Molecular mechanisms of Myc-induced tumor neovascularization

Myc诱导肿瘤新生血管形成的分子机制

• 批准号: 7267271
• 负责人: Andrei Thomas-Tikhonenko
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267271
• 关键词: ABT-510; Address; Adenocarcinoma; Anatomy; Angiogenesis Inhibitors; Angiogenic Switch; Antineoplastic Agents; Antisense Oligonucleotides; Apoptosis; Attenuated; Blood; Blood Vessels; Carcinoma; Cell Proliferation; Cells; Clinical Trials; Colon Adenocarcinoma; Colon Carcinoma; Colorectal Cancer; Complex; Data; Databases; Disease regression; Down-Regulation; Enrollment; Genetic; Goals; Growth; HCT116 Cells; Human; Hypervascular; In Vitro; Indium; Individual; Indolent; KRAS2 gene; Ki-ras Oncogene; Lesion; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Mucous Membrane; Mus; Mutation; Neoplasms; Oligoribonucleotides; Oncogene Proteins; Oncogenes; Patients; Pattern; Peptides; Pharmaceutical Preparations; Phenotype; Principal Investigator; Process; Production; Property; Protein Overexpression; Proteins; Public Health; Regulation; Repression; Research; Research Personnel; Retroviridae; Role; Silicon Dioxide; System; THBS1 gene; TP53 gene; Therapeutic; Therapeutic Effect; Thrombospondin 1; Transcript; Transcriptional Activation; Transgenic Mice; Translations; Tumor Suppressor Proteins; Untranslated Regions; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Xenograft procedure; angiogenesis; base; c-myc Genes; cellular transduction; connective tissue growth factor; in vivo; inhibitor/antagonist; knock-down; mRNA Stability; mRNA Transcript Degradation; member; neoplastic; neovascularization; preclinical study; research study; restoration; small hairpin RNA; therapeutic target; tumor; tumor growth; villin

DESCRIPTION (provided by applicant): The goal of this project is to investigate the molecular mechanisms by which the Myc oncoprotein enhances tumor neovascularization (the ingrowth of blood vessels into the nascent neoplasm). We have developed an experimental system wherein overexpression of this oncoprotein in murine colon carcinoma cells results in the hypervascular phenotype. We determined that this occurs without increased production of vascular endothelial growth factor (VEGF). Instead, Myc down-regulates the potent endogenous inhibitor of angiogenesis thrombospondin-1 and several other members of the TSR superfamily. Thrombospondin-1 is down-regulated primarily at the level of mRNA turnover, suggesting the involvement of microRNAs (miRNAs) which are known to mediate mRNA degradation. Indeed, Myc upregulates one of the miRNA clusters (miR17-92) whose predicted targets include thrombospondin-1 and other TSR proteins. miR17-92 knockdown with antisense 2'-O-methyl oligoribonucleotide partly restores Tsp1 and CTGF expression. Conversely, transduction of Ras-only cells with a miR17-92-encoding retrovirus reduces Tsp1 and CTGF levels. These key findings were also reproduced in HCT116 human colon carcinoma cells. Notably, miR17-92-transduced murine cells form larger, better-perfused tumors. Thus, we have formulated the following overall hypothesis: The contribution of Myc to tumor neovascularization is based on down-regulation of thrombospondin-1 and related proteins via a post-transcriptional mechanism involving the miR17-92 microRNA cluster. To corroborate this hypothesis, we propose to fulfill the following Specific Aims: 1. To dissect the molecular mechanisms underlying downregulation of TSR proteins by the miR17-92 cluster. 2. To establish the significance of Myc-dependent TSR protein down-regulation for neoplastic growth of Myc/Ras colonocytes and human colon cancer xenografts. 3. To elucidate the effects of transient Myc down-regulation on tumor vascularity and overall growth. After having fulfilled these Aims, we will be able to commence large-scale pre-clinical studies further validating miR17-92 and Myc as non-cell-autonomous therapeutic targets in vivo. RELEVANCE TO PUBLIC HEALTH: One of the promising anti-cancer drugs currently undergoing clinical trials is ABT-510. This drug mimics the effects of the natural tumor suppressor thrombospondin. Our research will help determine what types of colorectal cancer might be particularly sensitive to ABT-510 and allow for targeted patient enrollment. Additionally, our studies identify certain microRNAs as potential targets for anti-angiogenic therapies.

描述（由申请人提供）：本项目的目的是研究Myc癌蛋白增强肿瘤新生血管形成（血管向内生长进入新生肿瘤）的分子机制。我们已经开发了一种实验系统，其中这种癌蛋白在小鼠结肠癌细胞中的过度表达导致多血管表型。我们确定，这种情况发生时，血管内皮生长因子（VEGF）的生产没有增加。相反，Myc下调了有效的内源性血管生成抑制剂血小板反应蛋白-1和TSR超家族的其他几个成员。血小板反应蛋白-1主要在mRNA周转水平下调，表明已知介导mRNA降解的微小RNA（miRNA）的参与。事实上，Myc上调了一个miRNA簇（miR 17 -92），其预测的靶点包括血小板反应蛋白-1和其他TSR蛋白。用反义2 '-O-甲基寡核苷酸敲低miR 17 -92部分恢复Tsp 1和CTGF表达。相反，用编码miR 17 -92的逆转录病毒转导仅Ras细胞降低Tsp 1和CTGF水平。这些关键发现也在HCT 116人结肠癌细胞中重现。值得注意的是，miR 17 -92转导的鼠细胞形成更大、灌注更好的肿瘤。因此，我们提出了以下总体假设：Myc对肿瘤新血管形成的贡献是基于通过涉及miR 17 -92 microRNA簇的转录后机制下调血小板反应蛋白-1和相关蛋白。为了证实这一假设，我们建议实现以下具体目标：1。分析miR 17 -92簇下调TSR蛋白的分子机制。2.探讨Myc依赖性TSR蛋白下调对Myc/Ras结肠细胞和人结肠癌异种移植瘤生长的意义。3.阐明瞬时Myc下调对肿瘤血管分布和总体生长的影响。在实现这些目标后，我们将能够开始大规模的临床前研究，进一步验证miR 17 -92和Myc作为体内非细胞自主治疗靶点。与公众健康的相关性：目前正在进行临床试验的有希望的抗癌药物之一是ABT-510。这种药物模拟了天然肿瘤抑制因子血小板反应蛋白的作用。我们的研究将有助于确定哪些类型的结直肠癌可能对ABT-510特别敏感，并允许有针对性的患者入组。此外，我们的研究确定了某些microRNA作为抗血管生成疗法的潜在靶点。