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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

H. hepaticus infection up-regulates MIN-associated neutrophils(A) The tumor-associated inflammation was comparable in large-sized neoplasms of both H. hepaticus-infected and uninfected control mice. Neutrophils (black arrow-heads), myeloid precursor cells (white arrow-head), mast cells (black arrow) and macrophages (white arrow) at the periphery of tumors are shown. (B) Morphometric counts of MPO-positive cells (arrows) in MIN lesions. The numbers of neutrophils are significantly higher in H-hepaticus infected mice compared to controls. Hematoxylin and Eosin (A) IHC; Diaminobenzidine chromogen, Hematoxylin counterstain (B) Scale bars: 25 μm (A) and 50 μm (B) Numbers on the y-axis of bar graph correspond to the mean ± SEM of MPO+cells. ***p < 0.0001.
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Figure 3: H. hepaticus infection up-regulates MIN-associated neutrophils(A) The tumor-associated inflammation was comparable in large-sized neoplasms of both H. hepaticus-infected and uninfected control mice. Neutrophils (black arrow-heads), myeloid precursor cells (white arrow-head), mast cells (black arrow) and macrophages (white arrow) at the periphery of tumors are shown. (B) Morphometric counts of MPO-positive cells (arrows) in MIN lesions. The numbers of neutrophils are significantly higher in H-hepaticus infected mice compared to controls. Hematoxylin and Eosin (A) IHC; Diaminobenzidine chromogen, Hematoxylin counterstain (B) Scale bars: 25 μm (A) and 50 μm (B) Numbers on the y-axis of bar graph correspond to the mean ± SEM of MPO+cells. ***p < 0.0001.

Mentions: Knowing that inflammatory cells and factors were pivotal in etiopathogenesis of microbe-induced mammary [5, 17, 32] and prostate [18] tumors, we next examined whether inflammatory cells were increased in C3-1-TAg mice undergoing infection with H. hepaticus. We found the tumor-associated inflammatory cell component residing at the periphery of well-defined tumors (Figure 3A) consisted of abundant macrophages, neutrophils, myeloid precursor cells with ring-shaped nuclei [33, 34], mononuclear cells, and mast cells. The same types of inflammatory cells were found in the connective tissue stroma within the tumor, with the exception of mast cells, which were sparse. Mast cells as well as neutrophils, however, were topographically associated with early neoplastic lesions such as MIN in the non-tumoral areas of the mammary glands.


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)

H. hepaticus infection up-regulates MIN-associated neutrophils(A) The tumor-associated inflammation was comparable in large-sized neoplasms of both H. hepaticus-infected and uninfected control mice. Neutrophils (black arrow-heads), myeloid precursor cells (white arrow-head), mast cells (black arrow) and macrophages (white arrow) at the periphery of tumors are shown. (B) Morphometric counts of MPO-positive cells (arrows) in MIN lesions. The numbers of neutrophils are significantly higher in H-hepaticus infected mice compared to controls. Hematoxylin and Eosin (A) IHC; Diaminobenzidine chromogen, Hematoxylin counterstain (B) Scale bars: 25 μm (A) and 50 μm (B) Numbers on the y-axis of bar graph correspond to the mean ± SEM of MPO+cells. ***p < 0.0001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: H. hepaticus infection up-regulates MIN-associated neutrophils(A) The tumor-associated inflammation was comparable in large-sized neoplasms of both H. hepaticus-infected and uninfected control mice. Neutrophils (black arrow-heads), myeloid precursor cells (white arrow-head), mast cells (black arrow) and macrophages (white arrow) at the periphery of tumors are shown. (B) Morphometric counts of MPO-positive cells (arrows) in MIN lesions. The numbers of neutrophils are significantly higher in H-hepaticus infected mice compared to controls. Hematoxylin and Eosin (A) IHC; Diaminobenzidine chromogen, Hematoxylin counterstain (B) Scale bars: 25 μm (A) and 50 μm (B) Numbers on the y-axis of bar graph correspond to the mean ± SEM of MPO+cells. ***p < 0.0001.
Mentions: Knowing that inflammatory cells and factors were pivotal in etiopathogenesis of microbe-induced mammary [5, 17, 32] and prostate [18] tumors, we next examined whether inflammatory cells were increased in C3-1-TAg mice undergoing infection with H. hepaticus. We found the tumor-associated inflammatory cell component residing at the periphery of well-defined tumors (Figure 3A) consisted of abundant macrophages, neutrophils, myeloid precursor cells with ring-shaped nuclei [33, 34], mononuclear cells, and mast cells. The same types of inflammatory cells were found in the connective tissue stroma within the tumor, with the exception of mast cells, which were sparse. Mast cells as well as neutrophils, however, were topographically associated with early neoplastic lesions such as MIN in the non-tumoral areas of the mammary glands.

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