Biology of Tumor-Stroma Interaction

项目1，肿瘤-间质相互作用生物学的主要焦点将是一种新的可溶性因子，β 2- 微球蛋白（P2-M），由我们实验室发现并表征为主要生长因子， 前列腺癌（PCa）、骨基质和炎症细胞分泌的信号分子。p2-M是 显示促进骨模拟，癌细胞模仿其骨微环境的能力， PCa细胞在培养物和体内的生长和存活，并且不仅加速PCa而且促进乳腺、肺和 肾癌骨定植主要目标是：a）确定p2-M在驾驶中的功能 上皮细胞向间质细胞转化（EMT），癌症转移的第一步，以及RANKL增加 表达和骨转换，对于骨中的癌症定殖至关重要; B）机械地研究如何 32-M促进抗细胞凋亡和癌细胞存活; c）测试抗p2-M抗体的抗肿瘤作用 n小鼠;和d）开发和验证用于临床转化的新的信号传导途径相关的生物标志物。 该建议的总体假设是：1）B2-M是一种多效性信号分子，其促进了细胞内的细胞凋亡。 通过增加骨转换，PCa在骨中的生长和存活：2）B2-M介导的下游信号传导 信号通路是用于临床转化的极好的治疗靶标和预测性生物标志物。具体目标 目的1：确定P2-M如何增强人PCa细胞的生长和骨转移，重点是 EMT和RANKL介导的骨转换。目的2：剖析p2-M激活的生存机制 涉及VEGF/神经纤毛蛋白/Mcl-1信号传导增加和生存素表达增加。目标3：发展 靶向临床相关PCa骨中p2-M介导的生长和存活机制的策略 转移模型目的4：确定p2-M介导基因的共同分子标记 激活癌细胞，“反应性”前列腺和骨基质，并评估其临床效用， 生物标志物。这些目标将通过项目间和核心间的密切互动、共享 试剂、细胞系、动物模型和临床材料，并纳入PO-1的智力投入 调查员和学员。最终，在了解PCa骨的生物学和靶向方面取得了进展， 转移将改善PCa患者的诊断、预后和治疗。 相关性（参见说明）： 前列腺癌骨转移是致命的，目前没有有效的治疗方法。当前程序 该项目由对阐明调节基因表达的分子机制有共同兴趣的专家组成。 前列腺癌骨转移及其致死靶向有效治疗的发展 进展本提案中所述的战略可导致降低 前列腺癌骨转移患者。

The major focus of Project 1, Biology of Tumor-Stroma Interaction, will be on a novel soluble factor, beta 2- Vlicroglobulin (P2-M), discovered and characterized by our laboratory as a major growth factor and signaling molecule secreted by prostate cancer (PCa), bone stroma and inflammatory cells. p2-M was shown to promote osteomimicry, the ability of cancer cells to mimic their bone microenvironment, to induce growth and survival of PCa cells in culture and in vivo and accelerate not only PCa but also breast, lung and renal cancer bone colonization. The major objectives are:a) to define the function of p2-M in driving Epithelial to Mesenchymal Transition (EMT), the first step in cancer metastasis, and increased RANKL expression and bone turnover, critical for cancer colonization in bone; b) to mechanistically investigate how 32-M promotes anti-apoptosis and cancer cell survival; c) to test the anti-tumor effects of anti-p2-M antibody n mice; and d) to develop and validate new signaling pathway-related biomarkers for clinical translation. The overall hypotheses of this proposal are: 1) B2-M is a pleiotropic signaling molecule that promotes the growth and survival of PCa in bone bv increased bone turnover: 2) B2-M-mediated downstream signaling pathways are excellent therapeutic targets and predictive biomarkers for clinical translation. Specific Aims are: Aim 1: To determine how P2-M enhances human PCa cell growth and metastasis to bone, with a focus on EMT and RANKL-mediated bone turnover. Aim 2: To dissect p2-M-activated survival mechanisms involving increased VEGF/neuropilin/Mcl-1 signaling and increased survivin expression.. Aim 3: To develop strategies to target p2-M-mediated growth and survival mechanisms in clinically relevant PCa bone metastasis models. Aim 4: To determine the common molecular signatures of p2-M-mediated gene activation in cancer cells, "reactive" prostate and bone stroma, and to assess their clinical utility as biomarkers. These Aims will be accomplished with close inter-project and inter-core interaction, sharing reagents, cell lines, animal models and clinical materials and incorporating intellectual input from PO-1 investigators and trainees. Ultimately, progress in understanding the biology and targeting of PCa bone metastasis will improve the diagnosis, prognosis and treatment of PCa patients. RELEVANCE (See instructions): Prostate cancer bone metastasis is lethal and currently there is no effective therapy. The current Program Project comprised of experts with shared interests in elucidating the molecular mechanisms regulating prostate cancer bone metastasis and the development of effective therapeutic targeting of its lethal progression. The strategies described in this proposal could lead to reduced mortality and morbidity of patients with prostate cancer bone metastasis.