Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma.
Most children with neuroblastoma presenting after infancy have metastatic, chemoresistant disease. Amplification of the MYCN proto-oncogene is a significant marker of these poor-prognosis neuroblastoma tumors. Recent studies suggest that MYCN may function in part by promoting angiogenesis via vascular endothelial growth factor (VEGF). VEGF blockade has been validated as a therapeutic strategy in adult cancers. In these studies, we asked whether inhibition of VEGF signaling via VEGFR2 blockade in established MYCN-amplified neuroblastoma xenografts would: 1) restrict tumor growth; 2) induce hypoxia; and 3) alter tumor vasculature. The MYCN-amplified neuroblastoma human cell line NGP was implanted intrarenally in athymic female mice. After 5 weeks, mice with established tumors were selected, a cohort euthanized to provide day 0 controls, and the rest assigned to receive biweekly injections of DC101 (anti-murine VEGFR2 antibody) or vehicle. DC101 treatment did not inhibit progressive tumor growth in established NGP xenografts. Although tumor vasculature was not significantly disrupted, a modest increase in tumor hypoxia was demonstrated by pimonidazole staining, and expression of a previously described hypoxia metagene was increased by gene set enrichment analysis (GSEA) in DC101-treated tumors. DC101 treatment elicited increased: 1) expression of VEGFR1 and its ligand placental growth factor; and 2) increased Notch activation in tumor vasculature concurrent with expression of the Notch ligand Jagged1. This result suggests that established MYCN-amplified neuroblastoma tumors are relatively VEGF-independent, and display the ability to rapidly up-regulate hypoxia-responsive alternative proangiogenic mechanisms that may stabilize vasculature when VEGF is deficient.
Zaghloul
Nibal
N
Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Hernandez
Sonia L
SL
Bae
Jae-O
JO
Huang
Jianzhong
J
Fisher
Jason C
JC
Lee
Alice
A
Kadenhe-Chiweshe
Angela
A
Kandel
Jessica J
JJ
Yamashiro
Darrell J
DJ
D000818:Animals; D002455:Cell Division; D015687:Cell Hypoxia; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009447:Neuroblastoma / Q000098:blood supply*; D000090063:Proto-Oncogene Mas; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2