Endothelial-to-osteoblast transition in prostate cancer bone metastasis

前列腺癌骨转移中的内皮细胞向成骨细胞的转变

• 批准号: 10303067
• 负责人: SUE-HWA LIN
• 金额: $ 31.21万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303067
• 关键词: Angiogenesis Inhibition; BMP4; Biological Markers; Bone Development; Bone Marrow; Cell Survival; Cells; Clinical; Communication; Disease; Endothelial Cells; Endothelium; Funding; Gene Expression; Genes; Growth; Growth Factor; Human; Hybrid Cells; Immature Bone; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Morbidity - disease rate; Mus; Oncology; Osteoblasts; Osteogenesis; Outcome; Pathway interactions; Patients; Play; Process; Property; Prostate Cancer therapy; Prostatic Neoplasms; Proteins; Quality of life; Reporter; Resistance; Role; Sampling; Specimen; Tenascin; Testing; angiogenesis; beta catenin; bone; cancer cell; chemotherapy; connective tissue growth factor; implantation; improved; in vitro activity; in vivo; insight; mortality; neoplastic cell; notch protein; novel; osteoblast differentiation; osteoblast proliferation; overexpression; paracrine; patient derived xenograft model; prostate cancer cell; prostate cancer metastasis; prostate cancer model; prostate cancer progression; subcutaneous; targeted cancer therapy; therapy outcome; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; versican

Project Abstract/Summary Bone metastases are the major contributing factors to prostate cancer (PCa) morbidity and mortality. PCa bone metastases are uniquely osteoblastic and characterized by new bone formation, which promotes tumor growth in bone. Thus, bi-directional interaction between the PCa cells and their mis-induced bone plays a critical role in PCa progression in bone. It has been assumed that metastatic PCa induces new bone formation by stimulating the proliferation of osteoblasts in the bone marrow. However, we recently demonstrated that tumor-associated endothelial cells could give rise to osteoblasts through a little-appreciated process known as endothelial cell-to- osteoblast (EC-to-OSB) conversion, generating in the process EC-OSB hybrid cells with unique properties. Our studies showed that tumor-induced EC-to-OSB conversion is one mechanism that leads to osteoblastic bone metastasis of PCa. This new insight into the surprising bone-forming role of EC-OSB hybrid cells in PCa bone metastasis provides a novel rationale to target these cells in the tumor microenvironment. We hypothesize that tumor-induced EC-to-OSB conversion generates EC-OSB hybrid cells, which provide paracrine factors to support metastatic PCa growth in bone. Our objective is to target EC-OSB hybrid cells for improving therapy for bone metastasis. We will: Aim 1. Determine the mechanisms underlying endothelial cell-to-osteoblast (EC-to-OSB) transition. EC-to-OSB conversion requires both the inhibition of angiogenesis and activation of osteoblastogenesis pathways in endothelial cells. Our preliminary results indicate that BMP4 activates the Notch-Hey1 pathway to inhibit angiogenesis and the p38MAPK-β-catenin-OSX pathway to stimulate osteogenesis. We will examine how BMP4 integrates these two pathways to reprogram the endothelial cells. Aim 2. Identify EC-OSB hybrid cell secreted factors (EC-OSB factors) that promote PCa progression. EC-OSB hybrid cell secretome was examined by both iTRAQ (protein) and RNAseq (gene) analyses. Tenascin C was identified along with CTGF and versican, which together may constitute an “EC-to-OSB signature”. We will investigate the effects of these EC-OSB factors on PCa cell activity in vitro and in vivo. The “EC-OSB signature” will also be tested as biomarkers for osteoblastic bone metastasis using clinical samples. Aim 3. Develop strategies that target EC-OSB hybrid cells to improve therapy outcomes for PCa bone metastasis. The EC- OSB hybrid cells may contribute to de novo therapy resistance described previously. We will examine whether we can improve therapy outcomes for PCa bone metastasis by combining cabozantinib or cabazitaxel (targets PCa tumor) with Rad-223 (targets EC-OSB hybrid cells). Aim 4. Determine whether EC-to-OSB transition occurs in normal bone and the fraction of EC-OSB hybrid cells in tumor-induced bone. We generated a new Double Reporter Mice (col11-GFP/Tie2-cre/Rosa-tdTomato), in which EC are RFP+, OSB are GFP+, and EC-OSB are RFP+/GFP+, to examine whether EC-OSB hybrid cells are involved in normal bone development and their fraction in tumor-induced bone.

