The role of endothelial to mesenchymal transition (EndMT) in the tumor stroma

内皮间质转化（EndMT）在肿瘤基质中的作用

• 批准号: 7619566
• 负责人: ELISABETH M ZEISBERG
• 金额: $ 13.53万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619566
• 关键词: Address; Adult; Antibodies; Basic Science; Bone Marrow; Bone Marrow Transplantation; Cardiac; Cardiovascular system; Cell Culture Techniques; Cells; Confocal Microscopy; Disease; Embryonic Development; Endothelial Cells; Excision; Fellowship; Fibroblasts; Fibrosis; Galactosidase; Ganciclovir; Genetic; Goals; Herpesviridae; Implant; Knowledge; Laboratories; LacZ Genes; Lead; Medicine; Mesenchymal; Methods; Modeling; Mus; Organ; PECAM1 gene; Pancreas; Play; Population; Research; Research Personnel; Research Project Grants; Role; Site; Sorting - Cell Movement; Staining method; Stains; TK Gene; Testing; Thymidine Kinase; Time; Training; Transgenes; Transgenic Mice; Transgenic Organisms; Transplantation; Tumor Angiogenesis; Tumor Tissue; Tumor-Derived; Work; base; cancer therapy; design; embryonic stem cell; fibrogenesis; improved; insight; instructor; interest; melanoma; pancreatic neoplasm; progenitor; programs; promoter; research study; stem cell biology; subcutaneous; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The applicant's long-term goal is to direct a basic science research program exploring the role of endothelial cells and their progenitors in organ fibrosis and tumor progression. The applicant has been trained in somatic stem cell biology during her thesis work and was later able to apply this knowledge in cardiovascular research where she was additionally trained in embryonic stem cell biology. During the first part of a postdoctoral fellowship, the applicant expanded her knowledge on stem cell biology and gained new insights into embryonic development. During these studies, the applicant became interested in the cellular plasticity that is displayed by endothelial cells both during embryonic development and also in adult disease states. The applicant is now an Instructor in Medicine in the Kalluri laboratory, where both tumor angiogenesis and organ fibrosis are major research foci, and thus it was a natural extension of the applicant's interests to study endothelial cell plasticity in the setting of the tumor microenvironment. The applicant's previous studies for the first time demonstrated that in cardiac fibrosis endothelial cells contribute to the pool of fibroblasts via an endothelial transition and that inhibition of EndMT can lead to decreased fibrosis and improved cardiac function. The research project proposed here centers on testing the hypothesis that EndMT also plays a role in tumor fibrogenesis. This hypothesis is based on immunohistochemical staining which revealed cells that are double positive for both endothelial and fibroblasts in several tumor types, indicating that endothelial cells can undergo EndMT. The primary aim of the proposal is to provide genetic evidence that endothelial cells contribute to the fibroblast population in the tumor microenvironment by undergoing EndMT. For this purpose, endothelial lineage tracing by TielCre; R26RstoplacZ double transgenic mice, in which all cells of endothelial origin are irreversibly marked with lacZ, will be used. Second, the impact of EndMT on tumor progression will be evaluated by creating transgenic mice in which fibroblasts of endothelial origin will be selectively ablated. If the tested hypothesis is valid, EndMT might represent an important target for the treatment of cancer.

描述（由申请人提供）：申请人的长期目标是指导一项基础科学研究计划，探索内皮细胞及其祖细胞在器官纤维化和肿瘤进展中的作用。申请人在她的论文工作期间接受了体干细胞生物学的培训，后来能够将这些知识应用于心血管研究，她还接受了胚胎干细胞生物学的培训。在博士后奖学金的第一部分，申请人扩大了她对干细胞生物学的知识，并获得了对胚胎发育的新见解。在这些研究期间，申请人对内皮细胞在胚胎发育期间以及在成人疾病状态下显示的细胞可塑性产生了兴趣。申请人现在是Kendi实验室的医学讲师，肿瘤血管生成和器官纤维化是该实验室的主要研究焦点，因此，研究肿瘤微环境中的内皮细胞可塑性是申请人兴趣的自然延伸。申请人先前的研究首次证明，在心脏纤维化中，内皮细胞通过内皮转变促成成纤维细胞库，并且EndMT的抑制可导致纤维化减少和心脏功能改善。这里提出的研究项目集中在测试EndMT在肿瘤纤维化中也起作用的假设。这一假设是基于免疫组织化学染色，其揭示了在几种肿瘤类型中内皮细胞和成纤维细胞的双阳性细胞，表明内皮细胞可以经历EndMT。该提案的主要目的是提供遗传学证据，证明内皮细胞通过经历EndMT有助于肿瘤微环境中的成纤维细胞群体。为此，将使用TielCre; R26 RstoplacZ双转基因小鼠的内皮谱系追踪，其中所有内皮来源的细胞均用lacZ不可逆地标记。其次，将通过创建转基因小鼠来评估EndMT对肿瘤进展的影响，在转基因小鼠中，内皮来源的成纤维细胞将被选择性消融。如果测试的假设是有效的，EndMT可能是治疗癌症的重要靶点。