Endothelial cells by inactivation of VHL gene direct angiogenesis, not vasculogenesis via Twist1 accumulation associated with hemangioblastoma neovascularization

Abstract

Inactivation of the VHL tumour suppressor gene is a highly frequent genetic event in the carcinogenesis of central nervous system-(CNS) hemangioblastomas (HBs). The patterning of the similar embryonicvasculogenesis is an increasing concern in HB-neovascularization, and the classic vascular endothelial growth factor (VEGF)-mediated angiogenesis driven by VHL loss-of-function from human endothelium have been questioned. With this regard, we identify a distinct, VHL silencing-driven mechanism in which human vascular endothelial cells by means of increasing cell proliferation and decreasing cell apoptosis, is concomitant with facilitating accumulation of Twist1 protein in vascular endothelial cells in vitro. Importantly, this molecular mechanism is also pinpointed in CNS-HBs, and associated with the process of HB-neovascularization. In contrast with recent studies of HB-neovascularization, these modified cells did not endow with the typical features of vasculogenesis, indicating that this is a common angiogenesis implementing the formation of the vascular network. Taken together, these findings suggest that vasculogenesis and angiogenesis may constitute complementary mechanisms for HB-neovascularization, and could provide a rational recognition of single anti-angiogenic intervention including targeting to the Twist1 signalling for HBs.Hemangioblastomas (HBs) are high-vascularized neoplasms commonly arising in the cerebellum or brainstem [1][2][3][4] . The cytological origin and process of neovascularization remains tremendously controversial. Etiologically, HBs are divided into two subtypes, the sporadic HBs (takes up 75%) and familial HBs (VHL disease) (takes up 25%). Histologic examination showed numerous small capillary channels and abundant vacuolated 'stromal cells' in sporadic HBs and VHL-HBs 2 . Currently, surgical complete resection is the only curative treatment for sporadic HBs; however, surgical treatment of brain-stem HBs is a great challenge to neurosurgeons because of the location of HBs. Moreover, as an inherited multisystem disorder, VHL-HBs are difficult to be cured. So a better understanding of HB biological mechanisms may further provide useful insights into its therapeutic strategies.The cytological origin of HBs (including its neovascularization) and its evolutionary process remain controversial for nearly a century. The related studies are associated with the vascular progenitors including embryonic cells, reactive endothelial cells, stromal cells, and mast cells etc 5,6 . In recent years, increasing evidence has showed that many mesodermal makers were expressed in both sporadic and inherited HBs 7,8 , suggesting that HB-neovascularization is a similar embryologic vasculogenesis [9][10][11][12] . Then, as the classic hypothesis of HB-angiogenesis, the vascular endothelial growth factor (VEGF) secreted by stromal cells may bind to endothelial cells and trigger an intracellular signaling pathway in the endothelial cells that eventually results in cell proliferation and vascular formation 13 . In ...

Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin

“…TWIST1 induces angiogenesis in vivo [64,65]. This prompted us to examine the gene expression profile of angiogenesis related genes in MCF-7 cells.…”

Intermixed arteriovenous malformation and hemangioblastoma: case report and literature review

“…Third, in both HB and AVM, there is a significant genetic component to development, which overlaps between lesions. This overlap, such as must be appreciated in an intermixed lesion, continues to be elucidated as the individual processes of neovascularization in HB and AVM continues to be researched, including the differential role of component cell types, and their variable activation of angiogenic pathways [ 26 , 27 ].…”

“…These include primarily VEGF/VEGFR2, but also: Notch/Dll4, EphB4/EphrinB2 and SDF1α/CXCR4 pathways [ 33 ]. 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 ].…”

“…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 ].…”

“…Other multityrosine kinase inhibitor trials for HB were disappointing, with the dovitinib trial discontinued owing to toxicity, while erlotinib and sunitinib were found to be of limited benefit [ 79–82 ]. Emerging research into HB neovascularization mechanisms – such as Twist1 signaling, described above – may provide additional anti-angiogenic therapeutic targets [ 26 ].…”