PATHOGENESIS AND PROGRESSION OF PROSTATE CANCER

描述(申请人提供)：在我们监测小鼠模型中前列腺癌体内生长、退化和复发的能力的指导下，我们现在能够很好地分离疾病进展特定阶段的肿瘤。考虑到间质-上皮相互作用在前列腺癌发育和前列腺癌中的重要性，这一更新应用的中心主题是我们希望利用该模型的这一优势开始定义可能在前列腺癌进展和复发中起关键作用的异型细胞相互作用的重要介质。所有结果都将在人类前列腺癌样本中进行跟踪。我们的假说是基于多种分泌和诱导因子，包括骨形态发生蛋白(BMPs)和骨形态发生蛋白(BMP)诱导的基质细胞衍生因子1(SDF-1)的激活，SDF-1是我们已经确定的前列腺癌细胞和前列腺癌相关成纤维细胞(CAF)之间的一种新的相互作用，在前列腺癌的生长和进展中发挥关键的自分泌、旁分泌和内分泌功能，调节前列腺癌及其相关的CAF的生长和存活，调节癌细胞的血管内皮细胞和转移，以及在血管生成表型中发挥作用。对于雄激素剥夺治疗后复发的或雄激素耗竭非依赖性(ADI)癌症，我们假设诱导因子和细胞隔间(包括表观遗传和/或遗传进化的CAF)的额外变化可能是重要的贡献因素。我们的第一个目标是利用小鼠和人前列腺癌的细胞系统，阐明BMP诱导CAF细胞产生和分泌SDF-1的机制，并确定BMP-SDF-1轴在前列腺癌进展中的生物学作用。我们的目标是了解BMP和SDF-1在前列腺肿瘤细胞和肿瘤内非肿瘤细胞之间相互作用的机制。在第二个目标中，我们将从上皮室表型分布的变化以及间充质中潜在的分子和功能变化，特别是可能影响ADI癌细胞增殖和发展的CAF来表征ADI前列腺癌的进展。最后，第三个目标是利用研究系统来确定ADI癌细胞的来源。我们将定义前列腺癌进展过程中的前列腺干/祖细胞亚群，并在CAF与肿瘤上皮细胞进行性变化的共同进化的不同背景下表征这些亚群的功能。描述了一系列相互关联和平行的研究，使用小鼠模型、小鼠前列腺细胞、人类前列腺细胞和临床标本，以获得对导致总体前列腺癌进展、转移和复发的特定异型细胞相互作用的机械性洞察。与公共卫生相关：我们已经开发出模拟人类前列腺癌进展的小鼠模型。我们现在建议检查这些模型，以了解肿瘤生长、转移、在抗雄激素治疗下的消退以及雄激素耗竭非依赖性癌症的复发的机制，目的是确定前列腺癌治疗的新靶点。。

DESCRIPTION (provided by applicant): Guided by our ability to monitor in vivo growth, regression and relapse of prostate adenocarcinoma in mouse models, we are now well positioned to isolate tumors at specific stages of the disease progression. Considering the well recognized importance of stromal-epithelial interactions in prostate gland development and in prostate cancer, the central theme of this renewal application is formed on our desire to use this advantage of the model to begin to define important mediators of heterotypic cell interactions that may be critical in progression and recurrence of prostate cancer. All results will then be followed in human prostate cancer samples. Our hypothesis is based on the contention that the multiple secretory and inductive factors including bone morphogenetic proteins (BMPs) and BMP-induced activation of stromal cell-derived factor 1 (SDF-1), a novel interplay between prostate cancer cells and prostate cancer-associated fibroblasts (CAFs) that we have identified, serve critical autocrine, paracrine and endocrine functions in the regulation of growth and survival of prostate cancer cells and associated CAFs, in the intravasation and metastasis of the cancer cells, and in the angiogenic phenotype in the growth and progression of prostate cancer. For the recurrent or androgen depletion-independent (ADI) cancer that emerges following regression from androgen deprivation therapy, we hypothesize that additional changes in inductive factors and in the cellular compartments including epigenetically and/or genetically evolved CAFs may be important contributors. Our first aim is to elucidate the mechanisms by which BMP induces CAF cells to produce and secrete SDF-1, using cell systems from both mouse and human prostate cancer, and to define the biological effects of BMP-SDF-1 axis in prostate tumor progression. Our goal is to generate a mechanistic understanding by which BMP and SDF-1 mediate the reciprocal interactions between prostate tumor cells and non-tumor cells within the tumor. In the second aim we will characterize the progression of the ADI prostate cancer with respect to changes in the phenotypic distribution in the epithelial compartment, and with respect to potential molecular and functional changes in the mesenchyme, particularly CAFs that may influence the proliferation and progression of ADI cancer cells. Finally, the third aim concerns an exploitation of the study system to determine the origins of the ADI cancer cells. We will define the prostate stem/ progenitor cell subpopulations during prostate cancer progression, and characterize the functions of these subsets in the varied context of the coevolution of CAFs with the progressive changes in the neoplastic epithelial cells. A series of interconnected and parallel studies, using the mouse models, mouse prostate cells, human prostate cells, and clinical specimens is described to obtain mechanistic insight into specific heterotypic cell interactions that contribute to overall prostate cancer progression, metastasis and recurrence. PUBLIC HEALTH RELEVANCE: We have developed mouse models that mimic the progression of human prostate cancer. We now propose to examine the models to understand the mechanisms of cancer growth, metastasis, regression under anti-androgen therapy, and the recurrence of androgen depletion-independent cancer with the goal to identify new targets for prostate cancer therapy. .