An agonistic anti-Tie2 antibody suppresses the normal-to-tumor vascular transition in the glioblastoma invasion zone

Abstract

Brain tumours: antibody blocks blood vessel abnormalityAn antibody targeting key signalling pathways could prevent brain tumor vessels from being abnormal, thereby improving drug delivery into tumor tissues. Glioblastoma multiforme is considered one of the most deadly cancers and it invades brain tissue coupled with the loss of vascular integrity. This pathological vascular changes are closely associated with the hyperactivation of a signalling pathway called VEGFR2 and inactivation of another pathway, Tie2. Now, Injune Kim at the Korea Advanced Institute of Science and Technology, Weon Sup Lee at PharmAbcine Inc., both in Daejeon, South Korea, and co-workers have developed a Tie2-activating antibody that effectively stops vascular abnormalization in and around glioblastoma in the spontaneous mouse tumor model. As well as activating Tie2, the antibody suppresses the VEGFR2 pathway. The study therefore reveals a potential strategy for improving glioblastoma treatment through multiple vascular mechanisms. 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 diffuse 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 the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in the invasion-associated vascular transition. As angiopoietin-2 (ANGPT2) was expressed in only a portion of the central tumor vessels, we developed a ligand-independent tunica interna endothelial cell kinase 2 (Tie2)-activating antibody that can result in Tie2 phosphorylation in vivo. This agonistic anti-Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to the effects of 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 is spatiotemporally associated with GBM invasion and may be controlled by Tie2 activation via a novel mechanism of action.