Researchers from the Massachusetts Eye and Ear and the Harvard Medical School/ Massachusetts Institute of Technology (MA, USA) have revealed new understanding of the pathobiology behind the head and neck tumors termed vestibular schwannomas (VS), which may lead to new targeted drug therapies. The study was recently published in Cancer Biology and Therapy.
Vestibular schwannoma are the fourth most common intracranial tumor and arise from the Schwann cells of the vestibular nerve. Patients with these tumors often suffer from hearing loss and tinnitus. Several pathways have been independently implicated in VS pathobiology, yet the interactions among these pathways are not yet fully understood.
The authors investigated the potential cross-talk between hepatocyte growth factor (HGF) and VEGF-A in human VS. VEGF-A is key as it is inhibited by bevacizumab, a drug currently utilized to treat some types of VS. However, bevacizumab is only effective in 55% of patients, motivating the ongoing work to discover additional drug targets for this cancer.
Using freshly harvested human specimens from indicated surgeries, the authors confirmed previous findings that VEGF-A signaling is aberrantly upregulated in VS, and established that expression of HGF and its receptor cMET is also significantly increased in sporadic VS compared with healthy nerves.
In primary human VS and Schwann cell cultures, the team demonstrated that VEGF-A and HGF signaling pathways regulate each other. siRNAs targeting cMET decreased both cMET and VEGF-A protein levels, and siRNAs targeting VEGF-A reduced cMET expression. Furthermore, siRNA-mediated knockdown of VEGF-A or cMET, and pharmacologic inhibition of cMET decreased cellular proliferation in primary human VS cultures.
Senior author Konstantina Stankovic from Harvard Medical School concluded: “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.”
Sources: Dilwali S, Roberts D, Stankovic KM. Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells. Cancer Biology & Therapy, DOI: 10.4161/15384047.2014.972765 (2015) [Epub ahead of print]; Massachusetts Eye and Ear Infirmary press release via Newswise