PATHOGENESIS AND PROGRESSION OF PROSTATE CANCER

描述（由申请人提供）：在我们监测小鼠模型中前列腺腺癌的体内生长、消退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。考虑到基质-上皮相互作用在前列腺发育和前列腺癌中的公认重要性，本更新申请的中心主题是基于我们希望使用该模型的这一优势来开始定义异型细胞相互作用的重要介质而形成的，所述异型细胞相互作用可能在前列腺癌的进展和复发中至关重要。然后将在人前列腺癌样本中跟踪所有结果。我们的假设是基于这样的论点，即多种分泌和诱导因子，包括骨形态发生蛋白（BMP）和BMP诱导的基质细胞衍生因子1（SDF-1）的活化，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，在调节前列腺癌细胞和相关CAF的生长和存活中，在癌细胞的内渗和转移中，以及在前列腺癌的生长和进展中的血管生成表型中的旁分泌和内分泌功能。对于复发性或雄激素缺乏非依赖性（ADI）癌症，出现后回归雄激素剥夺治疗，我们假设，额外的变化，诱导因素和细胞室，包括表观遗传和/或遗传进化的CAF可能是重要的贡献者。我们的第一个目的是阐明BMP诱导CAF细胞产生和分泌SDF-1的机制，使用来自小鼠和人前列腺癌的细胞系统，并确定BMP-SDF-1轴在前列腺肿瘤进展中的生物学效应。我们的目标是产生一个机制的理解，BMP和SDF-1介导的前列腺肿瘤细胞和肿瘤内的非肿瘤细胞之间的相互作用。在第二个目标中，我们将描述ADI前列腺癌的进展，包括上皮细胞中表型分布的变化，以及间充质中潜在的分子和功能变化，特别是可能影响ADI癌细胞增殖和进展的CAF。最后，第三个目标涉及利用研究系统来确定ADI癌细胞的起源。我们将在前列腺癌进展过程中定义前列腺干/祖细胞亚群，并在CAFs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。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，人前列腺细胞，和临床标本的描述，以获得特定的异型细胞的相互作用，有助于整体前列腺癌的进展，转移和复发的机制洞察。公共卫生相关性：我们已经开发了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，以了解抗雄激素治疗下癌症生长、转移、消退的机制，以及雄激素耗竭非依赖性癌症的复发，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. .