title: The hepatocyte growth factor receptor as a potential therapeutic target for dedifferentiated liposarcoma.
abstract: Dedifferentiated liposarcomas (DDLPS) are highly resistant to conventional chemo- and radiotherapies, with surgical resection remaining the classic treatment strategy; therefore, there is a pressing need for novel anti-DDLPS-targeted chemotherapeutics. Hepatocyte growth factor receptor (Met) expression is elevated in DDLPS, but the functional role of Met signaling in this disease is not known. We found that the in vitro stimulation of DDLPS cells with hepatocyte growth factor (HGF) elevated the degree of PI3K/AKT and MAPK pathway signaling, and that pro-tumorigenic phenotypes such as cell proliferation, invasion, and migration were significantly enhanced. Conversely, Met knockdown using shRNA-mediated interference decreased HGF-induced Met signaling, the invasive and migratory nature of DDLPS cells in vitro, and the tumorigenicity of DDLPS cells in vivo. These data strongly support the role for Met as a DDLPS therapeutic target. To that end, using EMD1214063, an ATP-competitive kinase inhibitor that targets Met more specifically than other kinases, inhibited Met-dependent signaling, reduced the oncogenicity of DDLPS cells in vitro, and significantly increased the survival of nude mice bearing subcutaneous DDLPS xenografts. These findings support further investigations of HGF-induced Met signaling inhibition in DDLPS, as a potential strategy to enhance clinical outcomes for this disease.
authors.affiliation: 1] Department of Surgical Oncology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA [3] The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [4] Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, OH, USA.
authors.forename: Kate Lynn J
authors.initials: KL
authors.lastname: Bill
authors.affiliation: 1] Department of Surgical Oncology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA [2] The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Garnett
authors.affiliation: 1] Department of Surgical Oncology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA [2] The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ma
authors.affiliation: 1] Department of Surgical Oncology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA [3] The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Caitlin D
authors.initials: CD
authors.lastname: May
authors.affiliation: 1] Department of Surgical Oncology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA [2] The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.affiliation: 1] Department of Surgical Oncology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA [2] The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [3] Department of Pathology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA.
authors.forename: Alexander J
authors.identifier: 0000000263954499
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Surgery, The Sheba Medical Center, Tel Aviv, Israel.
authors.forename: Dina C
authors.initials: DC
authors.lastname: Lev
authors.affiliation: 1] Department of Surgical Oncology, University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA [2] The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [3] Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, OH, USA.
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008080:Liposarcoma / Q000378:metabolism*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C582858:EMD1214063; D011724:Pyridazines; D011743:Pyrimidines; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt