title: Overexpression of smad7 blocks primary tumor growth and lung metastasis development in osteosarcoma.
abstract: OBJECTIVE
  Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastasis is present at diagnosis. Because transforming growth factor-β (TGFβ) has been shown to promote metastasis in many solid tumors, we investigated the effect of the natural TGFβ/Smad signaling inhibitor Smad7 and the TβRI inhibitor SD-208 on osteosarcoma behavior.
  
  
  METHODS
  By using a mouse model of osteosarcoma induced by paratibial injection of cells, we assessed the impact of Smad7 overexpression or SD-208 on tumor growth, tumor microenvironment, bone remodeling, and metastasis development.
  
  
  RESULTS
  First, we demonstrated that TGFβ levels are higher in serum samples from patients with osteosarcoma compared with healthy volunteers and that TGFβ/Smad3 signaling pathway is activated in clinical samples. Second, we showed that Smad7 slows the growth of the primary tumor and increases mice survival. We furthermore demonstrated that Smad7 expression does not affect in vitro osteosarcoma cell proliferation but affects the microarchitectural parameters of bone. In addition, Smad7-osteosarcoma bone tumors expressed lower levels of osteolytic factors such as RANKL, suggesting that Smad7 overexpression affects the "vicious cycle" established between tumor cells and bone cells by its ability to decrease osteoclast activity. Finally, we showed that Smad7 overexpression in osteosarcoma cells and the treatment of mice with SD208 inhibit the development of lung metastasis.
  
  
  CONCLUSIONS
  Taken together, these results demonstrate that the inhibition of the TGFβ/Smad signaling pathway may be a promising therapeutic strategy against tumor progression of osteosarcoma, specifically against the development of lung metastasis.
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France. Inserm Liliane Bettencourt School, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Lamora
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Talbot
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Gwenola
authors.initials: G
authors.lastname: Bougras
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Leduc
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Chesneau
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Taurelle
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Verena
authors.initials: V
authors.lastname: Stresing
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Marie Cécile
authors.initials: MC
authors.lastname: Le Deley
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Marie Françoise
authors.initials: MF
authors.lastname: Heymann
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
authors.affiliation: INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes, France. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. CHU Hôtel Dieu, Nantes, France. franck.verrecchia@inserm.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Verrecchia
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D001862:Bone Resorption / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011621:Pteridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood; D047368:Tumor Burden / Q000235:genetics
chemical_list: D011621:Pteridines; C511004:SD-208; D051900:Smad3 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta