Prostate Cancer Bone Metastasis: Biology and Targeting

描述(申请人提供)：本计划项目的主要主题是前列腺癌(PCA)骨转移是由骨和前列腺微环境中肿瘤-间质相互作用所获得的渐进性变化驱动的。前列腺和骨基质中激活的基因赋予癌细胞生长和存活的优势，并编码基因产物，作为前列腺癌进展的新型预测生物标志物。我们对细胞内外活性氧簇(ROS)的发现表明，ROS可以介导PCa细胞表达关键的硫酸肝素蛋白多糖(HSPG)Perlecan(PLN)和β2-微球蛋白(？2-M)。β2-M、PLN和ROS之间似乎存在着紧密的信号关系，这些信号分子的表达通过这种关系来协调和调节。线粒体DNA突变的PCa细胞产生更高水平的ROS、β2-M和PLN。我们研究了这些分子生物标记物在原发和骨转移的人前列腺癌组织中的临床翻译。结果显示，上皮细胞向间充质细胞转化的驱动力Liv-1(p&lt；0.001)、胞质而非核的脑源性神经营养因子(p&lt；0.001)、β2-M(p=0.006)、前列腺癌ROS靶基因粘着斑激酶(p=0.010)以及PLN降解酶乙酰肝素酶(p&lt；0.001)与前列腺癌从正常、良性、局灶性癌向骨转移的进展密切相关。 在第一个项目项目资助期，我们取得了显著的进展，发现了改变范式的发现，合作发表了出版物，并成功地指导了下一代前列腺癌研究人员。这些项目成功地实现了所有拟议目标，反映在82份出版物中，其中37份被认为影响很大。在这一竞争性更新中，项目1集中在前列腺癌骨转移中？2-M介导的生长和信号通路的特征。项目2集中在已知的多个PLN结构域的特征，这些结构域与细胞外基质中的可溶性生长因子相互作用，最终影响肿瘤的生长和转移。项目3主要研究ROS介导的基因在前列腺上皮细胞中的表达和信号在骨基质相互作用中的反应。这些项目和核心将继续定义肿瘤-间质相互作用的生物学和靶向潜力，验证组织和血清样本中的生物标记物，并最终将这些发现转化为临床实践。

DESCRIPTION (provided by applicant): The overarching theme of this Program Project is that prostate cancer (PCa) bone metastasis is driven by progressive changes acquired through tumor-stroma interaction in the bone and prostate microenvironment. Genes activated in prostate and bone stroma confer growth and survival advantages to cancer cells and encode gene products that serve as novel predictive biomarkers for PCa progression. Our discoveries defining intra- and extra-cellular reactive oxygen species (ROS) show that ROS can mediate increased expression of perlecan (Pln), a key heparin sulfate proteoglycan (HSPG), and ?2-Microglobulin (?2-M) expression by PCa cells. There appears to be a tight signaling relationship among ?2-M, Pln, and ROS by which the expression of these signaling molecules is coordinated and regulated. PCa cells with mitochondrial DNA mutations produced increased levels of ROS, ?2-M and Pln. We investigated the clinical translation of these molecular biomarkers in primary and bone metastatic human PCa tissues. Results showed significant correlation of LIV-1 (p<0.001), a driver of epithelial to mesenchymal transition (EMT), cytoplasmic but not nuclear BDNF (p<0.001), ?2-M (p=0.006), focal adhesion kinase (FAK) (p=0.010), a target gene of ROS in human prostate cancer cells, and heparanase, a Pln degradative enzyme (p<0.001) with the progression of PCa from normal, benign, PIN, and localized cancer to bone metastasis. In the first Program Project funding period, we made remarkable progress with paradigm-shifting discoveries, collaborative publications, and successful mentoring of the next generation of prostate cancer researchers. The Projects successfully accomplished all of the proposed aims, reflected in 82 publications, 37 of which were considered to be high impact. In this competitive renewal, Project 1 focuses on characterization of ?2-M-mediated growth and signaling pathways in prostate cancer bone metastasis. Project 2 focuses on the characterization of multiple Pln domains known to interact with soluble growth factors in extracellular matrices to ultimately affect cancer growth and metastasis. Project 3 focuses on the characterization of ROS-mediated gene expression and signaling in prostate epithelial cells in response to bone stromal interaction. The Projects and Cores will continue to define the biology and targeting potential of tumor-stromal interaction, validate biomarkers in tissue and serum specimens and ultimately translate these discoveries into clinical practice.