Epithelial/stromal signaling in bladder and prostate cell proliferation

描述(申请人提供)：我们识别和治疗致命形式的前列腺癌和其他癌症的能力受到限制，因为我们不完全了解支配细胞增殖的生物学机制，或者这些机制中的错乱允许原始器官内和转移部位的病理性增殖。在我们最近对小鼠的研究中，我们发现了上皮和间质之间的信号反馈电路，这似乎是控制泌尿生殖器官增殖活动的中央控制机制。我们建议测试这种上皮/间质回路，特别是支持性间质反应，在控制膀胱和前列腺细胞增殖以及在这些泌尿生殖器官的恶性肿瘤中的作用。我们通过检测由泌尿系致病菌感染引起的膀胱损伤的戏剧性增殖反应，发现了这一控制回路。感染后，Sonic hedgehog(Shh)蛋白信号在尿路上皮基底层细胞中的表达增加，这会在基质细胞中触发反应，包括Wnt和FGF分泌的蛋白信号的表达增加；因此，上皮和间质细胞经历了戏剧性的和持续的增殖增加。揭示这一控制回路的关键是我们发现Gli1，一种对胚胎发育至关重要的Shh转录效应因子，似乎在胚胎后增殖反应中发挥着关键作用。我们发现，尽管膀胱中不存在显著的激素依赖性，但前列腺的增殖似乎也使用了Gli1，这表明了一种类似于膀胱的增殖控制机制。我们建议在小鼠膀胱和前列腺中测试信号通路在这一增殖控制通路中的作用，并研究这一通路在泌尿生殖系统恶性肿瘤中的活性。我们将使用膀胱细菌感染和去势后的睾酮替代作为再生增殖反应的触发因素，并将使用组织显微解剖和微阵列基因表达分析来描绘介导上皮/基质信号的信号通路。功能研究将利用遗传分析和药理学试剂。我们将使用小鼠模型、人类癌细胞株和斯坦福大学收集的大量冷冻保存的人类肿瘤组织来研究这种增殖控制电路在泌尿生殖器官恶性肿瘤中的作用。我们在这些研究中的重点将放在基质细胞的支持性反应上，它是促进生长和确定远处转移可能性的关键因素。我们的研究将提供新的泌尿生殖系统恶性肿瘤的诊断和治疗方法，方法是提高我们识别具有转移潜能的癌症的能力，并测试FDA批准的药物的效果，这些药物最近被发现有效地调节HH和WNT信号通路的活性。因此，我们的发现将直接有助于建立可用于快速设计和实施新的临床试验的知识基础。 公共卫生相关性：人们普遍认为癌症与细胞过度增殖有关，然而前列腺癌和其他癌症只有在从原发部位扩散并在新的部位生长时才是致命的，这一过程被称为转移。我们在这项工作中的目标是利用我们对增殖控制机制的新理解，这种机制涉及组织层之间的通信，以帮助识别和治疗潜在转移性前列腺癌和膀胱癌患者。

DESCRIPTION (provided by applicant): We are limited in our ability to recognize and treat lethal forms of prostate and other cancers by an incomplete understanding of the biological mechanisms that govern cell proliferation, or of the derangements in these mechanisms that permit pathological proliferation within the primary organ and at metastatic sites. In our recent studies in the mouse we have discovered a signal feedback circuit between epithelium and stroma that appears to be a central control mechanism governing proliferative activity in urogenital organs. We propose to test the role of this epithelial/stromal circuit, particularly a supportive stromal response, in the control of cell proliferation in bladder and prostate and in malignancies of these urogenital organs. We discovered this control circuit by examining the dramatic proliferative response to bladder injury caused by infection with uropathogenic bacteria. Upon infection, expression of the Sonic hedgehog (Shh) protein signal increases in a subset of basal cells of the urothelium, and this triggers a response in cells of the underlying stroma, including increased expression of Wnt and FGF secreted protein signals; consequently, epithelial and stromal cells undergo a dramatic and sustained increase in proliferation. The key to uncovering this control circuit was our finding that Gli1, a Shh transcriptional effector dispensable for embryonic development, nevertheless appears to play a critical role in post-embryonic proliferative responses. We have found that proliferation in the prostate, despite a striking hormonal dependence that is absent in bladder, also appears to employ Gli1, suggesting a proliferation control mechanism similar to that of the bladder. We propose to test the role of signaling pathways in this proliferative control circuit in murine bladder and prostate and to investigate the activity of this circuit in urogenital malignancies. We will use bacterial infection of the bladder and testosterone replacement in castrates as triggers for regenerative proliferation responses, and will delineate the signaling pathways that mediate epithelial/stromal signaling using tissue microdissection and microarray gene expression analysis. Functional studies will make use of genetic analysis and pharmacological agents. We will investigate the role of this proliferative control circuit in malignancies of urogenital organs using mouse models, human cancer cell lines, and the large Stanford collection of cryopreserved human tumor tissues. Our focus in these studies will be on the supportive response of stromal cells as a critical factor in fostering growth and specifying the likelihood of distant metastases. Our studies will provide new diagnostic and therapeutic approaches to urogenital malignancies by improving our ability to recognize cancers with metastatic potential and by testing the effects of FDA-approved pharmacological agents recently found to potently modulate activities of the Hh and Wnt signaling pathways. Our findings thus will contribute directly to a base of knowledge that can be used to rapidly design and implement new clinical trials. PUBLIC HEALTH RELEVANCE: Cancer is widely understood to be associated with excess cell proliferation, yet prostate and other cancers are lethal only when they spread from the primary site and grow in new locations, a process termed metastasis. Our goal in this work is to use our new understanding of a proliferation control mechanism that involves communication between tissue layers to help recognize and treat patients with potentially metastatic prostate and bladder cancers.