Extracellular Redox Signaling in mammary tumor-fibroblast interactions

乳腺肿瘤-成纤维细胞相互作用中的细胞外氧化还原信号传导

基本信息

项目摘要

DESCRIPTION (provided by applicant): There is a fundamental gap in knowledge of the role of oxidative stress in the extracellular environment in the etiology of breast cancer. Our long term goal is to elucidate the role of extracellular redox signaling in promoting mammary tumor-fibroblast interactions. Our preliminary data suggest that loss of an extracellular antioxidant enzyme, extracellular superoxide dismutase (EcSOD) is a frequent event in clinical breast cancer tissue and there is an inverse correlation between its expression and clinical stage. We also observed that re- expression of EcSOD in c-Met expressing breast cancer cells strongly attenuated oncogenic stimulation by mammary fibroblasts that overexpress the c-Met ligand, HGF. These findings led us to our hypothesis that loss of EcSOD expression contributes to breast cancer progression and metastasis through oxidative-mediated tumor-fibroblast interactions, via activating the HGF/c-Met axis. The objectives of this study are to identify the mechanisms involved in deregulating the expression of EcSOD in breast cancers and the consequences of the loss of EcSOD expression (and the resulting increase in extracellular oxidative stress) in promoting HGF/c- Met-mediated oncogenesis. We will first determine the involvement of aberrant DNA promoter methylation in regulating EcSOD gene silencing in clinical breast cancer tissues. Next, we will test a novel idea that oxidative tumor microenvironment is one of the key factors that promotes HGF/c-Met signaling. It has been well established that Hepatocyte growth factor (HGF) is often overexpressed and secreted by cancer-associated fibroblasts. This paracrine factor activates its receptor, c-Met on the surface of cancer epithelial cells. In the second aim, we will determine whether loss of EcSOD promotes tumorigenic transformation of normal mammary epithelial cells by HGF-overexpressing mammary fibroblasts. Conversely, we will evaluate whether re-expression of EcSOD in breast cancer cells will attenuate oncogenic stimulation induced by fibroblast- derived HGF. We will further examine whether NADPH oxidase-generated oxidative stress on the plasma membrane is involved in HGF/c-Met activation. We will utilize a 3-dimensional co-culture model that includes both the cancer epithelial cells and their oncogenic 'partner', fibroblasts. In addition t determining the tumorigenic stimulation of fibroblasts on cancer epithelial cells, we will also examine how cancer cells reciprocally alter the phenotype of fibroblasts. We will next investigate the effects of EcSOD on tumor growth and metastasis of c-Met expressing breast cancer cells using a syngeneic mouse model as well as using an orthotopic tumor-fibroblast model. Overall, our multi-pronged study will utilize overexpression, knock-down, inactive mutant protein expression, pharmaceutical SOD mimetic and chemical inhibition approaches to validate the role of extracellular oxidative stress in promoting progression and metastasis of breast cancer. Positive outcome will help in expanding our understanding of the role of extracellular oxidative stress in fueling cancer epithelial-fibroblast interactions, towards development of novel therapeutic interventions.
描述(由申请人提供):在乳腺癌病因学中细胞外环境中氧化应激的作用的知识存在根本性差距。我们的长期目标是阐明细胞外氧化还原信号在促进乳腺肿瘤成纤维细胞相互作用中的作用。我们的初步数据表明,细胞外抗氧化酶,细胞外超氧化物歧化酶(EcSOD)的损失是一个常见的事件,在临床乳腺癌组织,其表达和临床分期之间存在负相关。我们还观察到,在表达c-Met的乳腺癌细胞中EcSOD的再表达强烈减弱了过表达c-Met配体HGF的乳腺成纤维细胞的致癌刺激。这些发现使我们假设EcSOD表达的缺失通过氧化介导的肿瘤-成纤维细胞相互作用,通过激活HGF/c-Met轴促进乳腺癌进展和转移。本研究的目的是确定乳腺癌中EcSOD表达失调的机制以及EcSOD表达缺失(以及由此导致的细胞外氧化应激增加)在促进HGF/c-Met介导的肿瘤发生中的后果。我们将首先确定临床乳腺癌组织中异常DNA启动子甲基化参与调节EcSOD基因沉默。接下来,我们将测试一个新的想法,即氧化肿瘤微环境是促进HGF/c-Met信号传导的关键因素之一。肝细胞生长因子(HGF)通常由癌症相关的成纤维细胞过度表达和分泌。这种旁分泌因子激活癌上皮细胞表面的受体c-Met。在第二个目标,我们将确定是否损失的EcSOD促进肿瘤转化的正常乳腺上皮细胞的HGF过表达的乳腺成纤维细胞。相反,我们将评估乳腺癌细胞中EcSOD的再表达是否会减弱由成纤维细胞衍生的HGF诱导的致癌刺激。我们将进一步研究NADPH氧化酶产生的质膜氧化应激是否参与HGF/c-Met激活。我们将利用三维共培养模型,包括癌上皮细胞和它们的致癌“伙伴”成纤维细胞。除了确定成纤维细胞对癌上皮细胞的致瘤刺激外,我们还将研究癌细胞如何改变成纤维细胞的表型。接下来,我们将使用同系小鼠模型以及原位肿瘤成纤维细胞模型研究EcSOD对表达c-Met的乳腺癌细胞的肿瘤生长和转移的影响。总体而言,我们的多管齐下的研究将利用过表达、敲低、失活突变蛋白表达、药物SOD模拟物和化学抑制方法来验证细胞外氧化应激在促进乳腺癌进展和转移中的作用。积极的结果将有助于扩大我们对细胞外氧化应激在促进癌症上皮-成纤维细胞相互作用中的作用的理解,以开发新的治疗干预措施。

项目成果

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Melissa Lai Tee Teoh其他文献

Melissa Lai Tee Teoh的其他文献

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{{ truncateString('Melissa Lai Tee Teoh', 18)}}的其他基金

Extracellular Redox Signaling in mammary tumor-fibroblast interactions
乳腺肿瘤-成纤维细胞相互作用中的细胞外氧化还原信号传导
  • 批准号:
    8614255
  • 财政年份:
    2014
  • 资助金额:
    $ 27.47万
  • 项目类别:
Extracellular Redox Signaling in mammary tumor-fibroblast interactions
乳腺肿瘤-成纤维细胞相互作用中的细胞外氧化还原信号传导
  • 批准号:
    8786069
  • 财政年份:
    2014
  • 资助金额:
    $ 27.47万
  • 项目类别:
Extracellular Redox Signaling in mammary tumor-fibroblast interactions
乳腺肿瘤-成纤维细胞相互作用中的细胞外氧化还原信号传导
  • 批准号:
    8978298
  • 财政年份:
    2014
  • 资助金额:
    $ 27.47万
  • 项目类别:

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