Manipulation of macrophage Alu RNA metabolism by breast cancer cells

描述（由申请人提供）：巨噬细胞是分布在哺乳动物体内各处的终末分化的单核吞噬细胞的异质集合，具有组织清除、组织重塑等功能。这些细胞作为我们先天免疫系统和适应性免疫系统的主要应答者，发挥着不同的作用。作为其组织清除作用的一部分，在乳腺肿瘤发生部位募集的巨噬细胞摄取了大量由最初死亡的肿瘤细胞形成的细胞碎片。

DESCRIPTION (provided by applicant): Macrophages are a heterogeneous collection of terminally differentiated mononuclear phagocytes that are distributed all over the mammalian body to perform tissue clearing, tissue remodeling and other functions. These cells act in diverse capacities as the primary responders of our innate and adaptive immune systems. As a part of their tissue clearing roles, macrophages recruited at the site of breast tumor development ingest significant mass of cellular debris formed from the initially dying tumor cells. High levels of phagocytosis induce the production of reactive oxygen and nitrogen species which in turn elevates the expression of cytotoxic non- coding RNAs (ncRNAs) like Alu RNAs. If not interfered by the tumor cells, high levels of Alu RNA would produce severe inflammatory immune response through the activation of inflammasome and accelerated death of the overfed macrophages bringing collateral damage to the breast tumor cells. The preliminary data generated in the PI's laboratory revealed that during the breast tumor formation, inflammatory development of the recruited macrophages is prevented by the breast tumor cells through the reduction of the levels of Alu RNA in the tumor-associated macrophages converting them to accessory cells supporting tumor growth. We postulate that breast tumor cell-induced reduction in the level of cytotoxic Alu RNA in the tumor-associated macrophages creates a tissue microenvironment that fosters tumor progression. The long-term goal of the proposed research is to understand how breast tumor cells manipulate the macrophages to make them docile and supportive to the development of breast tumor. The central hypothesis is that as a part of the regulation of macrophage turnover, oxidative stress generated during intense phagocytosis by the macrophages at the site of tissue damage (e.g. breast tumor) induces the levels of cytotoxic Alu RNA in these cells. This response in the breast tumor-associated macrophages (TAMs) is suppressed by the tumor cells so that these longer-living immuno-suppressed macrophages in the tumor microenvironment can be utilized for further development and progression of the breast tumor. Specific Aim to test the hypothesis are: (a) Identification of the mediators secreted from the breast cancer cells that manipulate Alu RNA metabolism in the macrophages; and, (b) Evaluation of the mechanisms of manipulation of Alu RNA metabolism in the tumor-associated macrophages during breast tumor development. This research proposes an innovative basic mechanism to explain macrophage-assisted breast tumor development highlighting the critical importance of Alu RNAs in the maintenance and disposal of macrophages. The proposed research will make a significant contribution because it will not only highlight a new direction in the understanding of macrophage biology and the etiology of macrophage-associated breast tumor development but also will lead us towards the development of rational chemotherapy against such diseases of the breast.