ADAM17 in tumor associated leukocytes regulates inflammatory mediators and promotes mammary tumor formation
Laura R. Bohrer1,*, Thomas S. Chaffee1,*, Pavlina Chuntova2, Nicholas J. Brady2, Patrice M. Witschen3, Sarah E. Kemp1, Andrew C. Nelson1, Bruce Walcheck3 and Kathryn L. Schwertfeger1,4
1 Department of Lab Medicine and Pathology, University of Minnesota, MN, USA
2 Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, MN, USA
3 Department of Veterinary and Biomedical Sciences, University of Minnesota, MN, USA
4 Masonic Cancer Center, University of Minnesota, MN, USA
* These authors have contributed equally to this manuscript
Correspondence:
Kathryn L. Schwertfeger, email:
Keywords: Breast cancer, inflammation, macrophage, ADAM17, Cox-2
Received: June 13, 2016 Accepted: August 16, 2016 Published: August 21, 2016
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.
