Cholera-toxin suppresses carcinogenesis in a mouse model of inflammation-driven sporadic colon cancer

Abstract

Human studies and clues from animal models have provided important links between gastrointestinal (GI) tract bacteria and colon cancer. Gut microbiota antigenic stimuli play an important role in shaping the intestinal immune responses. Therefore, especially in the case of inflammation-associated colon cancer, gut bacteria antigens may affect tumorigenesis. The present study aimed to investigate the effects of the oral administration of a bacterial product with known immunomodulatory properties on inflammation-driven colorectal neoplasmatogenesis. For that, we used cholera-toxin and a well-established mouse model of colon cancer in which neoplasia is initiated by a single dose of the genotoxic agent azoxymethane (AOM) and subsequently promoted by inflammation caused by the colitogenic substance dextran sodium sulfate (DSS). We found that a single, low, non-pathogenic dose of CT, given orally at the beginning of each DSS treatment cycle downregulated neutrophils and upregulated regulatory T-cells and IL-10 in the colonic mucosa. The CT-induced disruption of the tumor-promoting character of DSS-induced inflammation led to the reduction of the AOM-initiated colonic polypoidogenesis. This result adds value to the emerging notion that certain GI tract bacteria or their products affect the immune system and render the microenvironment of preneoplastic lesions less favorable for promoting their evolution to cancer.

Old enemies meet new friends for colon cancer prevention

“…However, CT downregulated neutrophils and upregulated regulatory T-cells, interleukin (IL)-10 and tumor necrosis factor a (TNFa) in the colonic mucosa 3 ( Fig. 1).…”

“…We have recently used one such murine model to examine the extent to which the evolution of preneoplastic lesions in the colon depends on their immunological environment. 3 Toward that goal, mice were given a single dose of the genotoxic agent azoxymethane (AOM), which by itself did not lead to the formation of colonic polyps. Following AOM-treatment, mice underwent 3 repeated episodes of colitis induced by dextran sodium sulfate (DSS).…”

“…Since many of the bacteria that humans rarely encounter nowadays are pathogens, the search for beneficial antigens may not be restricted to our probiotic "new friends," 7-10 but involve some of our "old enemies" as well. 3 …”

Gut bacteria and cancer

“…In this context, a weakened T REG -mediated inhibitory loop imparts carcinogenic consequences of elevated IL-6 and possibly IL-17, leading to more frequent inflammation-associated distal cancers [82]. In this context, neutrophils have been identified in animal models as an important factor in cancer initiation and development [24–26, 70] [83] [84–88]. A distant neoplastic effect of a commensal gut microbe was recently shown in FVB-Tg(C3-1-TAg)cJeg/JegJ mammary tissue by a neutrophil-mediated mechanism [75].…”

“…Several of these studies have also highlighted the fact that early neoplastic lesions are less autonomous in their growth than previously thought [11, 22–26]. Instead, their thriving and evolution depends on their micro- and macro-environment[13–15, 17, 27, 28].…”