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

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

  • Published online on: February 1, 2009     https://doi.org/10.3892/ijo_00000163
  • Pages: 401-407
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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.

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February 2009
Volume 34 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Zaghloul, N., Hernandez, S.L., Bae, J., Huang, J., Fisher, J.C., Lee, A. ... Yamashiro, D.J. (2009). Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma. International Journal of Oncology, 34, 401-407. https://doi.org/10.3892/ijo_00000163
MLA
Zaghloul, N., Hernandez, S. L., Bae, J., Huang, J., Fisher, J. C., Lee, A., Kadenhe-Chiweshe, A., Kandel, J. J., Yamashiro, D. J."Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma". International Journal of Oncology 34.2 (2009): 401-407.
Chicago
Zaghloul, N., Hernandez, S. L., Bae, J., Huang, J., Fisher, J. C., Lee, A., Kadenhe-Chiweshe, A., Kandel, J. J., Yamashiro, D. J."Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma". International Journal of Oncology 34, no. 2 (2009): 401-407. https://doi.org/10.3892/ijo_00000163