title: Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors.
abstract: OBJECTIVE
  MET signaling has been suggested a potential role in malignant peripheral nerve sheath tumors (MPNST). Here, MET function and blockade were preclinically assessed.
  
  
  METHODS
  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.
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1104, Houston TX 77030, USA.
authors.forename: Keila E
authors.initials: KE
authors.lastname: Torres
authors.forename: Quan-Sheng
authors.initials: QS
authors.lastname: Zhu
authors.forename: Katelynn
authors.initials: K
authors.lastname: Bill
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Lopez
authors.forename: Markus P
authors.initials: MP
authors.lastname: Ghadimi
authors.forename: Xianbiao
authors.initials: X
authors.lastname: Xie
authors.forename: Eric D
authors.initials: ED
authors.lastname: Young
authors.forename: Juehui
authors.initials: J
authors.lastname: Liu
authors.forename: Theresa
authors.initials: T
authors.lastname: Nguyen
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.forename: Roman
authors.initials: R
authors.lastname: Belousov
authors.forename: Suizhau
authors.initials: S
authors.lastname: Wang
authors.forename: Guy
authors.initials: G
authors.lastname: Lahat
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Belinda
authors.initials: B
authors.lastname: Hernandez
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D018317:Nerve Sheath Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; C066855:HGF protein, human; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met