Epithelial/stromal signaling in bladder and prostate cell proliferation

描述（由申请人提供）：由于对控制细胞增殖的生物学机制或这些机制中允许原发器官内和转移部位病理性增殖的紊乱的不完全理解，我们识别和治疗前列腺癌和其他癌症致死形式的能力有限。 在我们最近的小鼠研究中，我们发现了上皮和间质之间的信号反馈回路，似乎是泌尿生殖器官增殖活性的中央控制机制。 我们建议测试的作用，这种上皮/基质电路，特别是支持性基质反应，在膀胱和前列腺的细胞增殖的控制和这些泌尿生殖器官的恶性肿瘤。 我们通过检查由尿路病原菌感染引起的膀胱损伤的戏剧性增殖反应发现了这个控制回路。 在感染后，Sonic hedgehog（Shh）蛋白信号的表达在尿路上皮的基底细胞亚群中增加，并且这触发了下面的基质的细胞中的应答，包括Wnt和FGF分泌的蛋白信号的表达增加;因此，上皮和基质细胞经历增殖的显著和持续增加。 揭示这一控制回路的关键是我们发现Gli 1，一个胚胎发育的Shh转录效应子，似乎在胚胎后增殖反应中起着关键作用。 我们已经发现，前列腺的增殖，尽管一个惊人的激素依赖性，是不存在的膀胱，也似乎采用Gli 1，这表明一个类似的膀胱的增殖控制机制。 我们建议测试的作用，在这个增殖控制电路在小鼠膀胱和前列腺的信号通路，并调查该电路在泌尿生殖系统恶性肿瘤的活动。 我们将使用细菌感染的膀胱和睾酮替代去势作为触发再生增殖反应，并将描绘信号通路，介导上皮/基质信号，使用组织显微切割和微阵列基因表达分析。 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、人类癌细胞系和大量的斯坦福大学冷冻保存的人类肿瘤组织来研究这种增殖控制回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是基质细胞的支持性反应，作为促进生长和指定远处转移的可能性的关键因素。 我们的研究将通过提高我们识别具有转移潜力的癌症的能力，并通过测试最近发现的FDA批准的有效调节Hh和Wnt信号通路活性的药理学药物的作用，为泌尿生殖系统恶性肿瘤提供新的诊断和治疗方法。 因此，我们的研究结果将直接有助于知识基础，可用于快速设计和实施新的临床试验。

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.