Lamora, A., Talbot, J., Bougras, G. et al. (10 more authors) (2014) Overexpression of Smad7 Blocks Primary Tumor Growth and Lung Metastasis Development in Osteosarcoma. Clinical Cancer Research, 20 (19). pp. 5097-5112. ISSN 1078-0432
Abstract
Purpose: 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-b (TGFb) has been shown to promote metastasis in many solid tumors, we investigated the effect of the natural TGFb/Smad signaling inhibitor Smad7 and the TbRI inhibitor SD-208 on osteosarcoma behavior. Experimental Design: 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 TGFb levels are higher in serum samples from patients with osteosarcoma compared with healthy volunteers and that TGFb/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. Conclusion: Taken together, these results demonstrate that the inhibition of the TGFb/Smad signaling pathway may be a promising therapeutic strategy against tumor progression of osteosarcoma, specifically against the development of lung metastasis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014 American Association for Cancer Research. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Apr 2016 12:58 |
Last Modified: | 28 Apr 2016 12:58 |
Published Version: | http://dx.doi.org/10.1158/1078-0432.CCR-13-3191 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Refereed: | Yes |
Identification Number: | 10.1158/1078-0432.CCR-13-3191 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:98152 |