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Calcineurin-NFAT regulates endothelial activation in pre-metastatic sites

钙调神经磷酸酶-NFAT 调节转移前部位的内皮活化

基本信息

批准号：
9378981
负责人：
Sandra Ryeom
金额：
$ 6.94万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9378981
关键词：
Adenoviruses Angiogenesis Inhibitors Angiogenic Factor Angiopoietin-2 Beds Biological Assay Biology Blood Bone Marrow Calcineurin Calcineurin inhibitor Cells Chimera organism Chromosomes, Human, Pair 21 Data Defect Detection Development Disease Disseminated Malignant Neoplasm Distant Down Syndrome Endothelial Cells Endothelium Engraftment Experimental Models Family Flow Cytometry Funding Genes Genetic Goals Growth Individual LacZ Genes Lead Liver Lung Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Metastatic to Modeling Mus NFAT Pathway Neoplasm Metastasis Nuclear Import Organ PPP3CA gene Pathway interactions Pharmacology Phosphoric Monoester Hydrolases Phosphotransferases Play Population Primary Neoplasm Process Publishing Recruitment Activity Reporter Reporting Role Signal Pathway Signal Transduction Site Solid Neoplasm Specificity Stream TEK gene TIE-2 Receptor Thrombospondin 1 Tissues Transactivation Transgenic Mice Tropism Tube Tumor Angiogenesis Vascular Endothelium Work angiogenesis attenuation base cancer cell clinically relevant in vivo inhibitor/antagonist insight mortality mouse model neoplastic cell novel novel therapeutics prevent public health relevance sarcoma therapeutic target transcription factor tumor growth tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Metastasis is responsible for most cancer-related mortality although it remains a poorly understood process. Metastatic tumor cells extravasate from the primary tumor and colonize in distant tissues with little understanding about mechanisms regulating colonization. The role of the vasculature in pre-metastatic sites and metastatic progression has not been extensively examined. Recent work from our lab shows that the calcineurin-NFAT pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. Our preliminary data implicates endothelial activation as a prerequisite for metastatic colonization with this effect mediated at least partially via activation of the calcineurin-NFAT signaling pathway. Calcineurin, a ser/thr phosphatase, activates NFAT family transcription factors to regulate the development of many tissues. We and others have shown that the calcineurin-NFAT pathway is a key intracellular mediator of VEGF-A signaling in endothelial cells and angiogenesis. The importance of calcineurin signaling in tumor angiogenesis is illustrated by the remarkable protection against solid tumors observed in Down syndrome (DS) individuals. Our previously published studies in a Down syndrome mouse model indicate that defects in tumor angiogenesis resulting in significantly decreased tumor growth is due in part to attenuation of calcineurin signaling in endothelial cell by the increased expression of chromosome 21-encoded inhibitors of this pathway, Down syndrome candidate region-1 (Dscr1) and Dual specificity kinase 1A (Dyrk1A). Here we propose to explore novel clinically relevant roles for this signaling pathway and two specific downstream targets, thrombospondin-1 (TSP-1) and angiopoietin-2 (ANG-2) in activating the vascular endothelium in pre-metastatic sites in the lung and liver. We hypothesize that endothelial activation primes pre-metastatic sites providing a receptive microenvironment for the engraftment and survival of metastatic tumor cells. We will genetically and pharmacologically manipulate the calcineurin-NFAT pathway, TSP-1 and ANG-2 expression in endothelial cells to determine the effects on lung and liver metastasis. We will utilize transgenic mouse models of primary tumors that spontaneously metastasize to the lung or liver as well as lung and liver colonization assays to investigate metastatic tumor cell engraftment. Our studies will better elucidate the biology of calcineurin-NFAT-TSP-1 and ANG-2 signaling in endothelial cells at metastatic sites and mechanisms underlying metastatic tumor cell colonization in distant tissues. These findings may also lead to new therapies to prevent widespread lung and liver metastasis.