| Autor: |
Edgar B. Cepeda, Andrea Malfettone, Joan Fernando, Conrado M. Fernández-Rodríguez, Esther Bertran, Patricia Sancho, Gianluigi Giannelli, Giulia Raimondi, Pedro M. Fernández-Salguero, Angels Fabra, Isabel Fabregat, Alberto Álvarez-Barrientos, Roser Vilarrasa-Blasi |
| Rok vydání: |
2014 |
| Předmět: |
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| Zdroj: |
International Journal of Cancer. 136:E161-E172 |
| ISSN: |
0020-7136 |
| DOI: |
10.1002/ijc.29097 |
| Popis: |
The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-β) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-β pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-β-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-β pathway, may predict lack of response to sorafenib in HCC patients. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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