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Gut bacteria require neutrophils to promote mammary tumorigenesis.

Lakritz JR, Poutahidis T, Mirabal S, Varian BJ, Levkovich T, Ibrahim YM, Ward JM, Teng EC, Fisher B, Parry N, Lesage S, Alberg N, Gourishetti S, Fox JG, Ge Z, Erdman SE - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Tumor multiplicity assessment in experimental groups of 15-week-old C3-1-TAg mice(A) Grossly visible tumors (arrow) found in each mouse were removed, placed on a petri dish and counted. (B) The statistical analysis of mammary tumor count data shows that infection with H. hepaticus accelerates tumorigenesis, whereas the depletion of neutrophils negates this effect. The y-axis depicts the mean ± SEM of mammary tumor counts. *p < 0.05. The points correspond to the mean of total tumors counted in each mouse.
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Figure 1: Tumor multiplicity assessment in experimental groups of 15-week-old C3-1-TAg mice(A) Grossly visible tumors (arrow) found in each mouse were removed, placed on a petri dish and counted. (B) The statistical analysis of mammary tumor count data shows that infection with H. hepaticus accelerates tumorigenesis, whereas the depletion of neutrophils negates this effect. The y-axis depicts the mean ± SEM of mammary tumor counts. *p < 0.05. The points correspond to the mean of total tumors counted in each mouse.

Mentions: It was previously shown that infection with enteropathogenic H. hepaticus rapidly induced mammary tumor formation in genetically-susceptible ApcMin/+ [ApcMin] mice [5, 6, 30, 31]. However, the use of ApcMin mice as a model of mammary cancer has certain peculiarities, raising doubts about broader relevancy of roles of gut microbiota in mammary epithelial carcinogenesis. To examine this evident gut microbe-mammary linkage further, we first tested orogastric challenge with H. hepaticus in the FVB-Tg(C3-1-TAg)cJeg/JegJ mouse model [29]. Within three weeks of infection, we found numerous small palpable tumors arising in multiple mammary tissue sites of three-month-old C3-1-TAg mice infected with H. hepaticus (Figure 1A). By comparison, sham media-dosed matched control animals had significantly fewer palpable tumors (Figure 1B).


Gut bacteria require neutrophils to promote mammary tumorigenesis.

Lakritz JR, Poutahidis T, Mirabal S, Varian BJ, Levkovich T, Ibrahim YM, Ward JM, Teng EC, Fisher B, Parry N, Lesage S, Alberg N, Gourishetti S, Fox JG, Ge Z, Erdman SE - Oncotarget (2015)

Tumor multiplicity assessment in experimental groups of 15-week-old C3-1-TAg mice(A) Grossly visible tumors (arrow) found in each mouse were removed, placed on a petri dish and counted. (B) The statistical analysis of mammary tumor count data shows that infection with H. hepaticus accelerates tumorigenesis, whereas the depletion of neutrophils negates this effect. The y-axis depicts the mean ± SEM of mammary tumor counts. *p < 0.05. The points correspond to the mean of total tumors counted in each mouse.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496224&req=5

Figure 1: Tumor multiplicity assessment in experimental groups of 15-week-old C3-1-TAg mice(A) Grossly visible tumors (arrow) found in each mouse were removed, placed on a petri dish and counted. (B) The statistical analysis of mammary tumor count data shows that infection with H. hepaticus accelerates tumorigenesis, whereas the depletion of neutrophils negates this effect. The y-axis depicts the mean ± SEM of mammary tumor counts. *p < 0.05. The points correspond to the mean of total tumors counted in each mouse.
Mentions: It was previously shown that infection with enteropathogenic H. hepaticus rapidly induced mammary tumor formation in genetically-susceptible ApcMin/+ [ApcMin] mice [5, 6, 30, 31]. However, the use of ApcMin mice as a model of mammary cancer has certain peculiarities, raising doubts about broader relevancy of roles of gut microbiota in mammary epithelial carcinogenesis. To examine this evident gut microbe-mammary linkage further, we first tested orogastric challenge with H. hepaticus in the FVB-Tg(C3-1-TAg)cJeg/JegJ mouse model [29]. Within three weeks of infection, we found numerous small palpable tumors arising in multiple mammary tissue sites of three-month-old C3-1-TAg mice infected with H. hepaticus (Figure 1A). By comparison, sham media-dosed matched control animals had significantly fewer palpable tumors (Figure 1B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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.

No MeSH data available.


Related in: MedlinePlus