Abstract
The association between chronic inflammation and cancer has long been recognized. The inflammatory bowel disease ulcerative colitis frequently progresses to colon cancer; however, the underlying mechanism is still unclear. S100a9 has been emerged as an important pro-inflammatory mediator in acute and chronic inflammation, and the aberrant expression of S100a9 also contributes to tumorigenic processes such as cell proliferation, angiogenesis, metastasis, and immune evasion. We previously revealed that S100a8 and S100a9 are highly activated and play an important role in the process of colitis-associated carcinogenesis, which suggests an attractive therapeutic target for ulcerative colitis and related colon cancer. Here, we report that administration of a neutralizing anti-S100a9 antibody significantly ameliorated dextran sulfate sodium (DSS)-induced colitis and accompanied by diminished cellular infiltrate of innate immunity cells (macrophages, neutrophils, and dendritic cells) and production of pro-inflammatory cytokines (Tnfα, Il1β, Ifnγ, Il6, Il17a, Il23a, Il4, and Il12a). The protective effect of anti-S100a9 antibody treatment was also observed in azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) mouse model. The inflammatory response, tumor cell proliferation, and immune cells infiltration in the colon tissues were suppressed by anti-S100a9 antibody. Gene expression profiling showed that key pathways known to be involved in CAC development, such as Wnt signaling pathway, PI3K–Akt signaling pathway, cytokine–cytokine receptor interaction, and ECM–receptor interaction pathway, were suppressed after treatment with anti-S100a9 antibody in CAC mice. In view of the protective effect of neutralizing anti-S100a9 antibody against DSS-induced colitis and AOM/DSS-induced CAC in mouse model, this study suggests that anti-S100a9 antibody may provide a novel therapeutic approach to treat ulcerative colitis and may decrease the risk for developing CAC.
Highlights
Ulcerative colitis and Crohn’s disease are collectively referred to as inflammatory bowel disease (IBD)
We discovered that the damage-associated molecular pattern S100a8 and S100a9 protein were upregulated dramatically throughout the “inflammation–dysplasia–carcinoma” sequence of CAC mouse model and in human colorectal cancer (CRC) specimens
In the mice treated with anti-S100a9 Ab, the concentration of S100a8/a9 proteins in the feces and serum was lower than that of the mice treated with control IgG Ab (Figures S1B,C in Supplementary Material), demonstrating that administration of anti-S100a9 Ab neutralized the S100a9 protein in dextran sulfate sodium (DSS)-induced acute colitis mice in vivo
Summary
Ulcerative colitis and Crohn’s disease are collectively referred to as inflammatory bowel disease (IBD). IBD ranks as a high-risk condition for the development of colorectal cancer (CRC), with a standardized incidence ratio of 2.4 (95% CI 0.6–6.0) in patients with extensive or pan ulcerative colitis [1, 2]. Colitis-associated cancer (CAC) is the CRC subtype that is associated with IBD, is difficult to treat, and has high mortality. More than 20% of IBD patients develop CAC within 30 years of disease onset [3]. The most successful approach to treat IBD has been approved to target the excessive activity of the adaptive immune system using biological agents such as infliximab, a monoclonal antibody against tumor necrosis factor alpha (TNFα). Other biological agents in clinical development, such as monoclonal antibodies against IL-17, IL-12/IL-23 and inhibitors of IL-6, CCR9, and Janus kinase, were found have limited treatment effects and safety issues such as increased risk of infection, autoimmunity, and malignancy [9], suggesting other therapeutic agents with enhanced safety and minimal toxicity are needed, and indicating there are some unknown key pathogenesis involved in the occurrence and progression of such diseases
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