Abstract 5222: Endothelial plasticity generates aberrant angiogenesis and therapy resistance in glioblastoma
Authors: Huang Menggui , Fan Yi 
Published: August 2015

Overgrown, abnormal vasculature characterizes the microenvironment that fuels cancer progression and induces therapeutic resistance. Here we reveal that endothelial plasticity drives excessive and abnormal tumor angiogenesis. Glioblastoma multiforme (GBM) is among the most lethal of human malignancies, distinguished by prominent vascularity and extreme vascular abnormality. We identify endothelial fibro-transformation (Endo-FT) in GBM, contributing significantly to aberrant vascularization, tumor progression, and therapeutic resistance. Utilizing human GBM specimens and allograft and genetic murine GBM models driven by RCAS/Ntv-a-mediated gene transfer of PDGF in Ink4a-Arf-/-PTEN-/- mice, we reveal robust Endo-FT in the tumor vasculature, characterized by endothelial cell (EC) expression of the fibroblast and mesenchymal cell markers including FSP-1, α-smooth muscle actin, N-cadherin. Moreover, genetic lineage tracing shows a prominent population of GBM-associated fibroblast-like cells with EC origin. Furthermore, glioma-conditioned medium induces EC in vitro acquisition of the fibroblast signature with decreased expression of EC-specific proteins including CD31, VE-cadherin, Tie2, VEGFR2, leading to enhanced cell proliferation, motility, and invasiveness, and vessel permeability. Interestingly, the fibroblast-like ECs retain the key EC-specific functions including Ac-LDL absorption and tube formation, suggesting Endo-FT without complete EC transition to fibroblasts.

Proteomic analysis identifies c-Met is a regulator of Endo-FT, requisite for the vascular abnormality. Pharmacological inhibition and siRNA-mediated knockdown of c-Met or neutralization with a HGF antibody remarkably abrogate tumor-conditioned medium-induced Endo-FT and EC malfunctions, suggesting a critical role of HGF/c-Met in Endo-FT. Furthermore, c-Met activation induces ETS-1-dependent matrix metalloproteinase (MMP)-14 expression, leading to VE-cadherin cleavage and Endo-FT.

Finally, we test the in vivo role of c-Met-mediated Endo-FT in GBM progression by using mice with Tie2-Cre-driven, EC-specific Met knockout. Met deletion in ECs significantly improves mouse survival and inhibits GBM growth after temozolomide (TMZ) treatment. Moreover, Met deletion in ECs abolishes Endo-FT and vascular abnormality, as shown by remarkable decreases in CD31+FSP-1+ cell population and intratumor hypoxia, and increases in vasculature-mediated perfusion and vascular pericyte coverage, suggesting that c-Met-mediated Endo-FT is required for vascular abnormality and GBM progression and therapeutic resistance.

In sum, these findings illustrate a novel mechanism controlling aberrant vascularization and GBM progression, and suggest that targeting Endo-FT may offer selective and efficient therapeutic strategies for the treatment-resistant GBM, and possibly other malignant tumors.

Citation Format: Menggui Huang, Yi Fan. Endothelial plasticity generates aberrant angiogenesis and therapy resistance in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5222. doi:10.1158/1538-7445.AM2015-5222