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，随着老年人口的增加，前列腺癌的发病率也在增加。转化生长因子-β(TGF-ss)在前列腺癌的发生、发展到去势抵抗中起核心作用。我们通过转基因小鼠模型特异性地证明了前列腺上皮细胞中转化生长因子-生长因子受体II(TGFBR2)的条件性敲除对肿瘤的形成或去势反应几乎没有影响。相反，间质成纤维细胞TGFBR2基因敲除导致腺癌的发展和抗去势生长。引人注目的是，在这些模型中，去势抵抗并不依赖于癌症的进展。我们发现，即使是TGFBR2-KO前列腺基质细胞与雄激素依赖的野生型前列腺上皮的组织重组也能抵抗去势。因此，去势抵抗和肿瘤形成是生化上可分离的事件。我们的初步数据表明，人类前列腺间质和转移性肿瘤相关骨微环境的共同进化涉及与转化生长因子-SS受体II表达异质性的出现相关的表观遗传学变化。我们将验证这一中心假设，即转化生长因子-生长抑素信号在间质-上皮相互作用中发挥重要作用，从而导致去势抵抗性前列腺癌(CRPC)。我们发现，前列腺成纤维细胞中转化生长因子-生长因子反应的丧失导致Wnt配体拮抗剂和CXCL12的表观遗传沉默增加。然而，当TGFBR2基因敲除的基质细胞与转化生长因子-ss信号转导的基质细胞共同培养时，CXCL12的表达被协同诱导。异型间质成纤维细胞在影响上皮去势反应中的相互作用是目标1的重点。在前列腺癌中，雄激素受体功能如何从促进发育和正常成人前列腺内稳的促分化作用异常地转换为在癌症中促进增殖的作用，目前尚不清楚。由于前列腺上皮雄激素应答是通过前列腺间质雄激素信号转导的，因此间质表观遗传信号的作用将是目标2的重点。TGFBR2基因敲除上调STAT3信号。STAT3在前列腺间质雄激素信号转导中的作用将根据其对雄激素受体活性的作用和相关上皮细胞的旁分泌作用来确定。慢性前列腺癌可发生在局部转移患者的前列腺中。然而，对于许多发生远处转移的患者来说，前列腺微环境对去势抵抗的作用并不那么重要。相反，成骨细胞和骨髓成纤维细胞是与转移性前列腺癌相互作用的主要细胞成分。转化生长因子-ss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的重点。我们在解决癌症相关间质变化在去势抵抗生长中的作用方面具有独特的地位。基于转化生长因子-ss在肿瘤抑制基因沉默和定义基质异质性中的作用，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的主要死亡原因。好了！

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. !