The role of insulin-like growth factors signaling in merlin-deficient human

Loss of the tumor suppressor merlin causes development of the tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas occurring spontaneously or as part of a hereditary disease Neurofibromatosis Type 2 (NF2). Current therapies, (radio) surgery, are not always effective. Therefore, there is a need for drug treatments for these tumors. Schwannomas are the most frequent of merlin-deficient tumors and are hallmark for NF2. Using our in vitro human schwannoma model, we demonstrated that merlin-deficiency leads to increased proliferation, cell–ma- trix adhesion, and survival. Increased proliferation due to strong activation of extracellular-signal-regulated kinase 1/ 2 (ERK1/2) is caused by overexpression/activation of platelet-derived growth factor receptor- b (PDGFR- b ) and ErbB2/ 3 which we successfully blocked with AZD6244, sorafenib, or lapatinib. Schwannoma basal proliferation is, however, only partly dependent on PDGFR- b and is completely independent of ErbB2/3. Moreover, the mechanisms underlying pathological cell–matrix adhesion and survival of schwannoma cells are still not fully understood. Here, we demon- strate that insulin-like growth factor-I receptor (IGF-IR) is strongly overexpressed and activated in human primary schwannoma cells. IGF-I and -II are overexpressed and released from schwannoma cells. We show that ERK1/2 is relevant for IGF-I-mediated increase in proliferation and cell–matrix adhesion, c-Jun

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