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: Sylwia Ammoun, M Caroline Schmid, Natalia Ristic, Lu Zhou, David Hilton, Emanuela Ercolano, Camille Carroll, C Oliver Hanemann
• Journal: Glia (Glia) Vol. 60 Issue 11 Pg. 1721-33 (Nov 2012) ISSN: 1098-1136 [Electronic] United States
• PMID: 22821509 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Neurofibromin 2
• Somatomedins
• Proto-Oncogene Proteins c-akt
• JNK Mitogen-Activated Protein Kinases

Topics

• Brain Neoplasms (metabolism, pathology)
• Cell Proliferation
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Neurilemmoma (metabolism, pathology)
• Neurofibromatosis 2 (metabolism, pathology)
• Neurofibromin 2 (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (physiology)
• Somatomedins (metabolism)