title: Regulation of osteosarcoma cell lung metastasis by the c-Fos/AP-1 target FGFR1.
abstract: Osteosarcoma is the most common primary malignancy of the skeleton and is prevalent in children and adolescents. Survival rates are poor and have remained stagnant owing to chemoresistance and the high propensity to form lung metastases. In this study, we used in vivo transgenic models of c-fos oncogene-induced osteosarcoma and chondrosarcoma in addition to c-Fos-inducible systems in vitro to investigate downstream signalling pathways that regulate osteosarcoma growth and metastasis. Fgfr1 (fibroblast growth factor receptor 1) was identified as a novel c-Fos/activator protein-1(AP-1)-regulated gene. Induction of c-Fos in vitro in osteoblasts and chondroblasts caused an increase in Fgfr1 RNA and FGFR1 protein expression levels that resulted in increased and sustained activation of mitogen-activated protein kinases (MAPKs), morphological transformation and increased anchorage-independent growth in response to FGF2 ligand treatment. High levels of FGFR1 protein and activated pFRS2α signalling were observed in murine and human osteosarcomas. Pharmacological inhibition of FGFR1 signalling blocked MAPK activation and colony growth of osteosarcoma cells in vitro. Orthotopic injection in vivo of FGFR1-silenced osteosarcoma cells caused a marked twofold to fivefold decrease in spontaneous lung metastases. Similarly, inhibition of FGFR signalling in vivo with the small-molecule inhibitor AZD4547 markedly reduced the number and size of metastatic nodules. Thus deregulated FGFR signalling has an important role in osteoblast transformation and osteosarcoma formation and regulates the development of lung metastases. Our findings support the development of anti-FGFR inhibitors as potential antimetastatic therapy.
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Weekes
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, UK.
authors.forename: T G
authors.initials: TG
authors.lastname: Kashima
authors.affiliation: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Zandueta
authors.affiliation: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Perurena
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, UK.
authors.forename: D P
authors.initials: DP
authors.lastname: Thomas
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sunters
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Vuillier
authors.affiliation: Department of Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Bozec
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: El-Emir
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Miletich
authors.affiliation: Laboratory of Pediatrics, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Patiño-Garcia
authors.affiliation: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Lecanda
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Grigoriadis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D002813:Chondrosarcoma / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases