Chronic bowel inflammation significantly increases the risk of colitis-associated cancer (CAC). Thiopurine treatments are associated with a decrease in CAC in inflammatory bowel disease and dysplasia. Abnormal Wnt/β-catenin signaling is characteristic of >90% of colorectal cancers. Autophagy is involved in colonic tumors and topical delivery of the thiopurine thioguanine (TG), i.e., known to alleviate colitis and augment autophagy. This study investigates TG’s effects in a murine model of CAC and potential mechanisms and shows that it acts directly on intestinal epithelial cell lines in vitro to inhibit the activity of β-catenin in a TGN-dependent manner. In a CAC mouse model, daily intrarectal TG prevented colitis in wild-type (WT) mice but not in mice with deficient autophagy in intestinal epithelial cells.
Although the pathogenesis of CAC in the setting of IBD is being more strongly linked to chronic inflammation and is challenging to detect endoscopically because of arising from flat dysplastic lesions, it has many features in common with the pathogenesis of sporadic and hereditary colon cancers, which are the second leading cause of cancer death globally. Hyperactivated Wnt/β-catenin signaling is considered a hallmark of colorectal tumorigenesis and has been recently implicated in immune evasion, invasion, and metastasis. With colorectal cancer (CRC), 90% of all tumors have a mutation(s) in the Wnt/β-catenin pathway. However, the role of Wnt/β-catenin signaling in CAC is less well-understood.
In summary, the dose size and TG duration for 85 days were significantly greater than previously reported. Systemic toxicity was found to be negligible. The anti-inflammatory effects of TG (administered rectally) depend upon the epithelial cell autophagy of the intestine.