Agonistic Tie2 antibody suppresses normal-to-tumor vascular transition in glioblastoma invading zone

Abstract Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffusive tumor-infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to tumor core was also found in human GBM. The levels of VEGF and VEGFR2 showed a spatial correlation with the extent of vascular abnormality spanning the tumor invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in invasion-associated vascular transition. As ANGPT2 was expressed only in a portion of the central tumor vessels, we developed a ligand-independent Tie2-activating antibody that can phosphorylate Tie2 in vivo. This agonistic Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo. Thus, our study reveals that the normal-to-tumor vascular transition spatio-temporally associates with GBM invasion and may be controlled by Tie2 activation with a novel mechanism-of-action.