A Comprehensive Procedure to Evaluate the <em>In Vitro</em> Performance of the Putative Hemangioblastoma Neovascularization Using the Spheroid Sprouting Assay

Abstract

The inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene plays a crucial role in the development of hemangioblastomas (HBs) within the human central nervous system (CNS). However, both the cytological origin and the evolutionary process of HBs (including neovascularization) remain controversial, and anti-angiogenesis for VHL-HBs, based on classic HB angiogenesis, have produced disappointing results in clinical trials. One major obstacle to the successful clinical translation of anti-vascular treatment is the lack of a thorough understanding of neovascularization in this vascular tumor. In this article, we present a comprehensive procedure to evaluate in vitro whether classic tumor angiogenesis exists in HBs, as well as its role in HBs. With this procedure, researchers can accurately understand the complexity of HB neovascularization and identify the function of this common form of angiogenesis in HBs. These protocols can be used to evaluate the most promising anti-vascular therapy for tumors, which has high translational potential either for tumors treatment or for aiding in the optimization of the anti-angiogenic treatment for HBs in future translations. The results highlight the complexity of HB neovascularization and suggest that this common form angiogenesis is only a complementary mechanism in HB neovascularization.

Intermixed arteriovenous malformation and hemangioblastoma: case report and literature review

“…HB neovascularization results from VHL-silencing associated mechanisms which include the classically appreciated VEGF-mediated angiogenesis in addition to VEGF-independent angiogenesis and vasculogenesis [ 12 , 26 , 34 , 35 ]. VEGF-independent mechanisms of angiogenesis also exist, increasingly discovered following disappointing clinical trials focused on VEGF-mediated angiogenesis [ 36 , 37 ]. Endothelial VHL-silencing associated Twist1 accumulation is a VEGF-independent mechanism of common angiogenesis that is only recently reported [ 26 , 37 ].…”

“…VEGF-independent mechanisms of angiogenesis also exist, increasingly discovered following disappointing clinical trials focused on VEGF-mediated angiogenesis [ 36 , 37 ]. Endothelial VHL-silencing associated Twist1 accumulation is a VEGF-independent mechanism of common angiogenesis that is only recently reported [ 26 , 37 ].…”

“…For HB, the clinical translation of anti-angiogenic therapeutics has been disappointing [ 73 ]. In HB, this is attributed, at least in part, to the lack of knowledge in terms of the cytological origin, evolutionary processes and neovascularization in this lesion [ 37 ]. A 2009 Dartmouth trial (NCT01015300) of anti-VEGF bevacizumab (Avastin) in VHL disease-associated unresectable/recurrent HB was terminated in 2012 due to low accrual, while a case report of favorable outcome exists [ 74 ].…”