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：
10053711
负责人：
LANCE L MUNN
金额：
$ 45.4万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053711
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 Fluid Balance Gene Silencing Glycocalyx Glycosaminoglycans Glypican Goals HDAC1 gene Heparitin Sulfate Histone Deacetylase Hyaluronic Acid Implant In Vitro Individual Integrins Intercellular Fluid Intervention Intestines Intra-abdominal Invaded Kidney Lateral Lead Ligation Link Liver Lung MAP Kinase Gene Malignant Epithelial Cell Malignant Neoplasms Matrix Metalloproteinases Mechanics Mediating Metastasis Induction Metastatic Neoplasm to the Kidney Metastatic Renal Cell Cancer Metastatic to Methods Micrometastasis Molecular Monitor Mus Neoplasm Metastasis Organ Outcome PTK2 gene Pathway interactions Patients Penetration Pharmaceutical Preparations Pharmacology Phenotype Pre-Clinical Model Primary Neoplasm Renal carcinoma Resolution Role Signal Pathway Signal Transduction Site Spleen Structure Structure of renal vein Surface System Testing Tissues Tracer Tumor Cell Invasion Tumor Tissue Ultrasonography Up-Regulation Ureter Work base blood perfusion cancer cell cell motility confocal imaging 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.

癌细胞从原发肿瘤迁移并定植远处器官的能力是最终的能力尽管许多分子和粘附途径已被确定，仍然没有有效的策略来限制患者的转移，这在很大程度上是由于我们缺乏。了解启动细胞侵入周围组织和血管的信号。工作中，我们发现流动的间质液产生的机械力会引起深刻的表型变化这些力通过细胞糖萼传递并影响细胞迁移、MMP 活性和我们认为糖萼——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的有前途的目标。使用体外分析和体内模型的紧密结合来确定成分和机械诱导细胞侵袭的负责途径，然后在小鼠中针对这些机制目标 1a 将使用基因沉默来去除糖萼的特定成分，以达到肾癌模型的目的。确定参与流诱导转移激活的关键结构，目标 1b 将检查糖萼下游的细胞内信号通路可能旨在抑制入侵。 2，我们将使用肾癌小鼠模型来确定糖萼成分如何促进局部血管内渗（目标 2a）和远处转移（目标 2b）。确定成分和目标后，我们将使用药物干预措施来阻止转移（目标 2c).最后，我们将改变原位小鼠肾癌的间质血流，以证明诱导这些研究有可能揭示体内的流动转移（目标 3）。启动肿瘤转移的机制，并将为利用新的治疗策略打开大门机械生物学信号通路。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vascular Normalization to Improve Treatment of COVID-19: Lessons from Treatment of Cancer.

血管正常化改善 COVID-19 的治疗：癌症治疗的经验教训。

DOI：
发表时间：
2021-05-15
期刊：
影响因子：
0
作者：
Munn, Lance L;Stylianopoulos, Triantafyllos;Jain, Natalie K;Hardin, C Corey;Khandekar, Melin J;Jain, Rakesh K
通讯作者：
Jain, Rakesh K

Vascular regulation of antitumor immunity.

抗肿瘤免疫的血管调节。

DOI：
发表时间：
2019-08-09
期刊：
影响因子：
0
作者：
Munn, Lance L;Jain, Rakesh K
通讯作者：
Jain, Rakesh K

Glycocalyx mechanotransduction mechanisms are involved in renal cancer metastasis.

糖萼机械传导机制参与肾癌转移。

DOI：
发表时间：
2022-02
期刊：
影响因子：
0
作者：
Moran, Heriberto;Cancel, Limary M;Huang, Peigen;Roberge, Sylvie;Xu, Tuoye;Tarbell, John M;Munn, Lance L
通讯作者：
Munn, Lance L

Endothelial glycocalyx, apoptosis and inflammation in an atherosclerotic mouse model.

动脉粥样硬化小鼠模型中的内皮糖萼、细胞凋亡和炎症。

DOI：
10.1016/j.atherosclerosis.2016.07.930
发表时间：
2016-09
期刊：
Atherosclerosis
影响因子：
5.3
作者：
Cancel, Limary M.;Ebong, Eno E.;Mensah, Solomon;Hirschberg, Carly;Tarbell, John M.
通讯作者：
Tarbell, John M.

The glycocalyx core protein Glypican 1 protects vessel wall endothelial cells from stiffness-mediated dysfunction and disease.

糖萼核心蛋白 Glypican 1 可保护血管壁内皮细胞免受硬度介导的功能障碍和疾病的影响。