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The role of insulin‐like growth factors signaling in merlin‐deficient human schwannomas
Author(s) -
Ammoun Sylwia,
Schmid M. Caroline,
Ristic Natalia,
Zhou Lu,
Hilton David,
Ercolano Emanuela,
Carroll Camille,
Hanemann C. Oliver
Publication year - 2012
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22391
Subject(s) - merlin (protein) , cancer research , biology , neurofibromatosis type 2 , schwannoma , growth factor , growth factor receptor , extracellular matrix , protein kinase b , signal transduction , microbiology and biotechnology , pathology , receptor , medicine , cancer , suppressor , biochemistry , genetics
Abstract 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–matrix 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‐β (PDGFR‐β) and ErbB2/3 which we successfully blocked with AZD6244, sorafenib, or lapatinib. Schwannoma basal proliferation is, however, only partly dependent on PDGFR‐β 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 demonstrate 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 N‐terminal kinases for increased proliferation and AKT for survival. We demonstrate new mechanisms involved in increased basal proliferation, cell–matrix adhesion, and survival of schwannoma cells. We identified therapeutic targets IGF‐IR and downstream PI3K for treatment of schwannoma and other merlin‐deficient tumors and show usefulness of small molecule inhibitors in our model. PI3K is relevant for both IGF‐IR and previously described PDGFR‐β signaling in schwannoma. © 2012 Wiley Periodicals, Inc.