Paracrine Mechanisms of Prostate Cancer Metastatic Progression

前列腺癌在转移到肝脏时是致命的。我们第一次发现了脂肪变性 与正常的健康肝脏相比，肝炎(脂肪肝)对前列腺癌细胞的接受性明显更强。这个 退伍军人容易发生PCA肝转移，因为他们有多种脂肪肝的危险因素。 在这个提议的过程中，我们的目标是确定这种有趣的转移的机制 现象。我们已经证明脂肪肝和原发性前列腺癌的微环境 有多行相似之处，包括神经内分泌分化的上皮细胞、Tenascin C基质 和endoglin在肿瘤间质细胞中的表达。我们已经报道了转化生长因子-β信号转导途径 原发灶或转移灶肿瘤微环境对旁分泌的调节作用 信号决定了相关癌症上皮细胞的扩张和治疗抵抗。内在化 受体是转化生长因子受体家族中的一员，对下游的信号转导起关键作用 Smad2/3到Smad1/5信令。这一信号开关可能是转化生长因子从反转录病毒转变为 从致癌作用转变为促致癌作用。初步数据支持脂肪酸氧化的诱导 在原发肿瘤和endoglin下游的肝细胞中作为肿瘤上皮扩张的决定因素 原发灶和转移灶均有。反过来，我们发现脂肪酸代谢可以诱导内吞 表情。我们将专门测试假设，升高的CD105-脂肪酸氧化轴在前列腺癌 微环境通过以下方式支持其在原发灶和肝转移灶的扩散 目标：目标。1.明确CD105和脂肪酸氧化在前列腺癌相关成纤维细胞中的作用，以支持 PCA扩展。瞄准。2.明确CD105和脂肪酸氧化在肝细胞支持PCA中的作用 扩张。我们将询问间质和上皮组织在血管生成和维持中的作用 肝脏中的致死性PCA表型。我们将使用体内组织重组和患者来源的异种移植 研究改变的癌症相关成纤维细胞和癌细胞相互作用的系统。我们将是第一次 时间评估endoglin拮抗剂作为限制PCa肝转移的手段。我们的研究将有助于 从备受欢迎的退伍军人医院系统获取人体组织。理解一种解释原因的机制 脂肪肝微环境支持PCa肿瘤并决定PCa如何适应转移 微环境是这个项目的目标。

Prostate cancer is lethal when it metastasizes to the liver. We have identified for the first time that a steatotic hepatitis (fatty liver) is significantly more receptive to prostate cancer cells than a normal healthy liver. The Veteran population is predisposed to PCa liver metastasis as they have the multiple risk factors for fatty liver. In the course of this proposal our objective is to determine the mechanism of this interesting metastatic phenomena. We have demonstrated that the fatty liver and the primary prostate cancer microenvironment have multiple lines of similarity, including neuroendocrine differentiation of the epithelia, tenascin C matrix expression, and endoglin expression in the tumor stromal cells. We have reported that TGF-ß signaling in the tumor microenvironment in the primary tumor site or the secondary metastatic site mediates paracrine signaling dictate the expansion and therapeutic resistance of the associated cancer epithelia. The endoglin receptor is a member of the TGF-ß receptor family that is critical for the switching from the downstream Smad2/3 to the Smad1/5 signaling. This signaling switch can be the determinant for TGF-ß going from an anti- tumorigenic role to that of a pro-tumorigenic role. Preliminary data support the induction of fatty acid oxidation in the primary tumor and hepatocytes downstream of endoglin as a determinant of tumor epithelial expansion at both primary tumor and metastatic site. In turn, we found that fatty acid metabolism can induce endoglin expression. We will specifically test the hypothesis that, elevated CD105-fatty acid oxidation axis in the PCa microenvironment is supportive of its expansion in the primary and liver metastatic site through the following aims: Aim. 1. Define the role of CD105 and fatty acid oxidation plays in PCa-associated fibroblasts to support PCa expansion. Aim. 2. Define the role of CD105 and fatty acid oxidation plays in hepatocytes to support PCa expansion. We will interrogate both stromal and epithelial contributions to the generation and maintenance of a lethal PCa phenotype in the liver. We will use in vivo tissue recombination and patient derived xenograft systems to study the interactions of altered cancer-associated fibroblasts and cancer cells. We will for the first time evaluate endoglin antagonism as a means of limiting PCa liver metastasis. Our studies will leverage access to human tissues from the well-annotated VA Hospital System. Understanding a mechanism for why the fatty liver microenvironment supports PCa tumors and determining how the PCa adapts to the metastatic microenvironment are the goals of this project.