Inhibition of angiogenesis by thrombospondin-1 (A2)

血小板反应蛋白-1 (A2) 抑制血管生成

• 批准号: 7876959
• 负责人: John W LAWLER
• 金额: $ 36.37万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876959
• 关键词: Affect; Agonist; Angiogenesis Inhibition; Animal Model; Antibodies; Apoptosis; Apoptotic; Area; Attenuated; Behavior; Blood Vessels; CD36 gene; Cell Membrane Proteins; Cell membrane; Cells; Cessation of life; Clinical Trials; Colon Carcinoma; Combined Modality Therapy; Complex; Data; Dermal; Development; Effectiveness; Endothelial Cells; Engineering; Event; Exhibits; Extracellular Protein; Fibroblast Growth Factor; Goals; Growth; Human; In Vitro; Integrins; Intervention; Knockout Mice; Knowledge; MAPK14 gene; MAPK8 gene; Mediating; Modeling; Molecular; Mus; Neoplasms; Nutrient; Oxygen; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiologic Neovascularization; Prevention; Process; Proteins; Receptor Signaling; Recombinant Proteins; Research; Resistance; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Small Interfering RNA; Staging; Stress; Structure; TNF-related apoptosis-inducing ligand; TNFRSF10A gene; TNFRSF10B gene; Testing; Therapeutic; Therapeutic Intervention; Therapy Clinical Trials; Thrombospondin 1; Tissues; Treatment Efficacy; Tumor Cell Line; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular remodeling; Work; Wound Healing; angiogenesis; base; cancer therapy; caspase-8; cell type; combinatorial; design; in vivo; inhibitor/antagonist; insight; mouse model; neoplastic cell; pre-clinical; public health relevance; receptor; subcutaneous; synthetic peptide; tumor; tumor growth

DESCRIPTION (provided by applicant): Thrombospondin-1 (TSP-1) regulates endothelial cell phenotype during the tissue remodeling that is associated with angiogenesis, wound healing and neoplasia. The importance of suppression of angiogenesis by TSP-1 is underscored by the observation that TSP-1-null mice exhibit increased tumor growth and that TSP-1-based therapeutics are currently in clinical trials for the inhibition of angiogenesis. The proposed studies focus on the following areas. Specific Aim 1. To determine the effectiveness of targeting tumor endothelial cells and tumor cells with 3TSR and TRAIL receptor agonist antibodies in preclinical mouse models. Others and we have found that the three type 1 repeats of TSP-1 (3TSR) and TNF-Related Apoptosis Inducing Ligand (TRAIL) can induce apoptosis of various tumor cells, including colon carcinomas, through the induction of endothelial cell apoptosis and tumor cell apoptosis, respectively. However, neither TRAIL nor 3TSR can induce complete tumor regression. Our studies have demonstrated that 3TSR can up- regulate death receptor (DR4 and DR5) in primary human dermal microvascular endothelial cells (HDMEC) and this sensitizes these normally TRAIL resistant cells to TRAIL-induced apoptosis. Furthermore, a combination of 3TSR and a TRAIL receptor agonist antibody results in dramatic inhibition of tumor growth in a murine model of colon cancer. The goals of this aim are to (1) establish that induction of endothelial cell apoptosis in colon cancer animal models involves CD36, activation of caspase-8 and -9, and up-regulation of murine DR5 (mDR5) and (2) test the therapeutic efficacy of combinatorial approaches using 3TSR to sensitize tumor endothelial cells to TRAIL-induced apoptosis in prevention and regression/intervention therapeutic trials using subcutaneous and orthotopic models of colon cancer. Specific Aim 2. To identify the receptors and signaling molecules that mediate the anti-angiogenic activity of TSP-1 and 3TSR. Whereas Fyn, JNK and p38 phosphorylation have been shown to be involved in TSP-1-induced endothelial cell apoptosis, the remaining components of this signal transduction pathway are unknown. We have found that CD36 associates with vascular endothelial cell growth factor receptor 2 (VEGFR2), integrins, tetraspanins and their associated signal transduction molecules. We hypothesize that the CD36/VEGFR2/integrin complexes in the endothelial cell membrane mediate 3TSR-induced apoptosis and facilitates cross-talk between pro- and anti-angiogenic signal transduction pathways. The goals of the proposed study are to determine (1) which components of the CD36/VEGFR2/integrin complexes are essential for TSP-1- or 3TSR-induced endothelial cell apoptosis, (2) whether these complexes enable endothelial cells to integrate pro- and anti-angiogenic signals in the tumor microenvironment and (3) determine how the presence of TSP-1 or 3TSR affects the structure and function of these complexes. These studies will provide key insights into the therapeutic potential of 3TSR and TRAIL combined therapy and will elucidate the molecular basis for the inhibition of angiogenesis by TSP-1. PUBLIC HEALTH RELEVANCE: The proposed research is designed to develop new strategies for inhibiting tumor growth by destroying the blood vessels that supply oxygen and nutrients to them. The goal of the proposed study is to determine how proteins that the body normally uses to limit blood vessel growth work. This knowledge will be used to develop therapeutic approaches for the treatment of cancer.

