title: Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression.
abstract: Rhabdomyosarcoma (RMS) is a soft tissue sarcoma, which may originate from impaired differentiation of mesenchymal stem cells (MSC). Expression of MET receptor is elevated in alveolar RMS subtype (ARMS) which is associated with worse prognosis, compared to embryonal RMS (ERMS). Forced differentiation of ARMS cells diminishes MET level and, as shown previously, MET silencing induces differentiation of ARMS. In ERMS cells introduction of TPR-MET oncogene leads to an uncontrolled overstimulation of the MET receptor downstream signaling pathways. In vivo, tumors formed by those cells in NOD-SCID mice display inhibited differentiation, enhanced proliferation, diminished apoptosis and increased infiltration of neutrophils. Consequently, tumors grow significantly faster and they display enhanced ability to metastasize to lungs and to vascularize due to elevated VEGF, MMP9 and miR-378 expression. In vitro, TPR-MET ERMS cells display enhanced migration, chemotaxis and invasion toward HGF and SDF-1. Introduction of TPR-MET into MSC increases survival and may induce expression of early myogenic factors depending on the genetic background, and it blocks terminal differentiation of skeletal myoblasts. To conclude, our results suggest that activation of MET signaling may cause defects in myogenic differentiation leading to rhabdomyosarcoma development and progression.
authors.affiliation: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Skrzypek
authors.affiliation: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kusienicka
authors.affiliation: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Szewczyk
authors.affiliation: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Adamus
authors.affiliation: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Lukasiewicz
authors.affiliation: Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Miekus
authors.affiliation: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Majka
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D009389:Neovascularization, Pathologic; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: MET; differentiation; mesenchymal stem cells (MSC); metastasis; rhabdomyosarcoma (RMS)