CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities
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Stéphane Terry1,2,3,4, Ihsan Y. El-Sayed1,2,5, Damien Destouches1,2,6, Pascale Maillé7, Nathalie Nicolaiew1,2, Guillaume Ploussard1,9, Fannie Semprez1,2, Cynthia Pimpie1,2, Himisha Beltran8, Arturo Londono-Vallejo3, Yves Allory1,2,7, Alexandre de la Taille1,2,9,*, David S. Salomon10,*, Francis Vacherot1,2,*
1Inserm, U955, Equipe 7, Créteil, France
2Université Paris-Est, UMR_S955, UPEC, F-94000, Créteil, France
3Institut Curie, Centre de Recherche, CNRS UMR 3244, Paris, F-75248, France
4Inserm, U753, Institut de Cancérologie Gustave Roussy, F-94805, Villejuif, France
5EDST/PRASE, Rafic Harriri Campus, Faculté des Sciences, Université Libanaise, Beyrouth, Liban
6Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), CNRS, F-94010, Créteil, France
7AP-HP, Hôpital H. Mondor, Département de pathologie, F-94000, Créteil, France
8Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA
9AP-HP, Hôpital H. Mondor, Service d’urologie, F-94000, Créteil, France
10Mouse Cancer Genetics Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
*These authors have contributed equally to this work
Stéphane Terry, e-mail: email@example.com
Keywords: prostate cancer, CRIPTO, mesenchymal-like cancer cells, EMT, FGFR, AKT
Received: August 15, 2014 Accepted: November 11, 2014 Published: January 22, 2015
Members of the EGF-CFC (Cripto, FRL-1, Cryptic) protein family are increasingly recognized as key mediators of cell movement and cell differentiation during vertebrate embryogenesis. The founding member of this protein family, CRIPTO, is overexpressed in various human carcinomas. Yet, the biological role of CRIPTO in this setting remains unclear. Here, we find CRIPTO expression as especially high in a subgroup of primary prostate carcinomas with poorer outcome, wherein resides cancer cell clones with mesenchymal traits. Experimental studies in PCa models showed that one notable function of CRIPTO expression in prostate carcinoma cells may be to augment PI3K/AKT and FGFR1 signaling, which promotes epithelial-mesenchymal transition and sustains a mesenchymal state. In the observed signaling events, FGFR1 appears to function parallel to AKT, and the two pathways act cooperatively to enhance migratory, invasive and transformation properties specifically in the CRIPTO overexpressing cells. Collectively, these findings suggest a novel molecular network, involving CRIPTO, AKT, and FGFR signaling, in favor of the emergence of mesenchymal-like cancer cells during the development of aggressive prostate tumors.
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