Prostate Cancer Bone Metastasis: Biology and Targeting

描述（由申请人提供）：该计划项目的首要主题是前列腺癌（PCa）骨转移是由骨和前列腺微环境中肿瘤-基质相互作用获得的进行性变化驱动的。前列腺和骨基质中激活的基因赋予癌细胞生长和存活优势，并编码作为PCa进展的新型预测生物标志物的基因产物。我们的发现定义内和细胞外的活性氧（ROS）表明，ROS可以介导的串珠素（PLN），硫酸肝素蛋白聚糖（HSPG）的关键表达增加，和？2-微球蛋白（？2-M）表达。似乎有一个紧密的信号关系？2-M、Pln和ROS，通过它们协调和调节这些信号分子的表达。PCa细胞线粒体DNA突变产生的ROS水平增加，？2-M和Pln。我们研究了这些分子生物标志物在原发性和骨转移性人PCa组织中的临床翻译。结果显示，LIV-1（上皮向间质转化（EMT）的驱动因子）、胞质而非核BDNF（p<0.001）、？2-M（p=0.006）、粘着斑激酶（FAK）（p=0.010）（人前列腺癌细胞中ROS的靶基因）和类肝素酶（p<0.001）（一种Pln降解酶）与PCa从正常、良性、PIN和局限性癌症到骨转移的进展。 在第一个计划项目资助期内，我们在范式转变发现、合作出版物以及对下一代前列腺癌研究人员的成功指导方面取得了显著进展。这些项目成功地实现了82份出版物所反映的所有拟议目标，其中37份被认为具有很大影响。在这个竞争性的更新，项目1的重点是表征？前列腺癌骨转移中2-M介导的生长和信号通路项目2的重点是表征已知与细胞外基质中的可溶性生长因子相互作用以最终影响癌症生长和转移的多个Pln结构域。项目3的重点是表征的ROS介导的基因表达和信号在前列腺上皮细胞在骨基质相互作用。项目和核心将继续定义肿瘤-基质相互作用的生物学和靶向潜力，验证组织和血清标本中的生物标志物，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.