Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation.
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.
Kadenhe-Chiweshe
Angela
A
Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
Papa
Joey
J
McCrudden
Kimberly W
KW
Frischer
Jason
J
Bae
Jae-O
JO
Huang
Jianzhong
J
Fisher
Jason
J
Lefkowitch
Jay H
JH
Feirt
Nikki
N
Rudge
John
J
Holash
Jocelyn
J
Yancopoulos
George D
GD
Kandel
Jessica J
JJ
Yamashiro
Darrell J
DJ
D000818:Animals; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D018197:Hepatoblastoma / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009367:Neoplasm Staging; D009369:Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012074:Remission Induction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000099175:Heparanase
D003094:Collagen; D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099175:Heparanase; C071927:perlecan