Abstract
Soluble tumor necrosis factor-α (sTNF-α) plays an important role in colitis-associated cancer (CAC); however, little is known about transmembrane TNF-α (tmTNF-α). Here, we observed an increase in sTNF-α mainly in colitis tissues from an azoxymethane/dextran sodium sulfate (DSS)-induced CAC mouse model whereas tmTNF-α levels were chiefly increased on epithelial cells at the tumor stage. The ratio of intracolonic tmTNF-α/sTNF-α was negatively correlated with the levels of pro-inflammatory mediators (IL-1β, IL-6, and NO) and M1 macrophages but positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and the level of the anti-inflammatory cytokine IL-10, suggesting an anti-inflammatory effect of tmTNF-α. This effect of tmTNF-α was confirmed again by the induction of resistance to LPS in colonic epithelial cell lines NCM460 and HCoEpiC through the addition of exogenous tmTNF-α or transfection of the tmTNF-α leading sequence that lacks the extracellular segment but retains the intracellular domain of tmTNF-α. A tmTNF-α antibody was used to block tmTNF-α shedding after the first or second round of inflammation induction by DSS drinking to shift the time window of tmTNF-α expression ahead to the inflammation stage. Antibody treatment significantly alleviated inflammation and suppressed subsequent adenoma formation, accompanied by increased apoptosis. An antitumor effect was also observed when the antibody was administered at the malignant phase of CAC. Our results reveal tmTNF-α as a novel molecular marker for malignant transformation in CAC and provide a new insight into blocking the pathological process by targeting tmTNF-α processing.
Highlights
Up to 20% of all human cancers result from chronic inflammation and persistent infection
Our results originally revealed that soluble Tumor necrosis factor-a (TNF-a) (sTNF-a) levels were increased in the inflammation phase, while transmembrane TNF-a (tmTNF-a) levels were enhanced during malignant transformation and peaked in the tumor phase
These findings suggest that tmTNF-a was rapidly processed into sTNF-a that promoted colitis, since sTNF-a, a pro-inflammatory cytokine, promotes colonic inflammation by inducing the expression of IL-1b and IL-6 in colonic epithelial cells through activating the NF-kB pathway [35]
Summary
Up to 20% of all human cancers result from chronic inflammation and persistent infection. Patients who suffer from inflammatory bowel disease (IBD) have a high risk of developing colitis-associated colorectal cancer (CAC) and have a high mortality from the disease [1, 2]. Chronic inflammation contributes to the development of low- and high-grade dysplasia that further converts colitis into colorectal cancer (CRC). TmTNF-a on the cell surface is cleaved by a metalloproteinase, TNF-a-converting enzyme (TACE), to release sTNF-a. Both forms of TNF-a are bioactive and display distinct functions. The release of sTNF-a increases in the mouse colon following azoxymethane/dextran sodium sulfate (AOM/DSS) treatment, and ablation of TNF receptor (TNFR) 1 results in reduced mucosal damage, macrophage and neutrophil recruitment, and tumor formation in mouse colon, suggesting a tumor-promoting role of TNF-a in CAC [12]. TNF-a antagonists inhibit CAC induction in mice by limiting TNF-induced infiltration of neutrophils and macrophages [12] and reduce the risk of both dysplasia and CAC when combined with other anti-inflammatory medications in the clinic [15]
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