ECTS2013 Poster Presentations Cancer and bone: basic, translational and clinical (31 abstracts)
Over-expression of Smad7 in osteosarcoma cells inhibits primary tumor growth, the associated bone osteolysis and the development of lung metastasis in murine xenograft model
Audrey Lamora 1, , Julie Talbot 1, , Bérengère Gobin 1, , Marion Leduc 1, , Julien Taurelle 1, , Régis Brion 1, , Dominique Heymann 1, , Françoise Rédini 1, & Franck Verrecchia 1,
1INSERM UMR 957, Nantes, France; 2Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Nantes, France.
Osteosarcoma, the main malignant primary bone tumor, affects a ‘young’ population composed of children and young adults. Current treatment consists of tumor resection associated with chemotherapy. Unfortunately in many cases, a lack of response to anti-tumor drugs is observed, leading to development of metastases and to the patient’s death. Because TGF-β promotes metastases from many solid epithelial tumors, we investigated the effect of inhibitory Smad7 overexpression on osteosarcoma behavior. In vitro, using three human osteosarcoma cell lines (HOS, SAOS2 and U2OS), we generated osteosarcoma cell clones constitutively expressing Smad7. By transfection of cells with (CAGA)9-lux or -800PAI1-lux, by measuring the level of Smad3 phosphorylation, and by measuring the PAI-1, CTGF and COL1A1 expression by qPCR, we demonstrated that the overexpression of Smad7 inhibits the transcriptional response mediated by Smad3/4 in osteosarcoma cell lines. In addition, expression of Smad7 efficiently reduced the capacity of osteosarcoma cells to invade Matrigel in Boyden migration chambers. Gelatin zymography identified reduced MMP-2 secretion by Smad7-expressing osteosarcoma cells as compared with their control counterparts. In vivo, using a xenograft model of osteosarcoma induced by paratibial injection of HOS or SAOS2 cells overexpressing Smad7 in mice, we showed that inhibition of the TGF-β signaling pathway significantly slows primary tumor growth and increases mice survival. The microarchitectural parameters which were assessed by radiography and by microscanner analysis showed an increased trabecular bone volume when Smad7 was over-expressed. In addition, Smad7 overexpression in osteosarcoma cells inhibits the development of lung metastasis. These results suggest that the inhibition of TGF-β signaling pathway could be a new therapeutic strategy against the tumor progression of osteosarcoma.
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Bone Abstracts
ISSN 2052-1219 (online)
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