Gut bacteria require neutrophils to promote mammary tumorigenesis

Abstract

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.

Old enemies meet new friends for colon cancer prevention

“…Also, the depletion of neutrophils negates this distant, immune-mediated, pro-tumorigenic effect and rescues mice from mammary tumors. 8 The latter observation demonstrates that gut microbiota effects transcend not only the local boundaries of the GI tract, but generations as well. Indeed, mice with a westernized-diet type, obesity-related gut microbiota have children and grandchildren, which although fed with normal diets, develop lung and liver cancers and lymphoma in particularly high rates.…”

“…Instead, it is influenced by the status of the immune system at the whole-organism level. [6][7][8][9] In our paradigm, the systematic immunological tone may affect co-existing dysplastic lesions in the body. The immune system, the hormonal profile and the psychological condition of human beings are interrelated.…”

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

“…Given our present study, we suspect that 5ClC could also be a contributor to the C→T mutations observed in sequenced tumors as part of one or several different mutational signatures. The well-established infiltration of tumors with immune cells, including neutrophils (2,9,58), provides a rich opportunity for HOCl production and, hence, 5ClC formation.…”

Understanding Luminal Microorganisms and Their Potential Effectiveness in Treating Intestinal Inflammation

“…Recent studies have also suggested that intestinal bacteria can modulate cancer development in distant non-intestinal tissues, such as prostate cancer and breast cancer due to Helicobacter hepaticus(12, 69). …”