The Role of TIMPs in Cell Growth, Tumor Progression and Metastasis

TIMP 在细胞生长、肿瘤进展和转移中的作用

基本信息

批准号：
10487189
负责人：
William Stetler-Stevenson
金额：
$ 67.43万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10487189
关键词：
ADAMTS Acute Disease Affect Alanine Angiogenesis Inhibition Angiogenesis Inhibitors Apoptosis Basement membrane Behavior Biological Breast Cancer cell line CD34 gene Cell Culture Techniques Cell Surface Receptors Cell physiology Cell surface Cells Chronic Disease Clinical Complex Data Development Disintegrins Elements Endothelial Cells Endothelium Epithelial Equilibrium Extracellular Matrix Family Fibroblasts Focal Adhesion Kinase 1 Future Gelatinase A Genes Glioblastoma Goals Growth Growth Factor Human Immune In Vitro Interstitial Collagenase Investigation Laboratories Lung Malignant neoplasm of lung Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mediating Metalloproteases Methods Modeling Mus Myeloid-derived suppressor cells Neoplasm Metastasis Normal tissue morphology Pathology Phosphorylation Physiology Primary Neoplasm Process Protease Inhibitor Proteins Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Regulation Reporting Research Role Signal Pathway Signal Transduction Structure Therapeutic Thrombospondins Tissue Inhibitor of Metalloproteinase-1 Tissue Inhibitor of Metalloproteinases Tissues Tumor Cell Migration Tumor Suppression Tumor Tissue Zinc cancer cell cell growth cell motility cell type density experimental study fibrosarcoma gene product in vivo inhibitor/antagonist member migration neoplastic cell novel recruit tumor tumor growth tumor microenvironment tumor progression tumorigenic uptake

项目摘要

Major Activities/Specific Objectives. The principal goal of our ongoing research effort is to develop an in depth mechanistic understanding of the MMP-independent activities of members of the TIMP family, in particular TIMP-2. We have identified the following specific objectives to obtain our goals: 1) examine the role of TIMPs in altering the growth and invasive potential of cancer cells in vitro; 2) study to effects of TIMPs on primary and metastatic tumor growth in vivo; 3) study the influence of TIMPs on recruitment of immune-modulatory cells (myeloid-derived suppressor cells (MDSC)) to the primary tumor and metastatic niche4) develop a better understanding of the uptake and role of intercellular TIMP. In prior experiments with forced expression of TIMP-2 in tumor cells we have observed suppression of primary tumor growth. The suppression of tumor growth was accompanied by a statistically significant decrease in tumor microvascular density count (CD 31+ or CD34+), a measure of antiangiogenic effects, as well as by increased tumor cell apoptosis (also possibly due to inhibition of angiogenesis). Somewhat unexpectedly, we also observed a decrease in focal adhesion kinase (FAK) in TIMP-2 expressing tumors and a significant decrease in FAK phosphorylation (Y397) in both TIMP-2 and Ala+TIMP-2 expressing tumor cells. Our observation that both FAK and/or AKT (Protein Kinase B, PKB) phosphorylation is reduced in TIMP-2 and Ala+TIMP-2 tumor tissues is significant in that: 1) FAK is upstream of AKT signaling, and both are involved in regulation of cell migration; 2) TIMP-2 and Ala+TIMP-2 expression reduced tumor cell migration in vitro. We previously reported decreased FAK phosphorylation in endothelial cells where it is involved in control of eNOS activity. A major focus in my lab has been to examine the effects of exogenous TIMP-2 in murine tumor models. We are studying the effects on tumor growth and metastasis with the aim of developing a better understanding of the mechanisms that may affect these processes.These recent findings suggest that TIMP-2 has a variety of effects on both tumor and host cells that combine to produce a potent anti-tumor activity that could be exploited clinically.

主要活动/具体目标。我们正在进行的研究工作的主要目标是深入了解 TIMP 家族成员（特别是 TIMP-2）独立于 MMP 的活动。为了实现我们的目标，我们确定了以下具体目标：1）检查TIMP在体外改变癌细胞生长和侵袭潜力方面的作用； 2）研究TIMPs对体内原发性和转移性肿瘤生长的影响； 3) 研究 TIMP 对免疫调节细胞（骨髓源性抑制细胞 (MDSC)）募集至原发肿瘤和转移灶的影响4) 更好地了解细胞间 TIMP 的摄取和作用。在先前在肿瘤细胞中强制表达 TIMP-2 的实验中，我们观察到原发性肿瘤生长受到抑制。肿瘤生长的抑制伴随着肿瘤微血管密度计数（CD 31+ 或 CD34+）（抗血管生成作用的衡量标准）的统计显着下降，以及肿瘤细胞凋亡的增加（也可能是由于血管生成的抑制）。有点出乎意料的是，我们还观察到表达 TIMP-2 的肿瘤中粘着斑激酶 (FAK) 减少，并且表达 TIMP-2 和 Ala+TIMP-2 的肿瘤细胞中 FAK 磷酸化 (Y397) 显着减少。我们观察到 FAK 和/或 AKT（蛋白激酶 B，PKB）磷酸化在 TIMP-2 和 Ala+TIMP-2 肿瘤组织中均降低，其意义在于：1) FAK 是 AKT 信号传导的上游，并且两者都参与细胞迁移的调节； 2)TIMP-2和Ala+TIMP-2表达减少体外肿瘤细胞迁移。我们之前报道过内皮细胞中 FAK 磷酸化降低，FAK 参与 eNOS 活性的控制。我实验室的一个主要重点是研究外源性 TIMP-2 在小鼠肿瘤模型中的作用。我们正在研究 TIMP-2 对肿瘤生长和转移的影响，目的是更好地了解可能影响这些过程的机制。这些最近的研究结果表明 TIMP-2 对肿瘤和宿主细胞具有多种影响，这些影响结合起来产生可以在临床上利用的有效抗肿瘤活性。