Innate Immune Inflammatory Response against Enteric Bacteria Helicobacter hepaticus Induces Mammary Adenocarcinoma in Mice

Abstract

Inflammation associated with bacterial infections is a risk factor for cancers in humans, yet its role in breast cancer remains poorly understood. We have previously shown that innate immune inflammatory response against intestinal bacteria is sufficient to induce colon cancer. Here we report that infecting Rag2-deficient C57BL/6 Apc Min/+ mice with an intestinal bacterial pathogen, Helicobacter hepaticus, significantly promotes mammary carcinoma in females and enhances intestinal adenoma multiplicity by a tumor necrosis factor A (TNFA)-dependent mechanism. The mammary and intestinal tumor development as well as the increase in proinflammatory mediators is suppressed by adoptive transfer of interleukin 10-competent CD4 + CD45RB lo CD25 + regulatory (T R ) cells. Furthermore, prior exposure of donor mice to H. hepaticus significantly enhances antitumor potency of their T R cells. Interestingly, these microbially experienced T R cells suppress tumorigenesis more effectively in recipient mice irrespective of their tumor etiology. These data suggest that infections with enteric pathogens enhance T R -cell potency and protect against epithelial cancers later in life, potentially explaining paradoxical increases in cancer risk in developed countries having more stringent hygiene practices. The possibility that dysregulated gut microbial infections in humans may lead to cancer in anatomically distant organs, such as breast, highlights the need for novel immune-based strategies in cancer prevention and treatment. (Cancer Res 2006; 66(15): 7395-400)

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

“…Taken together, these histopathological and gene expression data indicate that pharmacological inhibition of SMO by MDL 72527 reduces ETBFassociated intestinal chronic inflammation and proliferation. of the immune response to bacteria that may be involved in either promoting or protecting against intestinal inflammation and carcinogenesis (31)(32)(33)(34)(35)(36). The importance of bacterially-induced ROS in inflammation-associated carcinogenesis was demonstrated in mice lacking the H 2 O 2 detoxification enzymes gpx-1 and gpx-2.…”

Nitric oxide and TNF-α trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus -infected, Rag2 -deficient mice

“…Targeting inflammation and NO is clinically relevant, because mucinous colonic carcinoma seen in T EFF cell recipient mice most often affects young humans and has a poor prognosis associated with invasion of adjacent viscera and lymph nodes beyond the pericolonic region (33). Cotransfer of CD4 ϩ T REG and T EFF cells significantly protected against colon carcinogenesis (41), and NO was linked (44). Identifying which T REG subsets are most effective in the regulation of TNF-␣ and NO to prevent or treat infection-associated colon cancer is a future goal.…”

“…injection of 500 g/mouse Ly-6G antibody (BioExpress) thrice weekly for 10 weeks. Ten mice infected with H. hepaticus 6 weeks earlier were injected for 10 days with anti-TNF-␣ antibody (clone XT-3; BioExpress) at 200 mg per mouse thrice weekly as previously described (44). Mice were euthanized at 3-4 months after infection, and tissues were evaluated as described below.…”

Cancer-related inflammation

“…Interestingly, a poly morphism in the promoter of the gene encoding myeloperoxidase has been associated with resistance to the development of lung cancer in smo kers 90 . Therefore, although the evidence [87][88][89][90][91] suggests that inflammation causes cancer, formal proof is still required.…”