The role of endothelial progenitor cells in tumor growth and metastasis

内皮祖细胞在肿瘤生长和转移中的作用

• 批准号: 8245011
• 负责人: ROBERT I BENEZRA
• 金额: $ 61.33万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245011
• 关键词: Ablation; Address; Adult; Angiogenesis Inhibition; Angiogenic Switch; Animals; Automobile Driving; Biological Models; Blood Vessels; Bone Marrow; Cell Proliferation; Cells; Clinical; Competence; Defect; Development; Endothelial Cells; Endothelium; Gene Targeting; Genes; Genetic; Genetic Models; Genetically Engineered Mouse; Grant; Growth; Home environment; Homing; Human; Knockout Mice; Laboratories; Lead; Life; Malignant Neoplasms; Micrometastasis; Mouse Strains; Mus; Neoplasm Metastasis; Oligonucleotides; Patients; Peptides; Phenotype; Play; Population; Pre-Clinical Model; Primary Neoplasm; Principal Investigator; Property; Proteins; Recruitment Activity; Reporter; Role; Screening procedure; Site; Source; Specificity; Stem cells; Surface; Testing; Therapeutic; Therapeutic Intervention; Translations; Tumor Angiogenesis; Tumor Biology; Work; angiogenesis; base; cadherin 5; cell motility; cell type; in vivo; loss of function; mouse model; neovascularization; neovasculature; paracrine; pre-clinical; progenitor; promoter; public health relevance; research study; response; tumor; tumor growth

DESCRIPTION (provided by applicant): In this proposal we explore the role of bone marrow (BM) derived endothelial progenitor cells (EPCs) in development and spread of tumors in preclinical model systems. EPCs have been shown by a number of laboratories to be essential for the formation of an intact vascular network both at the primary tumor site and the metastatic niche. in As such these cells may be important targets for therapeutic intervention if they can be destroyed selectively. The precise identification, isolation and targeting of EPCs has been hindered by the fact that many EPC markers are shared by many different cell types. Indeed, controversies still exist about the EPC phenotype, and many studies have not only questioned the relatively low contribution, but also their significance in tumors neoangiogenesis. In order to definitively address the role of EPCs in tumor angiogenesis it is necessary ideally to uniquely define this population, inhibit the activity of genes essential for their function, ablate the population specifically and show that these cells are sufficient to rescue angiogenic defects in genetic models. In this proposal, we utilize the fact that Id1 and VE-cadherin double positive cells in the adult define the EPC population. We will induce loss of Id1 function in VE-cadherin+ EPCs and determine the consequence on tumor growth. Specific ablation of the VE-cadherin Id1+ cells will be performed. Purified EPCs will be used to rescue the angiogenic deficiency in the Id1 knockout mice. Finally, peptides which home specifically to EPCs will used to deliver inhibitory oligonucleotides to EPCs in order to test the functional significance of EPC-specific genes that we identify. These studies should help clarify the role of EPCs in tumor biology and provide a basis for their targeting as a potential therapeutic strategy in the management of human cancers. PUBLIC HEALTH RELEVANCE: In this proposal we characterize a specialized group of cells which are produced in the bone marrow in response to the growth of a tumor and are essential for the formation of a functional blood vessel supply both at the primary tumor site and at sites of metastatic growth. As such these cells (called "endothelial progenitor cells" or "EPCs") may be important targets for therapeutic intervention if they can be destroyed selectively. The precise identification, isolation and targeting of EPCs has been hindered by the fact that many of the proteins expressed on their surface used in their identification (called "markers") are shared by many different cell types. In the experiments being proposed we outline a strategy to circumvent this problem by using a combination of just two markers which we show uniquely identifies the EPC population. Using a set of genetically engineered mouse strains we go on to isolate the EPC population, identify new genes that are expressed specifically within them and, finally, destroy these cells during primary and metastatic tumor growth. Having devised a strategy to inhibit in living animals the expression of any given gene within blood vessel forming cells, we propose to adapt that strategy for targeting the EPC population in preclinical mouse models of cancer and ultimately in patients. These experiments can lead to the development of targeted therapies which can reduce primary tumor growth and metastatic burden with the hope of extending the lives of patients with aggressive cancers.

描述（由申请人提供）：在本提案中，我们探索了骨髓（BM）来源的内皮祖细胞（EPCs）在临床前模型系统中肿瘤发展和扩散中的作用。 许多实验室已经证明，EPCs对于原发肿瘤部位和转移灶的完整血管网络的形成至关重要。 因此，如果这些细胞可以被选择性地破坏，它们可能是治疗干预的重要靶点。 由于许多EPC标记物被许多不同的细胞类型所共有，因此EPCs的精确鉴定、分离和靶向一直受到阻碍。 事实上，关于EPC表型仍然存在争议，许多研究不仅质疑相对较低的贡献，而且质疑它们在肿瘤新生血管形成中的意义。 为了明确阐述EPCs在肿瘤血管生成中的作用，理想情况下有必要独特地定义该群体，抑制对其功能至关重要的基因的活性，特异性地消融该群体，并显示这些细胞足以挽救遗传模型中的血管生成缺陷。 在这个建议中，我们利用的事实，即Id 1和VE-钙粘蛋白双阳性细胞在成人定义的EPC群体。 我们将诱导VE-钙粘蛋白+ EPCs中Id 1功能的丧失，并确定对肿瘤生长的影响。 将对VE-钙粘蛋白Id 1+细胞进行特异性消融。 纯化的EPCs将用于挽救Id 1敲除小鼠中的血管生成缺陷。 最后，将特异性归巢于EPCs的肽用于向EPCs递送抑制性寡核苷酸，以测试我们鉴定的EPCs特异性基因的功能意义。 这些研究将有助于阐明EPCs在肿瘤生物学中的作用，并为它们作为人类癌症管理中潜在的治疗策略提供基础。 公共卫生关系：在这个提议中，我们描述了一组专门的细胞，它们在骨髓中产生，以响应肿瘤的生长，并且对于在原发肿瘤部位和转移生长部位形成功能性血管供应至关重要。 因此，这些细胞（称为“内皮祖细胞”或“EPCs”）可能是治疗干预的重要靶点，如果它们可以被选择性地破坏的话。 EPCs的精确鉴定、分离和靶向受到以下事实的阻碍，即用于其鉴定的在其表面上表达的许多蛋白质（称为“标记物”）由许多不同的细胞类型共享。 在提出的实验中，我们概述了一种策略，以规避这个问题，通过使用组合的两个标记，我们唯一识别的EPC人口。 使用一组基因工程小鼠品系，我们继续分离EPC群体，鉴定在其中特异性表达的新基因，并最终在原发性和转移性肿瘤生长期间破坏这些细胞。 在设计了一种策略来抑制活体动物中血管形成细胞内任何给定基因的表达后，我们建议调整该策略，以靶向临床前小鼠癌症模型和最终患者中的EPC群体。 这些实验可以导致靶向治疗的发展，这些治疗可以减少原发性肿瘤的生长和转移负担，希望延长侵袭性癌症患者的生命。