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Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway.

Lu R, Wu S, Zhang YG, Xia Y, Liu X, Zheng Y, Chen H, Schaefer KL, Zhou Z, Bissonnette M, Li L, Sun J - Oncogenesis (2014)

Bottom Line: In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS).Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain.Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Rush University, Chicago, IL, USA.

ABSTRACT
Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of β-catenin signaling in cancer.

No MeSH data available.


Related in: MedlinePlus

AvrA-expressing bacteria significantly increase colonic tumor incidence. (a) Colonic tumors in situ. Representative colons from the indicated groups 45 weeks after bacterial infection. Tumors are indicated by red arrows. (b) Tumor multiplicity. Average number of tumors in each experimental group. *P<0.05, **P<0.01. (c) Tumor location. The distance of each tumor from the anus was measured. *P<0.05. (d) Swiss rolls of representative colons from the indicated groups. Rectangles in the middle panel are shown at higher magnification in the lower panel. (e) Salmonella invasion. Localization of Salmonella in tumor tissue was assessed by immunofluorescence staining.
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fig2: AvrA-expressing bacteria significantly increase colonic tumor incidence. (a) Colonic tumors in situ. Representative colons from the indicated groups 45 weeks after bacterial infection. Tumors are indicated by red arrows. (b) Tumor multiplicity. Average number of tumors in each experimental group. *P<0.05, **P<0.01. (c) Tumor location. The distance of each tumor from the anus was measured. *P<0.05. (d) Swiss rolls of representative colons from the indicated groups. Rectangles in the middle panel are shown at higher magnification in the lower panel. (e) Salmonella invasion. Localization of Salmonella in tumor tissue was assessed by immunofluorescence staining.

Mentions: We collected tissue samples 45 weeks postinfection. Representative colons with tumors are shown in Figure 2a. There was a striking difference in tumor incidence in mice with AvrA+ and AvrA− bacterial colonization (Table 1). The tumor incidence was 51.4% in the AOM/DSS control group (no infection) and 60.6% in the parental PhoPC-infected mice, 56.3% in the AvrA- infected mice and 100% in the PhoPC AvrA−/AvrA+.


Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway.

Lu R, Wu S, Zhang YG, Xia Y, Liu X, Zheng Y, Chen H, Schaefer KL, Zhou Z, Bissonnette M, Li L, Sun J - Oncogenesis (2014)

AvrA-expressing bacteria significantly increase colonic tumor incidence. (a) Colonic tumors in situ. Representative colons from the indicated groups 45 weeks after bacterial infection. Tumors are indicated by red arrows. (b) Tumor multiplicity. Average number of tumors in each experimental group. *P<0.05, **P<0.01. (c) Tumor location. The distance of each tumor from the anus was measured. *P<0.05. (d) Swiss rolls of representative colons from the indicated groups. Rectangles in the middle panel are shown at higher magnification in the lower panel. (e) Salmonella invasion. Localization of Salmonella in tumor tissue was assessed by immunofluorescence staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150214&req=5

fig2: AvrA-expressing bacteria significantly increase colonic tumor incidence. (a) Colonic tumors in situ. Representative colons from the indicated groups 45 weeks after bacterial infection. Tumors are indicated by red arrows. (b) Tumor multiplicity. Average number of tumors in each experimental group. *P<0.05, **P<0.01. (c) Tumor location. The distance of each tumor from the anus was measured. *P<0.05. (d) Swiss rolls of representative colons from the indicated groups. Rectangles in the middle panel are shown at higher magnification in the lower panel. (e) Salmonella invasion. Localization of Salmonella in tumor tissue was assessed by immunofluorescence staining.
Mentions: We collected tissue samples 45 weeks postinfection. Representative colons with tumors are shown in Figure 2a. There was a striking difference in tumor incidence in mice with AvrA+ and AvrA− bacterial colonization (Table 1). The tumor incidence was 51.4% in the AOM/DSS control group (no infection) and 60.6% in the parental PhoPC-infected mice, 56.3% in the AvrA- infected mice and 100% in the PhoPC AvrA−/AvrA+.

Bottom Line: In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS).Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain.Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Rush University, Chicago, IL, USA.

ABSTRACT
Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of β-catenin signaling in cancer.

No MeSH data available.


Related in: MedlinePlus