Vestibular schwannoma (VS), the fourth most common intracranial tumor, arises from the Schwann cells of the vestibular nerve. Although several pathways have been independently implicated in VS pathobiology, interactions among these pathways have not been explored in depth. We have investigated the potential cross-talk between hepatocyte growth factor (HGF) and vascular endothelial growth factor-A (VEGF-A) in human VS, an interaction that has been described in other physiological and pathological cell types. We affirmed previous findings that VEGF-A signaling is aberrantly upregulated in VS, and established that expression of HGF and its receptor cMET is also significantly higher in sporadic VS than in healthy nerves. In primary human VS and Schwann cell cultures, we found that VEGF-A and HGF signaling pathways modulate each other. siRNAs targeting cMET decreased both cMET and VEGF-A protein levels, and siRNAs targeting VEGF-A reduced cMET expression. Additionally, siRNA-mediated knockdown of VEGF-A or cMET and pharmacologic inhibition of cMET decreased cellular proliferation in primary human VS cultures. Our data suggest cross-talk between these 2 prominent pathways in VS and highlight the HGF/cMET pathway as an additional important therapeutic target in VS.
Keywords: BrdU, 5-Bromo-2'-Deoxyuridine; DMSO, Dimethyl sulfoxide; GAN, Great auricular nerve; HCl, Hydrochloric acid; HGF, Gene encoding HGF protein; HGF, Hepatocyte growth factor; HRP, Horse-radish peroxidase; KDR, Gene encoding vascular endothelial growth factor receptor 2; MET, Gene encoding cMET protein; NF2, Neurofibromatosis type 2; PBS, Phosphate buffered saline; S100, Schwann cell/schwannoma cell marker; SD, Standard deviation; SEM, Standard error of mean; Schwann cells; VEGF-A, Vascular endothelial growth factor-A; VEGFA, Gene encoding VEGF-A protein; VEGFR2, Vascular endothelial growth factor receptor 2; VS, Vestibular schwannoma; cMET, MNNG HOS transforming gene, hepatocyte growth factor receptor; cross-talk; hepatocyte growth factor; mRNA, Messenger ribonucleic acid; siRNA; siRNA, Small interfering ribonucleic acid; vascular endothelial growth factor; vestibular schwannoma.