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: 7846164
• 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/7846164
• 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.

申请人的长期目标是指导一项基础科学研究计划，探索血管内皮细胞及其前体细胞在器官纤维化和肿瘤进展中的作用。申请者在她的论文工作中接受了身体干细胞生物学方面的培训，后来能够将这些知识应用于心血管研究，在那里她还接受了胚胎干细胞生物学方面的培训。在博士后奖学金的第一部分，申请者扩大了她在干细胞生物学方面的知识，并对胚胎发育有了新的见解。在这些研究中，申请人开始对内皮细胞在胚胎发育期间和成人疾病状态下所表现出的细胞可塑性感兴趣。申请人现在是Kalluri实验室的医学讲师，在该实验室，肿瘤血管生成和器官纤维化都是主要的研究重点，因此，在肿瘤微环境的背景下研究内皮细胞可塑性是申请人兴趣的自然延伸。申请人之前的研究首次证明，在心脏纤维化中，内皮细胞通过内皮细胞转变为成纤维细胞池做出贡献，抑制EndMT可以导致减少纤维化和改善心功能。这里提出的研究项目集中于验证EndMT在肿瘤纤维化形成中也发挥作用的假设。这一假设是基于免疫组织化学染色，发现在几种肿瘤类型中，细胞内皮细胞和成纤维细胞双重阳性，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，证明血管内皮细胞通过EndMT对肿瘤微环境中的成纤维细胞群做出贡献。为此，将使用TielCre；R26RstoPlacZ双转基因小鼠进行内皮谱系追踪，其中所有内皮起源的细胞都被不可逆地标记为LacZ。其次，将通过建立转基因小鼠来评估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地消融。如果验证的假说成立，EndMT可能代表着癌症治疗的一个重要靶点。