Gut bacteria require neutrophils to promote mammary tumorigenesis
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Jessica R. Lakritz1, Theofilos Poutahidis1,2, Sheyla Mirabal1, Bernard J. Varian1, Tatiana Levkovich1, Yassin M. Ibrahim1, Jerrold M. Ward3, Ellen C. Teng1, Brett Fisher1, Nicola Parry1, Stephanie Lesage1, Natalie Alberg1, Sravya Gourishetti1, James G. Fox1, Zhongming Ge1, Susan E. Erdman1
1Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Greece 54124
3Global VetPathology, Montgomery Village, MD 20886, USA
Susan E. Erdman, e-mail: [email protected]
Keywords: enteric, bacteria, microbes, mammary cancer, immune system
Received: January 05, 2015 Accepted: February 09, 2015 Published: March 20, 2015
Recent studies suggest that gastrointestinal tract microbiota modulate cancer development in distant non-intestinal tissues. Here we tested mechanistic hypotheses using a targeted pathogenic gut microbial infection animal model with a predilection to breast cancer. FVB-Tg(C3-1-TAg)cJeg/JegJ female mice were infected by gastric gavage with Helicobacter hepaticus at three-months-of-age putting them at increased risk for mammary tumor development. Tumorigenesis was multifocal and characterized by extensive infiltrates of myeloperoxidase-positive neutrophils otherwise implicated in cancer progression in humans and animal models. To test whether neutrophils were important in etiopathogenesis in this bacteria-triggered model system, we next systemically depleted mice of neutrophils using thrice weekly intraperitoneal injections with anti-Ly-6G antibody. We found that antibody depletion entirely inhibited tumor development in this H. hepaticus-infected model. These data demonstrate that host neutrophil-associated immune responses to intestinal tract microbes significantly impact cancer progression in distal tissues such as mammary glands, and identify gut microbes as novel targets for extra-intestinal cancer therapy.
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