Abstract
The presence of inflammatory cells within the tumor microenvironment has been tightly linked to mammary tumor formation and progression. Specifically, interactions between tumor cells and infiltrating macrophages can contribute to the generation of a pro-tumorigenic microenvironment. Understanding the complex mechanisms that drive tumor cell-macrophage cross-talk will ultimately lead to the development of approaches to prevent or treat early stage breast cancers. As described here, we demonstrate that the cell surface protease a disintegrin and metalloproteinase 17 (ADAM17) is expressed by macrophages in mammary tumors and contributes to regulating the expression of pro-inflammatory mediators, including inflammatory cytokines and the inflammatory mediator cyclooxygenase-2 (Cox-2). Furthermore, we demonstrate that ADAM17 is expressed on leukocytes, including macrophages, within polyoma middle T (PyMT)-derived mammary tumors. Genetic deletion of ADAM17 in leukocytes resulted in decreased onset of mammary tumor growth, which was associated with reduced expression of the Cox-2 within the tumor. These findings demonstrate that ADAM17 regulates key inflammatory mediators in macrophages and that leukocyte-specific ADAM17 is an important promoter of mammary tumor initiation. Understanding the mechanisms associated with early stage tumorigenesis has implications for the development of preventive and/or treatment strategies for early stage breast cancers.
Highlights
Breast tumor growth and progression require oncogenic changes within the epithelial cells, and interactions between tumor cells and the stromal environment
The control mice used for these studies were ADAM17fl/fl littermates that were negative for the Cre transgene (ADAM17WT)
To further examine the effects of a disintegrin and metalloproteinase 17 (ADAM17) deletion on inflammatory mediators, we assessed expression levels of Cox-2, which is a downstream target of pro-inflammatory mediators and a key regulator of tumor associated macrophage function [23, 24, 27]
Summary
Breast tumor growth and progression require oncogenic changes within the epithelial cells, and interactions between tumor cells and the stromal environment. Studies focusing on the tumor microenvironment have demonstrated that inflammation correlates with increased invasiveness and poor prognosis in breast cancer patients [1,2,3]. Inflammatory cells and their derived factors, including cytokines, chemokines and growth factors, which are important components involved in the normal wound healing response, are often present within the tumor microenvironment [4]. While numerous studies have focused on identifying key macrophage-derived factors that act on tumor cells to promote tumor growth and progression, less is known regarding the specific mechanisms that regulate the expression and release of these factors by macrophages
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