Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer.
Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer.
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DOI：
10.1158/0008-5472.can-11-3195
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Chan KS
中科院分区：
文献类型：
--
作者：
Ho PL;Lay EJ;Jian W;Parra D;Chan KS
人类膀胱癌的两种亚型，非侵袭性乳头状癌和肌肉浸润性癌，通过独立的病理和分子途径发展。人类浸润性膀胱癌的发展通常没有先前的非浸润性肿瘤阶段的临床证据。然而，还没有开发出一种动物模型来概括这种独特的浸润性膀胱癌的临床进展。在这项研究中，我们创建了一个新的转基因小鼠模型的浸润性膀胱癌的目标是一个积极的二聚体形式的Stat3的膀胱上皮基底细胞。当暴露于致癌物质亚硝胺时，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，其特征在于细胞角蛋白14（CK14）染色和增强的肿瘤球形成能力。活性Stat3也显示定位于主要由CK14+干细胞组成的人浸润性膀胱癌的细胞核。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起着关键作用。
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.