Molecular Tumorigenesis of Bladder Cancer

膀胱癌是一种表型、生物学行为和临床转归不同的异质性疾病。大约70%的BC是低级别的浅表乳头状肿瘤，这些肿瘤经常复发，但很少进展到高级别的肌肉侵袭期。其余的BC(约30%)表现为高级别和侵袭性，通常有低级别乳头状肿瘤的既往病史，但被认为是新生的或起源于扁平的高级别原位癌病变。BC的这两个主要表型变异是否由不同的分子变化引起，对于理解和有效地管理BC具有重要的意义。然而，由于缺乏协调一致的研究努力，这个问题的答案仍然难以捉摸。在过去的15年里，我们一直在通过尿路上皮特异性基因激活或切除或两者兼而有之的方式开发和分析基因工程小鼠，从而剖析BC途径的分子机制。由此产生的小鼠模型不仅概括了人类BC的许多显著特征，而且产生了关于基因和通路之间因果关系的新信息。目前的提议旨在获得对组合分子事件的更深入和更广泛的见解，这些事件一起充当

Bladder cancer (BC) is a heterogeneous disease entity exhaling divergent phenotype, biological behavior and clinical outcome. About 70% of BC present as low-grade, superficial papillary tumors that are frequently recurrent but infrequently progress to high-grade muscle-invasive stages. The rest (~30%) of BC are high- grade and invasive at presentation, and they usually do have a prior history of low-grade, papillary tumors but are believed to arise de novo or derive from flat, high-grade carcinoma in situ lesions. Whether these two major phenotypic variants of BC are caused by distinct molecular alterations is of central importance in understanding and effectively managing BC. However, answer to this question remains elusive due to the lack of concerted research efforts. Over the past 15 years, we have been dissecting the molecular mechanisms of BC pathways by developing and analyzing genetically engineered mice via urothelium- specific gene activation or ablation or both. The resulting mouse models not only recapitulate many salient features of human BC, but yield new information regarding the cause-effect relationship between genes and pathways. The present proposal is designed to gain much deeper and broader insights into the combinatorial molecular events that together serve as the