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: 8113675
• 负责人: ROBERT I BENEZRA
• 金额: $ 60.85万
• 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/8113675
• 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; 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小生境形成完整的血管网络至关重要。因此，如果能选择性地破坏这些细胞，它们可能成为治疗干预的重要目标。由于许多EPCs标记在许多不同的细胞类型中是共享的，这阻碍了EPCs的精确鉴定、分离和靶向。事实上，关于EPC表型仍然存在争议，许多研究不仅质疑其相对较低的贡献，而且质疑其在肿瘤新生血管生成中的意义。为了明确地解决EPCs在肿瘤血管生成中的作用，有必要对这一群体进行理想的定义，抑制其功能所需基因的活性，特异性地消融这一群体，并表明这些细胞足以在遗传模型中挽救血管生成缺陷。在这项建议中，我们利用成人中Id1和VE-cadherin双阳性细胞定义EPC群体的事实。我们将在VE-cadherin+ EPCs中诱导Id1功能丧失，并确定其对肿瘤生长的影响。将对VE-cadherin Id1+细胞进行特异性消融。纯化的EPCs将用于修复Id1基因敲除小鼠的血管生成缺陷。最后，将EPCs特异性归巢的肽用于向EPCs传递抑制性寡核苷酸，以测试我们鉴定的EPCs特异性基因的功能意义。这些研究应该有助于阐明EPCs在肿瘤生物学中的作用，并为其作为人类癌症管理的潜在治疗策略提供基础。