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

• 批准号: 10926577
• 负责人: William Stetler-Stevenson
• 金额: $ 59.23万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 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/10926577
• 关键词: Acute Disease; Affect; Alanine; Angiogenesis Inhibition; Angiogenesis Inhibitors; Apoptosis; Basement membrane; Behavior; Biological; Blood Vessels; Breast Cancer cell line; CD34 gene; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Chronic Disease; Clinical; Complex; Cultured Tumor Cells; Data; Development; Disintegrins; Elements; Endothelial Cells; Endothelium; Equilibrium; Extracellular Matrix; Family; Fibroblasts; Focal Adhesion Kinase 1; Future; Gelatinase A; Genes; Glioblastoma; Goals; Growth; Growth Factor; Growth Factor Inhibition; Human; Immune; In Vitro; Inhibition of Matrix Metalloproteinases Pathway; Interstitial Collagenase; Invaded; Investigation; Laboratories; 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; Therapeutic; Thrombospondins; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Tissues; Tumor Cell Migration; Tumor Suppression; Tumor Tissue; Vascular Endothelial Cell; Zinc; cancer cell; cell growth; cell motility; cell type; density; experimental study; fibrosarcoma; gene product; in vivo; inhibitor; lung cancer cell; member; migration; neoplastic cell; novel; recruit; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenic; uptake

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。

项目成果

TIMP-2 modulates cancer cell transcriptional profile and enhances E-cadherin/beta-catenin complex expression in A549 lung cancer cells.

TIMP-2 调节癌细胞转录谱并增强 A549 肺癌细胞中的 E-钙粘蛋白/β-连环蛋白复合物表达。

• 发表时间: 2013-01
• 作者: Bourboulia, Dimitra;Han, Huiying;Jensen;Gavil, Noah;Isaac, Biju;Wei, Beiyang;Neckers, Len;Stetler
• 通讯作者: Stetler

TIMP-2 modulates cancer cell transcriptional profile and enhances E-cadherin/beta-catenin complex expression in A549 lung cancer cells.

TIMP-2 调节癌细胞转录谱并增强 A549 肺癌细胞中的 E-钙粘蛋白/β-连环蛋白复合物表达。

• 发表时间: 2013-01
• 作者: Bourboulia, Dimitra;Han, HuiYing;Jensen;Gavil, Noah;Isaac, Biju;Wei, Beiyang;Neckers, Len;Stetler
• 通讯作者: Stetler

Extracellular Phosphorylation of TIMP-2 by Secreted c-Src Tyrosine Kinase Controls MMP-2 Activity.

分泌性 c-Src 酪氨酸激酶对 TIMP-2 的胞外磷酸化控制 MMP-2 活性。

• 发表时间: 2018-03-23
• 影响因子: 5.8
• 作者: Sánchez;Baker;Woodford, Mark R;Bullard, Renee;Wei, Beiyang;Mollapour, Mehdi;Stetler;Bratslavsky, Gennady;Bourboulia, Dimitra
• 通讯作者: Bourboulia, Dimitra

Expression of soluble and functional full-length human matrix metalloproteinase-2 in Escherichia coli.

可溶性和功能性全长人基质金属蛋白酶-2 在大肠杆菌中的表达。

• 发表时间: 2012-01
• 影响因子: 4.1
• 作者: Goncalves, Andrezza N.;Meschiari, Cesar A.;Stetler-Stevenson, William G.;Nonato, M. Cristina;Alves, Cleidson P.;Espreafico, Enilza M.;Gerlach, Raquel F.
• 通讯作者: Gerlach, Raquel F.

Novel anti-filamin-A antibody detects a secreted variant of filamin-A in plasma from patients with breast carcinoma and high-grade astrocytoma.

新型抗细丝蛋白-A 抗体可检测乳腺癌和高级别星形细胞瘤患者血浆中细丝蛋白-A 的分泌变体。

• 发表时间: 2009-09
• 影响因子: 5.7
• 作者: Alper, Ozge;Stetler;Harris, Lyndsay N;Leitner, Wolfgang W;Ozdemirli, Metin;Hartmann, Dan;Raffeld, Mark;Abu;Byers, Stephen;Zhuang, Zhengping;Oldfield, Edward H;Tong, Yanhe;Bergmann;Criss, Wayne E
• 通讯作者: Criss, Wayne E