项目摘要/总结 骨转移是前列腺癌（PCa）发病率和死亡率的主要影响因素。前列腺癌骨 转移瘤是独特的成骨细胞，其特征是新骨形成，从而促进肿瘤生长 骨。因此，PCa 细胞与其错误诱导的骨之间的双向相互作用在 PCa 中发挥着关键作用。 骨骼的进展。据认为，转移性 PCa 通过刺激 骨髓中成骨细胞的增殖。然而，我们最近证明，与肿瘤相关的 内皮细胞可以通过一个鲜为人知的过程（称为内皮细胞到-）产生成骨细胞 成骨细胞（EC 至 OSB）转化，在此过程中生成具有独特特性的 EC-OSB 混合细胞。我们的 研究表明，肿瘤诱导的 EC 向 OSB 的转化是导致成骨细胞形成的机制之一。 PCa骨转移。关于 EC-OSB 杂交细胞在 PCa 中令人惊讶的骨形成作用的新见解 骨转移为靶向肿瘤微环境中的这些细胞提供了新的原理。 我们假设肿瘤诱导的 EC 到 OSB 的转化产生 EC-OSB 混合细胞，从而提供 旁分泌因子支持骨转移性 PCa 生长。我们的目标是将 EC-OSB 混合电池用于 改善骨转移的治疗。我们将： 目标 1. 确定内皮细胞的潜在机制 细胞到成骨细胞（EC 到 OSB）的转变。 EC 向 OSB 的转化需要抑制血管生成 和内皮细胞中成骨细胞生成途径的激活。我们的初步结果表明 BMP4 激活 Notch-Hey1 通路抑制血管生成，激活 p38MAPK-β-catenin-OSX 通路刺激 成骨。我们将研究 BMP4 如何整合这两条途径来重新编程内皮细胞。目的 2. 鉴定促进 PCa 进展的 EC-OSB 混合细胞分泌因子（EC-OSB 因子）。 EC-定向刨花板 通过 iTRAQ（蛋白质）和 RNAseq（基因）分析检查杂交细胞分泌组。生腱蛋白 C 与 CTGF 和 versican 一起被识别，它们一起可能构成“EC-to-OSB 特征”。我们将 研究这些 EC-OSB 因子对体外和体内 PCa 细胞活性的影响。 “EC-OSB 签名” 还将使用临床样本作为成骨细胞骨转移的生物标志物进行测试。目标 3. 发展 针对 EC-OSB 杂交细胞的策略可改善 PCa 骨转移的治疗效果。欧盟- OSB 杂交细胞可能会导致先前描述的从头治疗耐药性。我们将检查我们是否 通过结合卡博替尼或卡巴他赛（针对 PCa 骨转移）可以改善 PCa 骨转移的治疗结果 肿瘤）与 Rad-223（针对 EC-OSB 杂交细胞）。目标 4. 确定是否发生 EC 到 OSB 的转变 正常骨中的比例和肿瘤诱导骨中 EC-OSB 杂交细胞的比例。我们生成了一个新的 Double 报告小鼠 (col11-GFP/Tie2-cre/Rosa-tdTomato)，其中 EC 为 RFP+，OSB 为 GFP+，EC-OSB 为 RFP+/GFP+，检查 EC-OSB 杂交细胞是否参与正常骨骼发育及其比例 在肿瘤诱导的骨中。