Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy

Ling Geng, Edwin Donnelly, Gerald McMahon, P. Charles Lin, Elaine Sierra-Rivera, Halina Oshinka, Dennis E. Hallahan

Research output: Contribution to journalArticlepeer-review

329 Scopus citations

Abstract

Certain refractory neoplasms, such as glioblastoma multiforme (GBM) and melanoma, demonstrate a resistant tumor phenotype in vivo. We observed that these refractory tumor models (GBM and melanoma) contain blood vessels that are relatively resistant to radiotherapy. To determine whether the vascular endothelial growth factor receptor-2 (Flk-1/KDR) may be a therapeutic target to improve the effects of radiotherapy, we used the soluble extracellular component of Flk-1 (ExFlk), which blocks vascular endothelial growth factor binding to Flk-1 receptor expressed on the tumor endothelium. Both sFlk-1 and the Flk-1-specific inhibitor SU5416 eliminated the resistance phenotype in GBM and melanoma microvasculature as determined by both the vascular window and Doppler blood flow methods. Human microendothelial cells and human umbilical vein endothelial cells showed minimal radiation-induced apoptosis. The Flk-1 antagonists sFIk-1 and SU5416 reverted these cell models to apoptosis-prone phenotype. Flk-1 antagonists also reverted GBM and melanoma tumor models to radiation-sensitive phenotype after treatment with 3 Gy. These findings demonstrate that the tumor microenvironment including the survival of tumor-associated endothelial cells contributes to tumor blood vessel resistance to therapy.

Original languageEnglish
Pages (from-to)2413-2419
Number of pages7
JournalCancer research
Volume61
Issue number6
StatePublished - Mar 15 2001

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