Paracrine mechanisms of prostate cancer hormonal resistance

描述（由申请人提供）： 摘要前列腺癌是最常见的癌症，并且随着退伍军人人口老龄化的增加而增加。转化生长因子-β（TGF-β）在前列腺癌、去势抵抗的起始和进展中起核心作用。我们通过转基因小鼠模型特别证明，前列腺上皮中TGF-β受体II型（Tgfbr 2）的条件性敲除对肿瘤发生或去势反应性几乎没有影响。相反，间质成纤维细胞Tgfbr 2基因敲除导致腺癌和去势抵抗性生长的发展。引人注目的是，这些模型中的去势抵抗并不依赖于癌症的进展。我们发现，甚至Tgfbr 2-KO前列腺基质细胞与雄激素依赖性野生型前列腺上皮细胞的组织重组体也变得去势抵抗。因此，去势抵抗和肿瘤发生是生物化学分离的事件。我们的初步数据表明，人类前列腺基质和转移性肿瘤相关骨微环境的共同进化涉及与TGF-β受体II型表达异质性出现相关的表观遗传变化。我们将检验中心假设，即TGF-β信号传导在负责去势抵抗性前列腺癌（CRPC）的间质-上皮相互作用中起重要作用。我们发现，前列腺成纤维细胞中TGF-β反应性的丧失导致Wnt配体拮抗剂和CXCL 12的表观遗传沉默升高。然而，当TGF-β信号传导活性基质细胞与Tgfbr 2敲除的基质细胞共培养时，它们协同诱导CXCL 12表达。异型间质成纤维细胞在影响上皮去势反应性方面的相互作用是目的1的焦点。在前列腺癌中，雄激素受体功能如何从发育和正常成人前列腺稳态中的促分化作用异常地转换为癌症中的促增殖作用，仍然知之甚少。由于前列腺上皮雄激素反应性是通过前列腺间质雄激素信号传导介导的，因此间质表观遗传信号传导的作用将是目标2的焦点。Tgfbr 2的敲除上调Stat 3信号传导。Stat 3在前列腺间质雄激素信号传导中的作用将根据其对雄激素受体活性的作用和对相关上皮细胞的旁分泌作用来确定。CRPC可在局部转移患者的前列腺中发展。然而，对于许多发生远处转移的患者，前列腺微环境对去势抵抗的作用不太相关。相反，成骨细胞和骨髓成纤维细胞是与转移的前列腺癌相互作用的主要细胞成分。TGF-β对构成转移性前列腺癌微环境的成骨细胞和骨髓成纤维细胞的作用是目标3的焦点。我们在解决去势抵抗性生长中发生的癌症相关基质变化的作用方面具有独特的优势。基于TGF-β在肿瘤抑制基因沉默中的作用和定义基质异质性，我们将使用新的细胞培养、组织重组异种移植和转基因小鼠模型来解决前列腺癌导致死亡的主要原因。!

DESCRIPTION (provided by applicant): ABSTRACT Prostate cancer is the most commonly diagnosed cancer and increasing with the expanding aging Veteran population. Transforming growth factor-beta (TGF-ss) plays a central role in prostate cancer, initiation and progression to castrate resistance. We specifically demonstrated through transgenic mouse models that the conditional knockout of the TGF-ss receptor type II (Tgfbr2) in prostate epithelia has little effect on tumorigenesis or castrate responsiveness. In contrast, the stromal fibroblastic Tgfbr2 knockout resulted in the development of adenocarcinoma and castrate-resistant growth. Strikingly, castrate resistance in these models was not dependent on cancer progression. We found that even tissue recombinants of Tgfbr2-KO prostate stromal cells with androgen dependent wild type prostate epithelia became castrate resistant. Thus, the castrate resistance and tumorigenesis are biochemically separable events. Our preliminary data indicate that the co-evolution of the human prostate stroma and metastatic tumor-associated bone microenvironment involves epigenetic changes associated with emergence of heterogeneity in TGF-ss receptor type II expression. We will test the central hypothesis that, TGF-ss signaling plays an important role in stromal-epithelial interactions responsible for castrate resistant prostate cancer (CRPC). We found that the loss of TGF-ss responsiveness in prostate fibroblastic cells results in elevated epigenetic silencing of Wnt ligand antagonists and CXCL12. However, there was cooperative induction of CXCL12 expression by TGF-ss signaling competent stromal cells when they were co-cultured with those having a knockout of Tgfbr2. The interaction of the heterotypic stromal fibroblastic cells in affecting the epithelial castrate responsiveness is the focus of Aim 1. It is still poorly understood how in prostate cancer androgen receptor function is abnormally switched from a pro- differentiation role in development and normal adult prostate homeostasis, to one pro-proliferation in cancer. Since prostate epithelial androgen responsiveness is mediated through prostate stromal androgen signaling, the role of stromal epigenetic signaling will be the focus of Aim 2. The knockout of Tgfbr2 up regulates Stat3 signaling. The role of Stat3 in prostate stromal androgen signaling will be determined in terms of its role on androgen receptor activity and paracrine role on the associated epithelia. CRPC can develop in the prostates of patients with local metastasis. However, for the many patients that develop distant metastasis, the role of the prostate microenvironment on castrate resistance is less relevant. Instead, the osteoblasts and bone marrow fibroblastic cells are primary cellular components that interact with the metastasized prostate cancer. The actions of TGF-ss on osteoblasts and bone marrow fibroblastic cells, that make up the metastatic prostate cancer microenvironment, is the focus of Aim 3. We are uniquely positioned to address the role of cancer associated stromal changes that occur in castrate resistant growth. Based on TGF-ss's role in tumor suppressor silencing and defining stromal heterogeneity, we will use novel cell culture, tissue recombination xenografting, and transgenic mouse models to address the primary cause for death due to prostate cancer. !