ORCID
- Ammoun, Sylwia: 0000-0002-1525-3583
- Carroll, Camille: 0000-0001-7472-953X
- Hanemann, Oliver: 0000-0002-1951-1025
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.
DOI
10.1002/glia.22391
Publication Date
2012-11-01
Publication Title
GLIA
Volume
60
Issue
11
ISSN
0894-1491
Organisational Unit
Peninsula Medical School
Keywords
Brain Neoplasms, Cell Proliferation, Humans, JNK Mitogen-Activated Protein Kinases, Neurilemmoma, Neurofibromatosis 2, Neurofibromin 2, Proto-Oncogene Proteins c-akt, Signal Transduction, Somatomedins
First Page
1721
Last Page
1733
Recommended Citation
Ammoun, S., Schmid, M., Ristic, N., Zhou, L., Hilton, D., Ercolano, E., Carroll, C., & Hanemann, C. (2012) 'The role of insulin-like growth factors signaling in merlin-deficient human schwannomas.', GLIA, 60(11), pp. 1721-1733. Available at: https://doi.org/10.1002/glia.22391
