HER2 and the link between inflammation and cancer stem cells

描述（由申请人提供）：许多人类肿瘤，包括乳腺癌，显示出一种分层组织，其中一组具有干细胞特性的肿瘤细胞驱动肿瘤生长和转移。近年来的研究表明，肿瘤干细胞（CSCs）除了受到外在炎症途径的调控外，还受到内在自我更新途径的调控。HER2的过表达已被证明可增加CSC的数量，但其潜在的分子机制仍在很大程度上未知。我们系统地剖析了her2下游信号通路，发现NFkB和STAT3通路对csc的自我更新最为重要。有趣的是，NFkB和STAT3的激活并不是由HER2的下游信号分子如MAPK或PI3K/AKT激酶直接介导的，而是由HER2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是一种众所周知的促炎细胞因子，它可以诱导包括IL-6在内的一系列细胞因子的表达，从而传播和维持炎症。因此，我们假设HER2诱导的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开启一系列细胞因子来调节体内的CSC群体。为了验证这一假设，我们将进行以下具体的

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.