title: A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.
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.
authors: Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
authors: Joan
authors: J
authors: Fernando
authors: Andrea
authors: A
authors: Malfettone
authors: Edgar B
authors: EB
authors: Cepeda
authors: Roser
authors: R
authors: Vilarrasa-Blasi
authors: Esther
authors: E
authors: Bertran
authors: Giulia
authors: G
authors: Raimondi
authors: Àngels
authors: À
authors: Fabra
authors: Alberto
authors: A
authors: Alvarez-Barrientos
authors: Pedro
authors: P
authors: Fernández-Salguero
authors: Conrado M
authors: CM
authors: Fernández-Rodríguez
authors: Gianluigi
authors: G
authors: Giannelli
authors: Patricia
authors: P
authors: Sancho
authors: Isabel
authors: I
authors: Fabregat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D056945:Hep G2 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib; D016212:Transforming Growth Factor beta / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D010671:Phenylurea Compounds; D016212:Transforming Growth Factor beta; D009536:Niacinamide; D000077157:Sorafenib
keywords: CD44; EMT; TGF-beta; liver cancer; sorafenib