The role of insulin-like growth factors signaling in merlin-deficient human schwannomas
dc.contributor.author | Ammoun, Sylwia | |
dc.contributor.author | Schmid, MC | |
dc.contributor.author | Ristic, N | |
dc.contributor.author | Zhou, L | |
dc.contributor.author | Hilton, D | |
dc.contributor.author | Ercolano, E | |
dc.contributor.author | Carroll, Camille | |
dc.contributor.author | Hanemann, Clemens Oliver | |
dc.date.accessioned | 2015-07-29T09:23:27Z | |
dc.date.available | 2015-07-29T09:23:27Z | |
dc.date.issued | 2012-11 | |
dc.identifier.issn | 0894-1491 | |
dc.identifier.issn | 1098-1136 | |
dc.identifier.uri | http://hdl.handle.net/10026.1/3483 | |
dc.description.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. | |
dc.format.extent | 1721-1733 | |
dc.format.medium | Print-Electronic | |
dc.language | en | |
dc.language.iso | eng | |
dc.publisher | Wiley | |
dc.subject | human schwannoma | |
dc.subject | insulin-like growth factors | |
dc.subject | proliferation | |
dc.subject | adhesion | |
dc.subject | survival | |
dc.title | The role of insulin-like growth factors signaling in merlin-deficient human schwannomas | |
dc.type | journal-article | |
dc.type | Journal Article | |
dc.type | Research Support, Non-U.S. Gov't | |
plymouth.author-url | https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000308444000008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008 | |
plymouth.issue | 11 | |
plymouth.volume | 60 | |
plymouth.publication-status | Published | |
plymouth.journal | Glia | |
dc.identifier.doi | 10.1002/glia.22391 | |
plymouth.organisational-group | /Plymouth | |
plymouth.organisational-group | /Plymouth/Faculty of Health | |
plymouth.organisational-group | /Plymouth/Faculty of Health/Peninsula Medical School | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA/UoA03 Allied Health Professions, Dentistry, Nursing and Pharmacy | |
plymouth.organisational-group | /Plymouth/Research Groups | |
plymouth.organisational-group | /Plymouth/Research Groups/FoH - Applied Parkinson's Research | |
plymouth.organisational-group | /Plymouth/Research Groups/FoH - Community and Primary Care | |
plymouth.organisational-group | /Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED) | |
plymouth.organisational-group | /Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR | |
plymouth.organisational-group | /Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CCT&PS | |
plymouth.organisational-group | /Plymouth/Research Groups/Plymouth Institute of Health and Care Research (PIHR) | |
plymouth.organisational-group | /Plymouth/Users by role | |
plymouth.organisational-group | /Plymouth/Users by role/Academics | |
plymouth.organisational-group | /Plymouth/Users by role/Researchers in ResearchFish submission | |
dc.publisher.place | United States | |
dcterms.dateAccepted | 2012-06-22 | |
dc.identifier.eissn | 1098-1136 | |
dc.rights.embargoperiod | Not known | |
rioxxterms.funder | Medical Research Council | |
rioxxterms.identifier.project | Molecular genetic studies of iron metabolism in Parkinson's disease and related neurodegenerative disorders | |
rioxxterms.versionofrecord | 10.1002/glia.22391 | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2012-11 | |
rioxxterms.type | Journal Article/Review | |
plymouth.funder | Molecular genetic studies of iron metabolism in Parkinson's disease and related neurodegenerative disorders::Medical Research Council |