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

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

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中文摘要
翻译
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的mmp独立活动的机制。我们确定了以下具体目标来实现我们的目标:1)检查TIMPs在体外改变癌细胞生长和侵袭潜力中的作用;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(髓源性抑制细胞(MDSC))向原发肿瘤和转移性壁龛募集的影响4)更好地了解细胞间TIMP的摄取和作用。在先前的实验中,在肿瘤细胞中强制表达TIMP-2,我们已经观察到原发肿瘤生长受到抑制。肿瘤生长的抑制伴随着肿瘤微血管密度计数(cd31 +或CD34+)的统计学显著下降,这是一种抗血管生成作用的测量,以及肿瘤细胞凋亡的增加(也可能是由于抑制血管生成)。出乎意料的是,我们还观察到表达TIMP-2的肿瘤细胞中局灶黏附激酶(FAK)的减少,以及表达TIMP-2和Ala+TIMP-2的肿瘤细胞中FAK磷酸化(Y397)的显著减少。我们观察到FAK和/或AKT (Protein Kinase B, PKB)磷酸化在TIMP-2和Ala+TIMP-2肿瘤组织中均降低,这表明:1)FAK位于AKT信号传导的上游,并且都参与细胞迁移的调节;2)体外表达TIMP-2和Ala+TIMP-2可减少肿瘤细胞的迁移。我们之前报道了内皮细胞中FAK磷酸化降低,其中FAK磷酸化参与控制eNOS活性。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作用,这些作用结合在一起产生了一种有效的抗肿瘤活性,可以在临床上加以利用。
英文摘要
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.
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Development of TIMP-2 derivatives or strategies as biologic therapies for cancer
  • 批准号:
    10486788
  • 项目类别:
  • 资助金额:
    $101.15万
  • 财政年份:
    --
  • 负责人:
    William Stetler-Stevenson
  • 依托单位:
Preclinical development of AlaTIMP-2 as an cancer therapeutic
  • 批准号:
    7966212
  • 项目类别:
  • 资助金额:
    $101.24万
  • 财政年份:
    --
  • 负责人:
    William Stetler-Stevenson
  • 依托单位:
Preclinical development of Ala+TIMP-2 as an cancer therapeutic
  • 批准号:
    8763396
  • 项目类别:
  • 资助金额:
    $94.35万
  • 财政年份:
    --
  • 负责人:
    William Stetler-Stevenson
  • 依托单位:
Development of TIMP-2 derivatives or strategies as biologic therapies for cancer
  • 批准号:
    10014569
  • 项目类别:
  • 资助金额:
    $81.72万
  • 财政年份:
    --
  • 负责人:
    William Stetler-Stevenson
  • 依托单位:
海外基金