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Targeting glycocalyx-mediated mechanisms of tumor metastasis

靶向糖萼介导的肿瘤转移机制

基本信息

批准号：
9238929
负责人：
LANCE L MUNN
金额：
$ 47.17万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9238929
关键词：
Adhesions Animal Model Autopsy Blood Vessels Brain CD44 Antigens CD44 gene Cancer Patient Candidate Disease Gene Cell Adhesion Molecules Cell Line Cell Migration Induction Cell surface Cells Clinical Core Protein Cytotoxic Chemotherapy Detection Disease Disease Progression Disseminated Malignant Neoplasm Distant Distant Metastasis Drug Targeting Excision Gene Silencing Glycocalyx Glycosaminoglycans Glypican Goals HDAC1 gene Heparitin Sulfate Histone Deacetylase Homeostasis Hyaluronic Acid Image Implant In Vitro Individual Integrins Intercellular Fluid Intervention Intestines Intra-abdominal Invaded Kidney Lateral Lead Ligation Link Liquid substance Liver Lung MAP Kinase Gene Malignant Neoplasms Matrix Metalloproteinases Mechanics Mediating Metastasis Induction Metastatic Neoplasm to the Kidney Metastatic Renal Cell Cancer Metastatic to Methods Micrometastasis Molecular Molecular Profiling Monitor Mus Neoplasm Metastasis Organ Outcome PTK2 gene Pathway interactions Patients Penetration Pharmaceutical Preparations Pharmacology Phenotype Pre-Clinical Model Primary Neoplasm Renal Cell Carcinoma Renal carcinoma Resolution Role Signal Pathway Signal Transduction Site Spleen Structure Structure of renal vein Surface System Testing Tissues Tracer Tumor Cell Invasion Tumor Initiators Tumor Tissue Ultrasonography Up-Regulation Ureter Work base blood perfusion cancer cell cell motility effective therapy glomerular filtration improved in vivo in vivo Model inhibitor/antagonist interstitial knock-down mechanical force mechanotransduction migration mortality mouse model novel strategies novel therapeutic intervention prevent proteoglycan core protein receptor response syndecan therapeutic target tumor tumor growth tumor microenvironment

项目摘要

The ability of cancer cells to migrate away from the primary tumor and colonize distant organs is the ultimate cause of mortality in cancer. Although many of the molecular and adhesion pathways have been identified, there is still no effective strategy for limiting metastasis in patients. This is in large part due to our lack of understanding of the signals that initiate cell invasion into the surrounding tissue and blood vessels. In previous work, we showed that mechanical forces from flowing interstitial fluid cause profound phenotypic changes in cancer cells. These forces are transmitted by the cell glycocalyx and influence cell migration, MMP activity and adhesion molecule expression. We propose that the glycocalyx– by virtue of its role in mechanotransduction— represents a new and promising target for inhibiting cancer migration and metastasis. In this project, we will use a tightly-integrated combination of in vitro analyses and in vivo models to determine the components and pathways responsible for mechanically-induced cell invasion, and then target these mechanisms in a mouse model of renal carcinoma. Aim 1a will use gene silencing to remove specific components of the glycocalyx to identify key structures involved in flow-induced activation of metastasis, and Aim 1b will examine the intracellular signaling pathways downstream of the glycocalyx that might be targeted to inhibit invasion. In Aim 2, we will use a mouse model of renal carcinoma to determine how the glycocalyx components contribute to local intravasation into the vasculature (Aim 2a) and distant metastasis (Aim 2b). With the key glycocalyx components and targets identified, we will then use pharmacological interventions to block metastasis (Aim 2c). Finally, we will alter interstitial flow in an orthotopic mouse renal carcinoma to demonstrate the induction of metastasis by flow in the in vivo setting (Aim 3). These studies have the potential to uncover the fundamental mechanisms that initiate tumor metastasis, and will open the door to new therapeutic strategies that exploit mechanobiological signaling pathways.

癌细胞从原发肿瘤转移到远处器官的能力是终极的