The Role of TIMPs in Cell Growth, Tumor Progression and Metastasis
The Role of TIMPs in Cell Growth, Tumor Progression and Metastasis
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:
至
关键词:
ADAMTSAcute DiseaseAffectAlanineAngiogenesis InhibitionAngiogenesis InhibitorsApoptosisBasement membraneBehaviorBiologicalBreast Cancer cell lineCD34 geneCell Culture TechniquesCell Surface ReceptorsCell physiologyCell surfaceCellsChronic DiseaseClinicalComplexDataDevelopmentDisintegrinsElementsEndothelial CellsEndotheliumEpithelialEquilibriumExtracellular MatrixFamilyFibroblastsFocal Adhesion Kinase 1FutureGelatinase AGenesGlioblastomaGoalsGrowthGrowth FactorHumanImmuneIn VitroInterstitial CollagenaseInvestigationLaboratoriesLungMalignant neoplasm of lungMatrix Metalloproteinase InhibitorMatrix MetalloproteinasesMeasuresMediatingMetalloproteasesMethodsModelingMusMyeloid-derived suppressor cellsNeoplasm MetastasisNormal tissue morphologyPathologyPhosphorylationPhysiologyPrimary NeoplasmProcessProtease InhibitorProteinsProto-Oncogene Proteins c-aktReceptor Protein-Tyrosine KinasesRegulationReportingResearchRoleSignal PathwaySignal TransductionStructureTherapeuticThrombospondinsTissue Inhibitor of Metalloproteinase-1Tissue Inhibitor of MetalloproteinasesTissuesTumor Cell MigrationTumor SuppressionTumor TissueZinccancer cellcell growthcell motilitycell typedensityexperimental studyfibrosarcomagene productin vivoinhibitor/antagonistmembermigrationneoplastic cellnovelrecruittumortumor growthtumor microenvironmenttumor progressiontumorigenicuptake
中文摘要
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成员的基质金属蛋白酶非依赖性活动。为了达到我们的目标,我们确定了以下特定目标:1)检测TIMPs在改变癌细胞体外生长和侵袭潜能中的作用;2)研究TIMPs在体内对原发和转移肿瘤生长的影响;3)研究TIMPs对免疫调节细胞(髓系抑制细胞)向原发肿瘤和转移瘤的募集的影响4)更好地了解细胞间TIMP的摄取和作用。在先前对肿瘤细胞强制表达TIMP-2的实验中,我们观察到了对原发肿瘤生长的抑制。伴随着肿瘤生长抑制的是肿瘤微血管密度计数(CD31或CD34)(衡量抗血管生成效果的指标)的统计显著下降,以及肿瘤细胞凋亡的增加(也可能是由于抑制血管生成)。有些出乎意料的是,我们还观察到在表达TIMP-2的肿瘤中粘着斑激酶(FAK)的减少,以及在表达TIMP-2和ALA TIMP-2的肿瘤细胞中FAK磷酸化(Y397)的显著降低。我们的观察发现,FAK和/或AKT(Protein Kinase B,PKB)在TIMP-2和ALA TIMP-2肿瘤组织中的磷酸化水平降低,主要是因为:1)FAK位于AKT信号的上游,两者都参与调节细胞的迁移;2)TIMP-2和ALA TIMP-2的表达减少了肿瘤细胞的体外迁移。我们先前报道了内皮细胞中FAK的磷酸化减少,在那里它参与了eNOS的活性控制。我实验室的一个主要关注点是检查外源性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。这些最新发现表明,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强大的抗肿瘤活性,可以用于临床。
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
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批准号:10486788
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项目类别:
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资助金额:$101.15万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Preclinical development of Ala+TIMP-2 as an cancer therapeutic
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批准号:8763396
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项目类别:
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资助金额:$94.35万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Development of TIMP-2 derivatives or strategies as biologic therapies for cancer
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批准号:10014569
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项目类别:
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资助金额:$81.72万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Preclinical development of AlaTIMP-2 as an cancer therapeutic
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批准号:7966212
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项目类别:
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资助金额:$101.24万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth and Differentiation: Tumor Angiogenesis
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批准号:8158279
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项目类别:
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资助金额:$62.76万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth and Differentiation: Tumor Angiogenesis
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批准号:8554031
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项目类别:
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资助金额:$75.21万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Development of TIMP-2 derivatives or strategies as biologic therapies for cancer
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批准号:10702503
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项目类别:
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资助金额:$80.78万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Preclinical development of AlaTIMP-2 as an cancer therapeutic
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批准号:8157696
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项目类别:
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资助金额:$94.14万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth and Differentiation: Tumor Angiogenesis
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批准号:8350064
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项目类别:
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资助金额:$64.29万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Preclinical development of TIMP-2 as a biologic therapy for cancer
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批准号:9153818
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项目类别:
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资助金额:$95.16万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Preclinical development of Ala+TIMP-2 as an cancer therapeutic
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批准号:8553037
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项目类别:
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资助金额:$112.81万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Preclinical development of AlaTIMP-2 as an cancer therapeutic
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批准号:8349393
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项目类别:
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资助金额:$96.44万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth and Differentiation: Tumor Angiogenesis
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批准号:8763694
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项目类别:
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资助金额:$62.9万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth, Tumor Progression and Metastasis
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批准号:10926577
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项目类别:
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资助金额:$59.23万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth, Tumor Progression and Metastasis
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批准号:10703000
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项目类别:
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资助金额:$53.85万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth, Tumor Progression and Metastasis
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批准号:10262704
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项目类别:
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资助金额:$55.93万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth and Differentiation: Tumor Angiogenesis
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批准号:7969797
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项目类别:
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资助金额:$67.5万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Preclinical development of TIMP-2 as a biologic therapy for cancer
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批准号:8938007
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项目类别:
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资助金额:$87.57万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
The Role of TIMPs in Cell Growth, Tumor Progression and Metastasis
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批准号:8938403
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项目类别:
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资助金额:$58.38万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
Preclinical development of TIMP-2 as a biologic therapy for cancer
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批准号:9556491
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项目类别:
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资助金额:$93.69万
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财政年份:--
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负责人:William Stetler-Stevenson
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依托单位:
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