Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer
Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation de Stat3 dans les cellules souches urothéliales induit le développement d'une forme invasive de cancer de la vessie
Two subtypes of human bladder cancer, non-invasive papillary and muscle-invasive cancer, develop through independent pathologic and molecular pathways. Human invasive bladder cancer frequently develops without prior clinical evidence of a non-invasive tumor stage. However, an animal model that recapitulates this unique clinical progression of invasive bladder cancer has not yet been developed. In this study we created a novel transgenic mouse model of invasive bladder cancer by targeting an active dimerized form of Stat3 to the basal cells of bladder epithelium. When exposed to the carcinogen nitrosamine, Stat3 transgenic mice developed invasive cancer directly from carcinoma in situ (CIS), bypassing the non-invasive papillary tumor stage. Remarkably, invasive bladder cancer driven by active Stat3 was predominantly comprised of stem cells, which were characterized by cytokeratin 14 (CK14) staining and enhanced tumor sphere-forming ability. Active Stat3 was also demonstrated to localize to the nucleus of human invasive bladder cancers that were primarily composed of CK14+ stem cells. Together, our findings demonstrate that Stat3-induced stem cell expansion plays a critical role in the unique clinical progression of invasive bladder cancer through the CIS pathway.
Cancer Research 2012