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.

癌细胞从原发性肿瘤迁移并定居远处的器官的能力是最终癌症死亡率的原因。尽管已经确定了许多分子和粘合剂途径，但仍然没有限制患者转移的有效策略。这在很大程度上是由于我们缺乏了解引发细胞侵袭周围组织和血管的信号。在上一个工作，我们表明，流动的间质流体的机械力引起了深刻的表型变化癌细胞。这些力是通过细胞糖蛋白传播的，并影响细胞迁移，MMP活性和粘附分子表达。我们提出，糖卵形 - 凭借其在机械转导中的作用 - 代表了抑制癌症迁移和转移的新目标。在这个项目中，我们将使用体外分析和体内模型的紧密集成组合来确定成分和负责机械诱导的细胞侵袭的途径，然后将这些机制靶向小鼠 AIM 1A将使用基因沉默来去除糖叶的特定组成部分确定与流动引起的转移激活有关的关键结构，AIM 1B将检查糖脂的下游细胞内信号通路可能旨在抑制侵袭。目标 2，我们将使用肾癌的小鼠模型来确定糖蛋白成分如何有助于局部进入脉管系统（AIM 2A）和远处转移（AIM 2B）。与钥匙糖蛋白确定的组件和目标，然后我们将使用药物干预措施来阻止转移（AIM 2C）。最后，我们将改变原位小鼠肾癌中的间质流，以证明诱导的诱导在体内环境中流动的转移（AIM 3）。这些研究有可能发现基本启动肿瘤转移的机制，并将为开发新的治疗策略打开大门机械生物学信号通路。