title: A Disintegrin And Metalloproteinase 12 produced by tumour cells accelerates osteosarcoma tumour progression and associated osteolysis.
abstract: BACKGROUND
  Osteosarcoma is the most common primary malignant bone tumour in children and adolescents for whom the prognosis remains unfavourable despite treatment protocols that combine chemotherapy and surgery. Metalloproteinases decisively contribute to cancer development and promotion by regulating cell growth, angiogenesis or inflammation. However, their role in osteosarcoma remains still unknown.
  
  
  METHODS
  A screening of a large panel of metalloproteinases and their inhibitors, carried out in osteolytic (K7M2 and POS-1) or osteoblastic (MOS-J) mouse osteosarcoma models, shows that a member of a family of cell surface metallopeptidases, A Disintegrin And Metalloproteinase 12 (ADAM12), is highly expressed in the K7M2 and POS-1 cell lines and weakly expressed in the MOS-J cell line. To investigate whether ADAM12, involved in several pathologic conditions characterised by abnormal cell growth, plays a role in osteosarcoma tumour growth, ADAM12 was overexpressed in MOS-J and downregulated in K7M2 cells.
  
  
  RESULTS
  In vivo experiments demonstrated that ADAM12 favours tumour growth, leading to a significant modification in animal survival. In vitro assays showed that ADAM12 knockdown in K7M2 cells slows cell proliferation. In addition, the study of microarchitectural parameters, assessed by micro-computed tomography (CT) analysis, showed that ADAM12 favours bone osteolysis, as demonstrated both in an ADAM12 overexpressing (MOS-J) and a knockdown (K7M2) model. Histological analysis showed that ADAM12 inhibited osteoblast activity and therefore enhanced bone resorption.
  
  
  CONCLUSIONS
  Our study demonstrates that ADAM12 expression not only favours tumour growth but also associates enhanced osteolysis with a significant reduction in animal survival, suggesting that ADAM12 could be a new therapeutic target in osteosarcoma.
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Georges
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Chesneau
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: Soizic
authors.initials: S
authors.lastname: Hervouet
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Taurelle
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: François
authors.initials: F
authors.lastname: Gouin
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Padrines
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Institut Universitaire de Technologie, Angers, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Fortun
authors.affiliation: LUNAM Université, France; INSERM, UMR-S 957, Nantes, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; CHU de Nantes, Nantes, France; Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Electronic address: franck.verrecchia@inserm.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Verrecchia
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology*; D000072199:ADAM12 Protein; D000293:Adolescent; D000328:Adult; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010014:Osteolysis / Q000378:metabolism / Q000473:pathology*; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human