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.
The proposed research is relevant to public health because it aims to understand the mechanism by which breast cancer cells manipulate the biology of the immunoregulatory Alu RNAs in the tumor-associated macrophages to seek assistance from these macrophages for further tumor development and progression. This study will lead to the development of new chemical regimen to prevent breast cancer. This research is thus relevant to the part of NIH's mission that pertains to developing fundamental knowledge as well as combative and curative measures in alleviating human maladies.
