Activated MET Is a Molecular Prognosticator and Potential Therapeutic Target for Malignant Peripheral Nerve Sheath Tumors
Keila E. Torres,Quansheng Zhu,Kate Lynn J. Bill,Kate Lynn J. Bill,Gonzalo Lopez,Gonzalo Lopez,Markus P. Ghadimi,Xianbiao Xie,Eric D. Young,Juehui Liu,Theresa Nguyen,Svetlana Bolshakov,Roman Belousov,Suizhau Wang,Guy Lahat,Jun Liu,Belinda F Hernandez,Alexander J. Lazar,Dina Lev,Dina Lev +19 more
TLDR
An important role is shown for MET in MPNST, supporting continued investigation of novel anti-MET therapies in this clinical context and Informative prognosticators and novel therapies are crucially needed to improve MPN ST management and outcomes.Abstract:
Purpose: MET signaling has been suggested a potential role in malignant peripheral nerve sheath tumors (MPNST). Here, MET function and blockade were preclinically assessed. Experimental Design: Expression levels of MET, its ligand hepatocyte growth factor (HGF), and phosphorylated MET (pMET) were examined in a clinically annotated MPNST tissue microarray (TMA) incorporating univariable and multivariable statistical analyses. Human MPNST cells were studied in vitro and in vivo ; Western blot (WB) and ELISA were used to evaluate MET and HGF expression, activation, and downstream signaling. Cell culture assays tested the impact of HGF-induced MET activation and anti-MET–specific siRNA inhibition on cell proliferation, migration, and invasion; in vivo gel-foam assays were used to evaluate angiogenesis. Cells stably transduced with anti-MET short hairpin RNA (shRNA) constructs were tested for growth and metastasis in severe combined immunodeficient (SCID) mice. The effect of the tyrosine kinase inhibitor XL184 (Exelixis) targeting MET/VEGFR2 (vascular endothelial growth factor receptor 2) on local and metastatic MPNST growth was examined in vivo . Results: All three markers were expressed in MPNST human samples; pMET expression was an independent prognosticator of poor patient outcome. Human MPNST cell lines expressed MET, HGF, and pMET. MET activation increased MPNST cell motility, invasion, angiogenesis, and induced matrix metalloproteinase-2 (MMP2) and VEGF expression; MET knockdown had inverse effects in vitro and markedly decreased local and metastatic growth in vivo . XL184 abrogated human MPNST xenograft growth and metastasis in SCID mice. Conclusions: Informative prognosticators and novel therapies are crucially needed to improve MPNST management and outcomes. We show an important role for MET in MPNST, supporting continued investigation of novel anti-MET therapies in this clinical context. Clin Cancer Res; 17(12); 3943–55. ©2011 AACR .read more
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Journal ArticleDOI
Malignant Peripheral Nerve Sheath Tumors
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References
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Met, metastasis, motility and more
TL;DR: Pivotal roles for Met in development and cancer have been established: Met controls cell migration and growth in embryogenesis; it also controls growth, invasion and metastasis in cancer cells; and activating Met mutations predispose to human cancer.
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Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases.
Barbara S. Ducatman,Bernd W. Scheithauer,David G. Piepgras,Herbert M. Reiman,Duane M. Ilstrup +4 more
TL;DR: The MPNST is an aggressive uncommon neoplasm, and large tumor size, the presence of neurofibromatosis, and total resection are the most important prognostic indicators.
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Malignant peripheral nerve sheath tumours in neurofibromatosis 1
TL;DR: The lifetime risk of MPNST in NF1 is much higher than previously estimated and warrants careful surveillance and a low threshold for investigation.
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Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients.
Tanya N. Basu,David H. Gutmann,Jonathan A. Fletcher,Thomas W. Glover,Francis S. Collins,Julian Downward +5 more
TL;DR: Evidence is presented that the ras proteins in malignant tumour cell lines from patients with type 1 neurofibromatosis are in a constitutively activated state, as judged by the guanine nucleotide bound to them, and are necessary for cellular proliferation, and support the hypothesis that NF1 is a tumour-suppressor gene whose product acts upstream of ras.
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Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor.
Luigi Naldini,Luca Tamagnone,Elisa Vigna,Martin Sachs,Guido Hartmann,Walter Birchmeier,Yasushi Daikuhara,Hirohito Tsubouchi,Francesco Blasi,Paolo M. Comoglio +9 more
TL;DR: Data show that urokinase acts as a pro‐HGF/SF convertase, and suggest that some of the growth and invasive cellular responses mediated by this enzyme may involve activation of HGF/ SF.
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