Molecular Tumorigenesis of Bladder Cancer

膀胱癌是一种表现出不同表型、生物学行为的异质性疾病。 和临床结果。大约70%的BC表现为低级别的浅表乳头状肿瘤，通常 复发，但很少进展到高级别的肌肉侵袭期。不列颠哥伦比亚省其余地区(约30%)为高档 临床表现为侵袭性，通常有低级别乳头状肿瘤的病史。 但被认为是新生的或起源于扁平的高级别原位癌病变。不管这两个人 BC的主要表型变异是由不同的分子变化引起的，在 了解并有效管理卑诗省。然而，这个问题的答案仍然难以捉摸，因为 缺乏协调一致的研究努力。在过去的15年里，我们一直在解剖分子 通过尿路上皮特异性基因工程小鼠的建立和分析研究BC通路的机制 基因激活或消融或两者兼而有之。由此产生的小鼠模型不仅概括了许多突出的 人类BC的特征，但产生了关于基因和BC之间因果关系的新信息 小路。目前的提议旨在获得更深入和更广泛的见解，以组合 分子事件共同充当触发BC沿着两个主要表型形成的“驱动力” 小路。目标1将定义能够与突变的成纤维细胞协同作用的分子改变 生长因子受体3(FGFR3)启动低级别、浅乳头状癌。这一目标将集中在(I) 位于9p21的p51 NK4b、p161NK4a和p19ARF三种抑癌基因缺失 在早期人类BC中缺失；以及(Ii)突变的FGFR3通过成纤维细胞生长因子信号增加信号。 目标2将研究功能获得性p53突变以及与pRb家族合作的影响 触发高级别侵袭性BC的不足。细胞培养、基因工程模型的结合 人类研究将被用来实现这些目标。总的来说，这些研究应该有助于确定 尿路上皮肿瘤发生的“分子驱动因素”及其作用 设计新的生物标志物面板，以改善BC的诊断、预后预测和新的治疗方法。

Bladder cancer (BC) is a heterogeneous disease entity exhibiting 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 "drivers" to trigger BC formation along the two major phenotypic pathways. Aim 1 will define the molecular alterations that are capable of synergizing with mutated fibroblast growth factor receptor 3 (FGFR3) to initiate low-grade, superficial papillary BC. This Aim will focus on (i) the deficiency of pi 51 NK4b, p16lNK4a and p19ARF, three tumor suppressors located on 9p21 and frequently deleted in early-stage human BC; and (ii) the increased signaling of mutated FGFR3 through FGF signaling. Aim 2 will examine the effects of gain-of-function p53 mutations and those in collaboration with pRb family deficiency in triggering high-grade invasive BC. A combination of cell culture, genetically engineered models and human studies will be used to accomplish the objectives. Collectively, these studies should help define the "molecular drivers" that are responsible for urothelial tumorigenesis along divergent pathways and help devise new biomarker panels for improved diagnosis, prognosis prediction and novel therapies of BC.