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: 8447575
• 负责人: ROBERT I BENEZRA
• 金额: $ 57.42万
• 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/8447575
• 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; 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; screening; 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.

描述（由申请人提供）：在本提案中，我们探讨了骨髓（BM）来源的内皮祖细胞（EPC）在临床前模型系统中肿瘤的发育和扩散中的作用。 许多实验室已证明 EPC 对于原发肿瘤部位和转移灶处完整血管网络的形成至关重要。 因此，如果可以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。 许多不同细胞类型共有许多 EPC 标记，这一事实阻碍了 EPC 的精确识别、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。 为了明确阐明 EPC 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，特异性消融该群体并表明这些细胞足以挽救遗传模型中的血管生成缺陷。 在本提案中，我们利用成人中 Id1 和 VE-钙粘蛋白双阳性细胞定义 EPC 群体的事实。 我们将诱导 VE-钙粘蛋白+ EPC 中 Id1 功能的丧失，并确定对肿瘤生长的影响。 将进行 VE-钙粘蛋白 Id1+ 细胞的特异性消融。 纯化的 EPC 将用于挽救 Id1 敲除小鼠的血管生成缺陷。 最后，专门针对 EPC 的肽将用于将抑制性寡核苷酸递送至 EPC，以测试我们确定的 EPC 特异性基因的功能意义。 这些研究应有助于阐明 EPC 在肿瘤生物学中的作用，并为其作为治疗人类癌症的潜在治疗策略提供基础。