Researchers from the Eaton-Peabody Laboratories of Massachusetts Eye and Ear and the Harvard Medical School/ Massachusetts Institute of Technology Program in Speech and Hearing Bioscience and Technology have revealed new understanding of the pathobiology behind a head and neck tumor that may someday lead to new methods of targeted drug therapy.
Their paper, "Interplay Between VEGF-A and cMET Signaling in Human Vestibular Schwannomas and Schwann Cells," by Sonam Dilwali, B.S., Daniel Roberts, M.D., Ph.D., and Konstantina M. Stankovic, M.D., Ph.D., FACS, is online in the Feb. 20 issue of Cancer Biology and Therapy.
Vestibular schwannoma (VS), the fourth most common intracranial tumor, arises from the Schwann cells of the vestibular nerve. Patients with this tumor typically present with hearing loss and tinnitus. Although several pathways have been independently implicated in VS pathobiology, interactions among these pathways have not been explored in depth.
The authors investigated the potential cross-talk between hepatocyte growth factor (HGF) and vascular endothelial growth factor-A (VEGF-A) in human VS. VEGF-A is important because it is inhibited by bevacizumab, the drug currently used to treat some VSs. However, bevacizumab is effective in only 55% of patients, motivating the ongoing work to discover additional drug targets in VSs.
Using freshly harvested human specimens from indicated surgeries, the authors 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, they 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 two prominent pathways in VS and highlight the HGF/cMET pathway as an additional important therapeutic target in VS," said senior author Dr. Stankovic, , an assistant professor of otology and laryngology at Harvard Medical School.