描述（由申请人提供）：血小板反应蛋白-1（TSP-1）在与血管生成、伤口愈合和肿瘤相关的组织重塑过程中调节内皮细胞表型。 TSP-1缺失小鼠表现出肿瘤生长增加的观察结果强调了TSP-1抑制血管生成的重要性，并且基于TSP-1的疗法目前正在进行抑制血管生成的临床试验。拟议的研究重点关注以下领域。具体目标 1. 在临床前小鼠模型中确定 3TSR 和 TRAIL 受体激动剂抗体靶向肿瘤内皮细胞和肿瘤细胞的有效性。其他人和我们发现TSP-1（3TSR）和TNF相关凋亡诱导配体（TRAIL）的三个1型重复序列可以分别通过诱导内皮细胞凋亡和肿瘤细胞凋亡来诱导包括结肠癌在内的多种肿瘤细胞的凋亡。然而，TRAIL 和 3TSR 都不能诱导肿瘤完全消退。我们的研究表明，3TSR 可以上调原代人真皮微血管内皮细胞 (HDMEC) 中的死亡受体（DR4 和 DR5），这使这些通常对 TRAIL 耐药的细胞对 TRAIL 诱导的细胞凋亡敏感。此外，3TSR 和 TRAIL 受体激动剂抗体的组合可显着抑制小鼠结肠癌模型中的肿瘤生长。该目标的目标是 (1) 确定结肠癌动物模型中内皮细胞凋亡的诱导涉及 CD36、caspase-8 和 -9 的激活以及小鼠 DR5 (mDR5) 的上调，以及 (2) 测试使用 3TSR 使肿瘤内皮细胞对 TRAIL 诱导的细胞凋亡敏感的组合方法在预防和消退/干预中的治疗效果 使用结肠癌皮下和原位模型的治疗试验。具体目标 2. 鉴定介导 TSP-1 和 3TSR 抗血管生成活性的受体和信号分子。尽管 Fyn、JNK 和 p38 磷酸化已被证明参与 TSP-1 诱导的内皮细胞凋亡，但该信号转导途径的其余成分尚不清楚。我们发现CD36与血管内皮细胞生长因子受体2（VEGFR2）、整合素、四跨膜蛋白及其相关信号转导分子相关。我们假设内皮细胞膜中的 CD36/VEGFR2/整合素复合物介导 3TSR 诱导的细胞凋亡，并促进促血管生成信号转导途径和抗血管生成信号转导途径之间的串扰。拟议研究的目标是确定（1）CD36/VEGFR2/整合素复合物的哪些成分对于 TSP-1 或 3TSR 诱导的内皮细胞凋亡至关重要，（2）这些复合物是否使内皮细胞能够在肿瘤微环境中整合促血管生成和抗血管生成信号，以及（3）确定 TSP-1 或 3TSR 的存在如何影响结构和功能 这些复合物。这些研究将为 3TSR 和 TRAIL 联合疗法的治疗潜力提供重要见解，并将阐明 TSP-1 抑制血管生成的分子基础。公共健康相关性：拟议的研究旨在开发新策略，通过破坏向肿瘤提供氧气和营养的血管来抑制肿瘤生长。这项研究的目的是确定人体通常用来限制血管生长的蛋白质如何发挥作用。这些知识将用于开发癌症治疗方法。