LAUSR

Abstract Background: Central nervous system (CNS) hemangioblastoma (HB) is the most common tumor in the von Hippel Lindau (VHL) disorder, the hereditary tumor syndrome caused by the biallelic mutations of the VHL gene. The disrupted VHL and Elongin protein interaction on hypoxia-inducible factor-1α (HIF-1α) induces a set of hypoxia-inducible genes, resulting in an unchecked endothelial cell proliferation that then leads to hemangioblastoma formation. However, recent studies have shown that disruptive germline mutations of VHL need not result in hemangioblastoma, though it can cause other manifestations of the VHL syndrome. Similarly, sporadic hemangioblastoma can occur rarely without a somatic biallelic VHL mutation. The VHL protein was earlier found to be associated with the deposition of matrix fibronectin (FN) protein in the renal extracellular matrix. Methods: The present study was designed to investigate the deposition of the matrix FN protein in VHL-associated hemangioblastoma. Results: Seven HB tumor samples from the VHL syndrome had lower expressions of tissue FN compared to the control cerebellum samples or the control blood vessel sample. On comparing the VHL and FN protein expressions in a timed endothelial tube assay, the VHL protein expression was absent during the initial phase of tube formation but started expressing after 6 h. The levels of matrix form of FN gradually increased along with the VHL expression during the maturation of tube formation. Tube formation was found to be enhanced with extraneously added soluble FN and inhibited by matrix FN. Similarly, tube formation was inhibited by a modified tripeptide (RGD) inhibitor of integrin (-αVβ3), namely, Cyclo-Ala-Arg-Gly-Asp-3-aminomethylbenzoyl. Conclusions: Our study implicates that the extracellular deposition and matrix formation of FN is important for vascular endothelial proliferation, and that its absence has roles in the development of hemangioblastoma in the VHL syndrome.