American Association for Cancer Research
10780432ccr133191-sup-123160_1_supp_0_nxcslg.pdf (76.59 kB)

Supplemental Figure S1 from Overexpression of Smad7 Blocks Primary Tumor Growth and Lung Metastasis Development in Osteosarcoma

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journal contribution
posted on 2023-03-31, 19:13 authored by Audrey Lamora, Julie Talbot, Gwenola Bougras, Jérôme Amiaud, Marion Leduc, Julie Chesneau, Julien Taurelle, Verena Stresing, Marie Cécile Le Deley, Marie Françoise Heymann, Dominique Heymann, Françoise Redini, Franck Verrecchia

This supplementary figure demonstrates that Smad7 and SD-208 inhibit the Smad3 signaling pathway in SAOS2 cells and that Smad7 does not inhibit the MAPK pathway in response to TGF-β.



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-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.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 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.Conclusion: 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. Clin Cancer Res; 20(19); 5097–112. ©2014 AACR.