title: The role of insulin-like growth factors signaling in merlin-deficient human schwannomas.
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.
authors: Clinical Neurobiology, Peninsula Medical School, Plymouth University, Plymouth PL68BU, United Kingdom.
authors: Sylwia
authors: S
authors: Ammoun
authors: M Caroline
authors: MC
authors: Schmid
authors: Natalia
authors: N
authors: Ristic
authors: Lu
authors: L
authors: Zhou
authors: David
authors: D
authors: Hilton
authors: Emanuela
authors: E
authors: Ercolano
authors: Camille
authors: C
authors: Carroll
authors: C Oliver
authors: CO
authors: Hanemann
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009442:Neurilemmoma / Q000378:metabolism* / Q000473:pathology; D016518:Neurofibromatosis 2 / Q000378:metabolism* / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013002:Somatomedins / Q000378:metabolism*
chemical_list: D025581:Neurofibromin 2; D013002:Somatomedins; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases