miRNA-mediated Stromal Cell Survival under Stress Supports Breast Cancer Growth

miRNA 介导的基质细胞在压力下的存活支持乳腺癌的生长

• 批准号: 8902016
• 负责人: Radhika R Pochampally
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902016
• 关键词: Apoptotic; Autophagocytosis; Binding; Biogenesis; Biological Models; Biology; Breast Cancer Cell; Breast Cancer Model; Cancer Biology; Cancer Cell Growth; Cell Cycle; Cell Death; Cell Survival; Cells; Clinical; Collaborations; Data; Degenerative Disorder; Development; Dicer Enzyme; Effectiveness; Environment; Exhibits; Extracellular Matrix; Genes; Goals; Growth; Growth Factor; Housing; Human; Hypoxia; In Vitro; Inflammatory; Injury; Institutes; Insulin-Like Growth Factor I; Knowledge; Laboratories; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mesenchymal; Mesenchymal Differentiation; Mesenchymal Stem Cells; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mus; Nutrient; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Play; Primary Neoplasm; Property; Regulation; Research; Resistance; Role; Serum; Small RNA; Solid Neoplasm; Sorbus; Stem cells; Stress; Stromal Cells; Testing; Therapeutic; Tumor Burden; Tumor Suppressor Genes; Universities; Vascularization; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; cell growth; cytokine; deprivation; design; differential expression; established cell line; improved; in vitro Model; in vivo; insight; malignant breast neoplasm; medical schools; mouse model; multidisciplinary; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; research study; response; small hairpin RNA; stem; success; therapeutic target; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Multipotential Mesenchymal Stromal cells (MSCs) hold great potential for treating human degenerative diseases and injuries. Recent studies regarding the biology of breast cancer stroma indicate that mesenchymal stem cells (MSCs) provide the supportive stroma for breast tumors. However, there is a significant gap in our understanding of the survival mechanisms used by stromal cells under stressful conditions normally observed within solid tumors, such as hypoxia or nutrient deprivation. Most of the currently available therapeutic strategies only target the cancer cells and not the tumor-associated stroma. Indeed, a more detailed understanding of the molecular mechanisms involved in MSC survival and the resultant stromal supportive functions, is essential for improving the design and selection of therapeutic targets against breast cancer. In this study, properties of a MSC subpopulation that survive serum deprivation will be used as model to understand role of stromal cells in breast cancers especially during adverse conditions such as hypoxia or nutrient deprivation. The serum deprived MSCs (SD-MSCs) utilize autophagy to survive and secrete survival factors such as IGF-1, TGF� etc that support breast cancer cells. The microRNAs (miRNAs) function by binding to a cognate targets mRNA and facilitates their specific degradation. Our preliminary data uncovered a novel mechanism of linking SD-MSC survival to miRNA regulation, in addition to intracellular differential regulation of miRNA we show the miRNA expression the secretome of SD-MSCs that includes exosomes. The overall goal of this project is to understand the stromal supportive properties of MSCs in solid tumors specifically breast cancers. The specific hypothesis for this study is we hypothesize that MSCs in the tumor stroma survive nutrient deprived and hypoxic conditions of the tumor microenvironment by differentially regulating the expression of specific miRNAs, which can be targeted to abrogate their facilitative effects on breast cancer development and progression. To achieve this goal the following aims are proposed (1) Determine the key miRNA mediated mechanism governing survival of stromal cells in response to serum deprivation and hypoxia. (2) Understand the role of exosomal pathway in governing the tumor supportive properties of MSCs. (3 To identify the specific miRNAs that can be targeted as novel anti-cancer strategies in primary tumor models. The experiments proposed here to study the role of miRNA pathway in the stromal cell support using primary tumor initiating cells and MSCs will be important to understand how stromal cells survive under adverse conditions and support the tumor cells surrounding them. In addition, novel therapeutic targets to abrogate stromal cell survial will be indentified.

描述（由申请人提供）：多能间充质基质细胞（MSCs）在治疗人类退行性疾病和损伤方面具有巨大的潜力。近年来有关乳腺癌间质生物学的研究表明，间充质干细胞（mesenchymal stem cells, MSCs）为乳腺肿瘤的形成提供了支持基质。然而，我们对基质细胞在实体瘤中通常观察到的应激条件下（如缺氧或营养剥夺）的生存机制的理解存在重大差距。目前大多数可用的治疗策略仅针对癌细胞，而不是肿瘤相关基质。事实上，更详细地了解MSC存活的分子机制和由此产生的基质支持功能，对于改进乳腺癌治疗靶点的设计和选择至关重要。在这项研究中，骨髓间充质干细胞亚群在血清剥夺中存活的特性将被用作模型，以了解基质细胞在乳腺癌中的作用，特别是在缺氧或营养剥夺等不利条件下。血清剥夺MSCs （SD-MSCs）利用自噬生存，分泌支持乳腺癌细胞的生存因子如IGF-1、TGF -等。microRNAs （miRNAs）通过与同源靶mRNA结合并促进其特异性降解而发挥作用。我们的初步数据揭示了SD-MSC存活与miRNA调控之间的新机制，除了miRNA的细胞内差异调控外，我们还显示了SD-MSC分泌组（包括外泌体）中miRNA的表达。该项目的总体目标是了解间充质干细胞在实体肿瘤特别是乳腺癌中的基质支持特性。本研究的具体假设是，我们假设肿瘤基质中的MSCs通过差异调节特定mirna的表达，在肿瘤微环境的营养缺乏和缺氧条件下存活下来，可以靶向消除其对乳腺癌发展和进展的促进作用。为了实现这一目标，我们提出了以下目标：(1)确定miRNA介导的基质细胞在血清剥夺和缺氧反应中存活的关键机制。(2)了解外泌体途径在调控间充质干细胞的肿瘤支持特性中的作用。(3)在原发肿瘤模型中鉴定可作为新型抗癌策略的特异性mirna。本文提出的利用原代肿瘤起始细胞和间充质干细胞研究miRNA通路在基质细胞支持中的作用的实验，对于了解基质细胞如何在不利条件下存活并支持其周围的肿瘤细胞具有重要意义。此外，新的治疗靶点，以消除基质细胞的生存将被确定。