Department of Urology, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Res. 2012 Jul 1;72(13):3135-42. doi: 10.1158/0008-5472.CAN-11-3195. Epub 2012 Apr 24.
Two subtypes of human bladder cancer, noninvasive papillary and muscle-invasive cancer, develop through independent pathologic and molecular pathways. Human invasive bladder cancer frequently develops without prior clinical evidence of a noninvasive 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 noninvasive papillary tumor stage. Remarkably, invasive bladder cancer driven by active Stat3 was predominantly composed of stem cells, which were characterized by cytokeratin 14 (CK14) staining and enhanced tumor sphere-forming ability. Active Stat3 was also shown to localize to the nucleus of human invasive bladder cancers that were primarily composed of CK14+ stem cells. Together, our findings show that Stat3-induced stem cell expansion plays a critical role in the unique clinical progression of invasive bladder cancer through the CIS pathway.
两种人类膀胱癌亚型，非浸润性乳头状和肌肉浸润性癌，通过独立的病理和分子途径发展。人类浸润性膀胱癌通常在没有非浸润性肿瘤阶段的临床证据的情况下发展。然而，尚未开发出能够重现这种独特的浸润性膀胱癌临床进展的动物模型。在这项研究中，我们通过将活性二聚体形式的 Stat3 靶向膀胱上皮的基底细胞，创建了一种新型的浸润性膀胱癌转基因小鼠模型。当暴露于致癌剂亚硝胺时，Stat3 转基因小鼠直接从原位癌（CIS）发展为浸润性癌症，绕过了非浸润性乳头状肿瘤阶段。值得注意的是，由活性 Stat3 驱动的浸润性膀胱癌主要由干细胞组成，其特征是角蛋白 14（CK14）染色和增强的肿瘤球体形成能力。活性 Stat3 也被证明定位于主要由 CK14+干细胞组成的人类浸润性膀胱癌的核内。总之，我们的研究结果表明，Stat3 诱导的干细胞扩增通过 CIS 途径在浸润性膀胱癌的独特临床进展中发挥关键作用。
