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的不完全理解，或者对这些机制中允许原发器官和转移部位的病理增殖的紊乱，我们在识别和治疗致命形式的前列腺癌和其他癌症方面的能力有限。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回路，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/基质回路的作用，特别是支持基质反应，在膀胱和前列腺以及这些泌尿生殖器官的恶性肿瘤中控制细胞增殖。我们通过检查由尿路致病菌感染引起的膀胱损伤的显著增殖反应，发现了这个控制回路。感染后，尿路上皮基底细胞的一个亚群中Sonic hedgehog （Shh）蛋白信号的表达增加，从而触发下层基质细胞的反应，包括Wnt和FGF分泌蛋白信号的表达增加；因此，上皮细胞和基质细胞经历了急剧和持续的增殖增加。揭示这一控制回路的关键是我们发现Gli1，一种在胚胎发育中不可或缺的Shh转录效应因子，似乎在胚胎后增殖反应中起着关键作用。我们发现前列腺的增殖，尽管在膀胱中没有明显的激素依赖性，但似乎也使用Gli1，这表明增殖控制机制与膀胱相似。我们建议测试信号通路在小鼠膀胱和前列腺增生控制回路中的作用，并研究该回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阉割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述介导上皮/基质信号传导的信号通路。功能研究将利用遗传分析和药理学手段。我们将利用小鼠模型、人类癌细胞系和斯坦福大学大量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放在基质细胞作为促进生长和确定远处转移可能性的关键因素的支持反应上。我们的研究将为泌尿生殖系统恶性肿瘤提供新的诊断和治疗方法，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fda批准的药理学药物的作用，这些药物最近被发现可以有效地调节Hh和Wnt信号通路的活性。因此，我们的发现将直接有助于快速设计和实施新的临床试验的知识基础。

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.