HER2 Regulation of Vestibular Schwannomas

 

Dr. Joni Doherty

 

Vestibular schwannomas are among the most common intracranial lesions and can lead to devastating and debilitating complications, especially in association with Neurofibromatosis type 2 (NF2). Current treatment modalities are limited to surgery and radiotherapy, which both carry additional risks to the patient. Development of a tumor-specific pharmacotherapy is necessary to add to the armamentarium for treatment in difficult cases, such as patients with NF2. Both sporadic and NF2-associated schwannomas display mutation of the NF2 gene, leading to loss of function of the tumor suppressor schwannomin. The precise function of schwannomin is not known, but it has been shown to translocate to the cell membrane where it associates with the HER2 (ErbB2) receptor, paxillin, and b1-integrin in a cell-density-dependent manner¹. Contact inhibition of growth limits proliferation and appears to be regulated by schwannomin via HER2 receptor internalization. HER2 and neuregulin stimulation are critically involved with Schwann cell growth, survival, proliferation, and differentiation. The mitogenic response of neuregulin stimulation is mediated by HER2/HER3 receptor dimerization and signaling through the PI3K/Akt and MAPK pathways in rodent Schwann cells, but similar events have not been investigated in human Schwann cells or schwannomas. Elucidation of the role of schwannomin and HER2 in the pathogenesis of Schwann cell tumors will be a critical step in developing pharmacologic agents to eradicate schwannomas. Since the erbB family of epidermal growth factor receptors can form all combinations of heterodimers with preference for HER2, it will be important to establish which HER2 partners and ligands promote human Schwann cell tumorigenesis, as well as elucidating the intracellular signaling involved. HER2 and HER3 expression have been demonstrated via immunohistochemistry in human spiral ganglion Schwann cell cultures and VS^{2, 3}. We demonstrate HER2 and HER3 expression as well as HER2 activation in two primary human schwannoma cell lines and a human Schwann cell line via Western blotting techniques. Preliminary studies also suggest HER4 (ErbB4) expression and dimerization with HER2 in VS cell lines. In addition, VS cell proliferation in response to neuregulin is abrogated by ErbB2-specific inhibitors. Current studies are aimed at characterizing expression of ErbB receptors and their ligands using QPCR on a human VS tumor bank and cell lines. Future studies will investigate the PI3K and MAPK intracellular signaling pathways in response to neuregulins and ErbB-specific inhibitors, including the HER2-specific blocking monoclonal antibody, Trastuzumab, the EGFR-specific Erbitux, Gefitinib, and the naturally-occuring, secreted auto inhibitory HER2-splice variant, Herstatin^4,5. Herstatin expression will also be investigated in tumors and cell lines. The effect of HER2-specific inhibitors on proliferation and survival of human schwannoma cell lines will be investigated with the goal of identifying a potential pharmacotherapeutic for treating VS in NF2.

 

1. Fernandez-Valle C, Tang Y, Richard J, et al. Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology. Nat Genet 2002;31:354-62.

2. Hansen MR, Vjapurkar U, Koland JG, Green SH. Reciprocal signaling between spiral ganglion neurons and Schwann cells involves neuregulin and neurotrophins. Hear Res 2001;161:87-98.

3. Hansen MR, Linthicum FH, Jr. Expression of neuregulin and activation of erbB receptors in vestibular schwannomas: Possible autocrine loop stimulation. Otol Neurotol 2004;25:155-9.

4. Doherty JK, Bond C, Jardim A, et al. The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc Natl Acad Sci USA 1999;96:10869-74.

5. Justman QA, Clinton GM. Herstatin, an autoinhibitor of the human epidermal growth factor receptor 2 tyrosine kinase, modulates epidermal growth factor signaling pathways resulting in growth arrest. J Biol Chem 2002;277(23):20618-24.

 

 

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