HER2 and the link between inflammation and cancer stem cells

HER2 以及炎症和癌症干细胞之间的联系

• 批准号: 8562650
• 负责人: Hexin Chen
• 金额: $ 29.49万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-08 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8562650
• 关键词: Address; Animal Model; Biochemical; Breast; Breast Cancer Cell; Cell model; Cells; Clinical; Complex; Cytokine Gene; Cytokine Network Pathway; Data; Drug Targeting; Drug resistance; ERBB2 gene; Epithelial Cells; Gene Expression; Generations; Genomics; Goals; Human; IL6 gene; IL8 gene; Immune; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Knockout Mice; Link; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Mediator of activation protein; Microarray Analysis; Molecular; Molecular Profiling; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Outcome; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Property; Proteins; Recombinant Interleukin-1; Recombinant Proteins; Recruitment Activity; Recurrence; Regulation; Resistance; Resistance development; Role; STAT3 gene; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Stem cells; Stromal Cells; System; Testing; Transgenic Mice; antibody inhibitor; cancer stem cell; cell type; cytokine; in vivo; kinase inhibitor; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel therapeutics; outcome forecast; overexpression; public health relevance; self-renewal; stem; stem cell population; therapeutic development; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Many human tumors, including breast cancer, display a hierarchical organization in which a subset of tumor cells with stem cell properties drives tumor growth and metastasis. Recent studies have shown that cancer stem cells (CSCs) are regulated by intrinsic self-renewal pathways in addition to extrinsic inflammatory pathways. Overexpression of HER2 has been shown to increase the CSC population but the underlying molecular mechanism is still largely unknown. We have systematically dissected the HER2-downstream signaling pathways and found that the NFkB and STAT3 pathways are the most important for self-renewal of CSCs. Interestingly, activation of NFkB and STAT3 is not directly mediated by signaling molecules immediately downstream of HER2, such as MAPK or PI3K/AKT kinases, but instead is mediated by HER2-induced interleukin-1 (IL-1) and interleukin-6 (IL-6) cytokines. IL-1 is a well-known proinflammatory cytokine that can induce the expression of a cascade of cytokines including IL-6 to propagate and sustain inflammation. Therefore, we hypothesize that HER2 induction of IL-1 serves as an important link between inflammation and cancer stem cells that switches on a cascade of cytokines in both tumor and stromal cells to regulate the CSC population in vivo. To test this hypothesis, we will pursue the following specific aims. In Aim 1, we will elucidate the molecular mechanism by which HER-2 regulates the expression of IL-1 and IL-6 in breast cancer cells. Using a series of biochemical approaches, we will first identify the key HER2-downstream signaling pathways responsible for induction of IL-1 expression in breast cancer cells and address whether IL1 in turn activates IL- 6 expression. In aim 2, we will study the function and mechanism of HER2-induced IL-1 and IL-6 signaling in the maintenance and regulation of cancer stem cells. We will use recombinant proteins and knockdown cell models to study how the interplay between IL-1-induced NFkB signaling and IL-6-induced STAT3 signaling regulates the CSC population. In aim 3, we will investigate the sources and functions of IL-1 and IL-6 in promotion of HER2-induced mammary tumorigenesis. We will cross MMTV-Her2 transgenic mice with IL-1 and IL-6 knockout mice models to study the functions of these two cytokines in Her2/neu-induced tumor onset and progression. Successful completion of this study will help us understand the mechanism and functions of HER2-induced IL1 and IL6 cytokines in the generation and maintenance of the CSC population both in vitro and in vivo.

描述（由申请人提供）：许多人类肿瘤，包括乳腺癌，显示出分层组织，其中具有干细胞特性的肿瘤细胞亚群驱动肿瘤生长和转移。最近的研究表明，除了外源性炎症途径外，癌症干细胞（CSCs）还受到内源性自我更新途径的调节。HER 2的过表达已显示出增加CSC群体，但潜在的分子机制仍在很大程度上未知。我们已经系统地剖析了HER 2下游信号通路，发现NFkB和STAT 3通路对于CSC的自我更新是最重要的。有趣的是，NFkB和STAT 3的激活不是由紧邻HER 2下游的信号分子（例如MAPK或PI 3 K/AKT激酶）直接介导的，而是由HER 2诱导的白细胞介素-1（IL-1）和白细胞介素-6（IL-6）细胞因子介导的。IL-1是众所周知的促炎细胞因子，其可以诱导包括IL-6在内的细胞因子级联的表达以传播和维持炎症。因此，我们假设HER 2诱导IL-1是炎症和癌症干细胞之间的重要联系，它在肿瘤和基质细胞中启动细胞因子级联反应，以调节体内CSC群体。为了验证这一假设，我们将进行以下具体研究： 目标。在目的1中，我们将阐明HER-2调节乳腺癌细胞中IL-1和IL-6表达的分子机制。使用一系列生物化学方法，我们将首先确定负责诱导乳腺癌细胞中IL-1表达的关键HER 2下游信号通路，并解决IL-1是否反过来激活IL- 6表达。在目标2中，我们将研究HER 2诱导的IL-1和IL-6信号传导在癌症干细胞维持和调节中的功能和机制。我们将使用重组蛋白和敲低细胞模型来研究IL-1诱导的NF κ B信号传导和IL-6诱导的STAT 3信号传导之间的相互作用如何调节CSC群体。目的3：探讨IL-1和IL-6在促进HER 2诱导的乳腺肿瘤发生中的来源和功能。我们将MMTV-Her 2转基因小鼠与IL-1和IL-6基因敲除小鼠模型杂交，以研究这两种细胞因子在Her 2/neu诱导的肿瘤发生和发展中的作用。本研究的成功完成将有助于我们理解HER 2诱导的IL 1和IL 6细胞因子在体外和体内CSC群体的产生和维持中的机制和功能。