title: The decreased metastatic potential of rhabdomyosarcoma cells obtained through MET receptor downregulation and the induction of differentiation.
abstract: Rhabdomyosarcoma (RMS) is the most common type of pediatric soft tissue sarcoma. The MET receptor has an important role in the biology of RMS, and its overexpression and hyperactivation correlate with the metastatic ability of RMS. Consequently, interfering with MET expression or functionality may constitute a sound strategy for reducing the progression and metastatic potential of RMS. Our study reveals that downregulation of the MET receptor leads to changes in the morphology of ARMS cell in vivo. Tumors acquire a spindle shape that is characteristic of muscle fibers. Inhibition of MET expression or function leads to (i) a decreased expression of the early myogenic marker MyoD, (ii) a decreased ability of ARMS cells to metastasize to bone marrow cavities, (iii) downregulation of CXCR4 receptor expression and (iv) a decreased migration of MET-depleted cells towards gradients of HGF and SDF-1. Finally, we demonstrate that in vitro differentiation of alveolar RMS cells decreases their metastatic behavior by reducing both the expression of the MET and CXCR4 receptors and their migratory response to HGF and SDF-1. These findings suggest that blockers of MET receptor function and inducers of RMS cells differentiation may be clinically useful for reducing the aggressiveness and metastatic potential of RMS and may have significant implications for its treatment.
authors: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University School of Medicine, Cracow, Poland.
authors: K
authors: K
authors: Miekus
authors: E
authors: E
authors: Lukasiewicz
authors: D
authors: D
authors: Jarocha
authors: M
authors: M
authors: Sekula
authors: G
authors: G
authors: Drabik
authors: M
authors: M
authors: Majka
mesh_terms: D000818:Animals; D019046:Bone Marrow Neoplasms / Q000556:secondary; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D015536:Down-Regulation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017570:MyoD Protein / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D017570:MyoD Protein; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases