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.