We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.
- Authors
Fernando, Joan; Malfettone, Andrea; Cepeda, Edgar B.; Vilarrasa‐Blasi, Roser; Bertran, Esther; Raimondi, Giulia; Fabra, Àngels; Alvarez‐Barrientos, Alberto; Fernández‐Salguero, Pedro; Fernández‐Rodríguez, Conrado M.; Giannelli, Gianluigi; Sancho, Patricia; Fabregat, Isabel
- Abstract
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.
- Publication
International Journal of Cancer, 2015, Vol 136, Issue 4, pE161
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.29097