metabolism Enzyme Activation Female Gene Expression Regulation, Neoplastic Glucuronidase / metabolism Heparan Sulfate Proteoglycans / metabolism Hepatoblastoma / blood supply Hepatoblastoma / enzymology Hepatoblastoma / genetics Hepatoblastoma / pathology Humans Mice Mice, Nude Models, Biological Neoplasm Staging Neoplasms / blood supply Neoplasms / enzymology Neoplasms / pathology Neovascularization, Pathologic / genetics Phosphorylation Protein Binding Proto-Oncogene Proteins c-akt / metabolism Remission Induction Vascular Endothelial Growth Factor A / antagonists & inhibitors* Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism Vascular Endothelial Growth Factor Receptor-2 / genetics Vascular Endothelial Growth Factor Receptor-2 / metabolism* Xenograft Model Antitumor Assays
IF 4.484
Times Cited 43
Human and Animal Cells