Molecular Tumorigenesis of Bladder Cancer

膀胱癌(BC)在美国最常见的癌症中排名第五，每年新增诊断病例7.5万例，5年患病率超过50万例。就每个病例而言，BC是诊断和治疗成本最高的癌症。然而，尽管它的患病率、临床挑战和社会经济影响，BC一直是最少研究和资助的癌症之一。因此，BC的发病机制仍然知之甚少；几乎没有生物标志物可以可靠地预测BC的进展；在过去的30年里，几乎没有开发出新的治疗方法。在过去的两年里，一组在BC的分子通路、化学致癌、分子和细胞生物学以及信号转导方面拥有强大、多样但互补的专业知识的研究人员联合起来，使用多学科的方法来解决BC。吴学儒博士从事膀胱生物学和癌症研究超过24年，在他的领导下，该团队密切合作，协同工作，产生了大量的初步数据和可检验的假说，为三个相互依赖的研究项目奠定了基础，这些研究项目围绕一个共同的主题--两条主要的BC途径的分子肿瘤发生：低级别非侵袭性BC与高级别侵袭性BC。这一P01计划旨在解决几个关键和紧迫的问题。哪些组合分子事件可以沿着不同的表型途径驱动BC的形成，以及来自开发和分析基因工程小鼠的见解如何有助于BC的诊断和管理(项目1；P1)？丙烯醛是烟草烟雾引起的BC的重要致癌物吗？不同的BC通路是否有不同的DNA损伤和修复能力(P2)？那么，XIAP在BC侵袭和进展中的新作用、上游调节因子、下游效应因子以及作用机制是什么(P3)？这一高度协作和协同的团队努力的结果应该有助于我们在理解BC的发病机制方面的重大飞跃，从而导致这种高度流行但研究极少的疾病的新生物标记物和疗法的开发。

Bladder cancer (BC) ranks the fifth among the most prevalent cancers in the United States, with -75,000 new cases diagnosed annually and a 5-year prevalence of over half a million cases. On a per-case basis, BC is the costliest cancer to diagnose and treat. However, in spite of its prevalence, clinical challenges and socioeconomic ramifications, BC is persistently one of the least researched and funded cancers. As a result, the pathogenesis of BC remains poorly understood; few biomarkers exist to reliably predict BC progression; and few novel therapeutics have been developed during the last three decades. Over the last two years, a group of investigators with strong, diverse yet complementary expertise in molecular pathways of BC, chemical carcinogenesis, molecular and cell biology and signal transduction have joined forces to tackle BC using a multidisciplinary approach. Under the leadership of Dr. Xue-Ru Wu, who has been studying bladder biology and cancer for over 24 years, the Team has collaborated closely and synergistically, resulting in the generation of large amounts of preliminary data and testable hypotheses that have laid the foundation for three inter-dependent research projects centering on a common theme - the molecular tumorigenesis for the two major BC pathways: low-grade non-invasive BC versus high-grade invasive BC. This P01 Program is designed to address several critical and pressing problems. What are the combinatorial molecular events that can drive BC formation along the divergent phenotypic pathways and how insights from developing and analyzing genetically engineered mice could benefit BC diagnostics and management (Project 1; P1)? Is acrolein an important carcinogen for tobacco-smoke-caused BC, and are distinct BC pathways underlined by different DNA damage and repair capacities (P2)? And, what are the novel role, upstream regulators, downstream effectors as well as the mechanisms of action of XIAP in BC invasion and progression (P3)? Results from this highly collaborative and synergetic team effort should contribute to the major leap forward in our understanding of the pathogenesis of BC, thus leading to the development of novel biomarkers and therapeutics for this highly prevalent but extremely under-studied disease.