Related Experiment Video
Updated: Jul 4, 2026
Analyzing Murine Schwann Cell Development Along Growing Axons
Published on: November 21, 2012
Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated
Sylwia Ammoun1, Christine Flaiz, Natalia Ristic
1Clinical Neurobiology, Peninsula College for Medicine and Dentistry, Research Way, Plymouth, United Kingdom.
Abstract:
Schwannomas are tumors of the nervous system that occur sporadically and in patients with the cancer predisposition syndrome neurofibromatosis type 2 (NF2). Schwannomas and all NF2-related tumors are caused by loss of the tumor suppressor merlin. Using our human in vitro model for schwannoma, we analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways, their upstream growth factor receptors, and their role in schwannoma cell proliferation and adhesion to find new systemic therapies for these tumors that, to date, are very difficult to treat. We show here that human primary schwannoma cells show an enhanced basal Raf/mitogen-activated protein/ERK kinase/ERK1/2 pathway activity compared with healthy Schwann cells. Due to a strong and prolonged activation of platelet-derived growth factor receptor beta (PDGFRbeta), which is highly overexpressed, ERK1/2 and AKT activation was further increased in schwannoma, leading to increased proliferation. Using specific inhibitors, we discovered that ERK1/2 activation involves the integrin/focal adhesion kinase/Src/Ras signaling cascades and PDGFRbeta-mediated ERK1/2 activation is triggered through the phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway. Due to the complexity of signals leading to schwannoma cell proliferation, potential new therapeutic agents should target several signaling pathways. The PDGFR and c-Raf inhibitor sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for treatment of advanced renal cell cancer, inhibits both basal and PDGFRbeta-mediated ERK1/2 and AKT activity and decreases cell proliferation in human schwannoma cells, suggesting that this drug constitutes a promising tool to treat schwannomas. We conclude that our schwannoma in vitro model can be used to screen for new therapeutic targets in general and that sorafenib is possible candidate for future clinical trials.
Insights
This study reveals that targeting multiple signaling pathways, including PDGFRbeta and ERK1/2, with drugs like sorafenib shows promise for treating difficult schwannoma tumors. Further clinical trials are suggested for this novel therapeutic approach.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Schwannomas are nervous system tumors often linked to neurofibromatosis type 2 (NF2), caused by merlin tumor suppressor loss.
- Current treatments for schwannomas are limited, necessitating the exploration of novel therapeutic strategies.
- Understanding the complex signaling pathways involved in schwannoma proliferation is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the roles of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways in schwannoma cell proliferation and adhesion.
- To identify upstream growth factor receptors and signaling cascades contributing to schwannoma development.
- To evaluate the potential of existing drugs, such as sorafenib, as systemic therapies for schwannoma.
Main Methods:
- Utilized a human in vitro schwannoma model for analyzing signaling pathways.
- Assessed basal and growth factor-induced activation of ERK1/2 and AKT pathways.
- Employed specific inhibitors to elucidate signaling cascades, including integrin/focal adhesion kinase/Src/Ras and phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathways.
- Investigated the effect of sorafenib on signaling pathway activity and schwannoma cell proliferation.
Main Results:
- Human schwannoma cells exhibit enhanced basal ERK1/2 pathway activity compared to healthy Schwann cells.
- Overexpression and activation of platelet-derived growth factor receptor beta (PDGFRbeta) significantly increase ERK1/2 and AKT activation, promoting proliferation.
- ERK1/2 activation involves integrin/focal adhesion kinase/Src/Ras and PDGFRbeta-mediated signaling through the PI3K/PKC/Src/c-Raf pathway.
- Sorafenib effectively inhibits both basal and PDGFRbeta-mediated ERK1/2 and AKT activity, reducing schwannoma cell proliferation.
Conclusions:
- Targeting multiple signaling pathways, including PDGFRbeta and ERK1/2, is essential for effective schwannoma treatment.
- Sorafenib demonstrates potential as a therapeutic agent for schwannoma by inhibiting key proliferation pathways.
- The developed in vitro schwannoma model serves as a valuable platform for screening new therapeutic targets and drugs for clinical trials.
