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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

Effects of H. hepaticus on mammary gland carcinogenesisTumors of both H. hepaticus-infected and uninfected control C3-1-TAg mice shared similar histomorphological patterns. (A) Neoplastic cells arranged in solid sheets, cords or nests with minimal gland formation and small amounts of intervening stroma. (B) Glandular-like growth was seen in occasional areas at the periphery of the tumors. Note irregular glands in moderate to large amounts of desmoplastic stroma. (C) Large solid cord arrangement of neoplastic cells with variably sized areas of either diffuse or commedo type intratumoral necrosis. (D) The initial stages of mammary tumorigenesis. From left to the right there is progressively increased epithelial pseudostratification, cellular atypia, nuclear pleomorphism and mitotic figures. (E) Classification of abnormal glands in non-tumoral areas according to their histological stage. The mammary glands of H. hepaticus-infected mice are in more advanced stages of neoplastic progression compared to those of uninfected controls. Hematoxylin and Eosin (A, B, C and D); Scale bars: 250 μm (A, B and C) and 25 μm (D).
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Figure 2: Effects of H. hepaticus on mammary gland carcinogenesisTumors of both H. hepaticus-infected and uninfected control C3-1-TAg mice shared similar histomorphological patterns. (A) Neoplastic cells arranged in solid sheets, cords or nests with minimal gland formation and small amounts of intervening stroma. (B) Glandular-like growth was seen in occasional areas at the periphery of the tumors. Note irregular glands in moderate to large amounts of desmoplastic stroma. (C) Large solid cord arrangement of neoplastic cells with variably sized areas of either diffuse or commedo type intratumoral necrosis. (D) The initial stages of mammary tumorigenesis. From left to the right there is progressively increased epithelial pseudostratification, cellular atypia, nuclear pleomorphism and mitotic figures. (E) Classification of abnormal glands in non-tumoral areas according to their histological stage. The mammary glands of H. hepaticus-infected mice are in more advanced stages of neoplastic progression compared to those of uninfected controls. Hematoxylin and Eosin (A, B, C and D); Scale bars: 250 μm (A, B and C) and 25 μm (D).

Mentions: The unencapsulated expansile tumors in both H. hepaticus- and sham-treated mice had the typical C3-1-TAg mouse mammary adenocarcinoma histomorphology (Figures 2A–2C). In the non-tumoral mammary tissue, ducts and terminal duct lobular units (TDLU) showed a spectrum of hyperplastic, preneoplastic, and early neoplastic lesions depicting the well-characterized stages of the C3-1-TAg mouse mammary tumorigenesis progression (Figure 2D). In the non-tumoral areas the affected mammary epithelia of H. hepaticus-treated mice appeared to be in more advanced tumorigenesis stages by comparison with the uninfected controls. In order to confirm this observation we determined histomorphometrically the percentage of abnormal glands at each one of four critical histological stages of mammary tumorigenesis in H. hepaticus-infected and non-infected mice. We found that the classification of abnormal glands according to their histological stage differed significantly between experimental groups (P = 0.0307), with H. hepaticus-infected mice having a higher percentage of abnormal glands with mammary intraepithelial neoplasia (MIN) when compared to controls (Figure 2E).


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)

Effects of H. hepaticus on mammary gland carcinogenesisTumors of both H. hepaticus-infected and uninfected control C3-1-TAg mice shared similar histomorphological patterns. (A) Neoplastic cells arranged in solid sheets, cords or nests with minimal gland formation and small amounts of intervening stroma. (B) Glandular-like growth was seen in occasional areas at the periphery of the tumors. Note irregular glands in moderate to large amounts of desmoplastic stroma. (C) Large solid cord arrangement of neoplastic cells with variably sized areas of either diffuse or commedo type intratumoral necrosis. (D) The initial stages of mammary tumorigenesis. From left to the right there is progressively increased epithelial pseudostratification, cellular atypia, nuclear pleomorphism and mitotic figures. (E) Classification of abnormal glands in non-tumoral areas according to their histological stage. The mammary glands of H. hepaticus-infected mice are in more advanced stages of neoplastic progression compared to those of uninfected controls. Hematoxylin and Eosin (A, B, C and D); Scale bars: 250 μm (A, B and C) and 25 μm (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Effects of H. hepaticus on mammary gland carcinogenesisTumors of both H. hepaticus-infected and uninfected control C3-1-TAg mice shared similar histomorphological patterns. (A) Neoplastic cells arranged in solid sheets, cords or nests with minimal gland formation and small amounts of intervening stroma. (B) Glandular-like growth was seen in occasional areas at the periphery of the tumors. Note irregular glands in moderate to large amounts of desmoplastic stroma. (C) Large solid cord arrangement of neoplastic cells with variably sized areas of either diffuse or commedo type intratumoral necrosis. (D) The initial stages of mammary tumorigenesis. From left to the right there is progressively increased epithelial pseudostratification, cellular atypia, nuclear pleomorphism and mitotic figures. (E) Classification of abnormal glands in non-tumoral areas according to their histological stage. The mammary glands of H. hepaticus-infected mice are in more advanced stages of neoplastic progression compared to those of uninfected controls. Hematoxylin and Eosin (A, B, C and D); Scale bars: 250 μm (A, B and C) and 25 μm (D).
Mentions: The unencapsulated expansile tumors in both H. hepaticus- and sham-treated mice had the typical C3-1-TAg mouse mammary adenocarcinoma histomorphology (Figures 2A–2C). In the non-tumoral mammary tissue, ducts and terminal duct lobular units (TDLU) showed a spectrum of hyperplastic, preneoplastic, and early neoplastic lesions depicting the well-characterized stages of the C3-1-TAg mouse mammary tumorigenesis progression (Figure 2D). In the non-tumoral areas the affected mammary epithelia of H. hepaticus-treated mice appeared to be in more advanced tumorigenesis stages by comparison with the uninfected controls. In order to confirm this observation we determined histomorphometrically the percentage of abnormal glands at each one of four critical histological stages of mammary tumorigenesis in H. hepaticus-infected and non-infected mice. We found that the classification of abnormal glands according to their histological stage differed significantly between experimental groups (P = 0.0307), with H. hepaticus-infected mice having a higher percentage of abnormal glands with mammary intraepithelial neoplasia (MIN) when compared to controls (Figure 2E).

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