Molecular mechanisms of Myc-induced tumor neovascularization

Myc诱导肿瘤新生血管形成的分子机制

基本信息

批准号：
7392173
负责人：
Andrei Thomas-Tikhonenko
金额：
$ 29.93万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/7392173
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

项目摘要

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）：该项目的目的是研究MYC癌蛋白增强肿瘤新生血管形成（血管向新生肿瘤的生长）的分子机制。我们已经开发了一个实验系统，在其中这种癌蛋白在鼠结肠癌细胞中的过表达导致高血管表型。我们确定这是在没有增加血管内皮生长因子（VEGF）产生的情况下发生的。取而代之的是，MYC下调了血栓形成蛋白1和TSR超家族的其他几个成员的有效内源性内源性抑制剂。血小板传播1主要在mRNA周转水平下下调，这表明已知会介导mRNA降解的microRNA（miRNA）的参与。实际上，MYC上调了一个miRNA簇（miR17-92），其预测的靶标包括血小板传播-1和其他TSR蛋白。 MiR17-92用反义2'-O-甲基寡核苷酸敲低部分恢复TSP1和CTGF的表达。相反，使用miR17-92编码逆转录病毒的仅RAS细胞转导可降低TSP1和CTGF水平。这些关键发现也在HCT116人类结肠癌细胞中复制。值得注意的是，miR17-92转导的鼠类细胞形成更大的，更完善的肿瘤。因此，我们已经提出了以下总体假设：MYC对肿瘤新血管形成的贡献是基于涉及miR17-92 microRNA簇的转录后机制对血小板蛋白-1和相关蛋白的下调。为了证实这一假设，我们建议实现以下特定目的：1。解剖MiR17-92簇下调TSR蛋白的分子机制。 2。为了确定依赖MYC的TSR蛋白下调对MYC/RAS结肠细胞和人类结肠癌异种移植物的肿瘤生长的重要性。 3。阐明瞬时MYC下调对肿瘤血管性和整体生长的影响。在实现了这些目标之后，我们将能够开始大规模的临床前研究，进一步验证MiR17-92和MYC在体内作为非细胞自主治疗靶标。与公共卫生有关：目前正在临床试验的有前途的抗癌药物之一是ABT-510。该药物模仿天然肿瘤抑制剂血小板传播的作用。我们的研究将有助于确定哪种类型的大肠癌可能对ABT-510特别敏感，并允许有针对性的患者入学。此外，我们的研究将某些microRNA视为抗血管生成疗法的潜在靶标。