Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma

Nibal Zaghloul, Sonia L. Hernandez, Jae O. Bae, Jianzhong Huang, Jason C. Fisher, Alice Lee, Angela Kadenhe-Chiweshe, Jessica J. Kandel, Darrell J. Yamashiro

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)401-407
Number of pages7
JournalInternational journal of oncology
Volume34
Issue number2
DOIs
StatePublished - 2009
Externally publishedYes

Keywords

  • Angiogenesis
  • Neuroblastoma
  • Notch
  • Placental growth factor
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma'. Together they form a unique fingerprint.

Cite this