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

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.

Can enoxaparin reduce thromboembolism related events after primary TKA in Asian patients?

The purpose of this study was to investigate the efficacy and safety of enoxaparin in preventing venous and arterial thromboembolism related events after primary total knee arthroplasty (TKA) in Asian patients. Four hundred twenty nine patients (621 TKAs) did not receive thromboprophylaxis after TKA and 907 patients (1,336 TKAs) received enoxaparin after the procedure. We assessed clinically significant venous and arterial thromboembolism related events and bleeding complications. Total thromboembolism related events occurred in 13 patients (3.03%) without thromboprophylaxis and 17 patients (1.87%) with enoxaparin (P = 0.183). Our study showed that the incidence of clinically significant thromboembolism related events after TKA was very low in Asian patients. Enoxaparin had no benefits in reducing thromboembolism related events in Asian patients.