Loss of intestinalO-glycans promotes spontaneous duodenal tumors

Abstract

Mucin-type O-glycans, primarily core 1- and core 3-derived O-glycans, are the major mucus barrier components throughout the gastrointestinal tract. Previous reports identified the biological role of O-glycans in the stomach and colon. However, the biological function of O-glycans in the small intestine remains unknown. Using mice lacking intestinal core 1- and core 3-derived O-glycans [intestinal epithelial cell C1galt1(-/-);C3GnT(-/-) or double knockout (DKO)], we found that loss of O-glycans predisposes DKO mice to spontaneous duodenal tumorigenesis by ∼1 yr of age. Tumor incidence did not increase with age; however, tumors advanced in aggressiveness by 20 mo. O-glycan deficiency was associated with reduced luminal mucus in DKO mice before tumor development. Altered intestinal epithelial homeostasis with enhanced baseline crypt proliferation characterizes these phenotypes as assayed by Ki67 staining. In addition, fluorescence in situ hybridization analysis reveals a significantly lower bacterial burden in the duodenum compared with the large intestine. This phenotype is not reduced with antibiotic treatment, implying O-glycosylation defects, rather than bacterial-induced inflammation, which causes spontaneous duodenal tumorigenesis. Moreover, inflammatory responses in DKO duodenal mucosa are mild as assayed with histology, quantitative PCR for inflammation-associated cytokines, and immunostaining for immune cells. Importantly, inducible deletion of intestinal O-glycans in adult mice leads to analogous spontaneous duodenal tumors, although with higher incidence and heightened severity compared with mice with O-glycans constitutive deletion. In conclusion, these studies reveal O-glycans within the small intestine are critical determinants of duodenal cancer risk. Future studies will provide insights into the pathogenesis in the general population and those at risk for this rare but deadly cancer.

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

“…However, it should be noted that there are some contradictory reports regarding the biological role of aberrant O‐glycosylation in a few malignancies. For example, Gao et al reported that loss of intestinal O‐glycans significantly promotes spontaneous duodenal tumours in mice and aberrant O‐glycosylation may serve as critical determinants of duodenal cancer risks49; however, Bergstrom et al unexpectedly found that, although mice deficiency in intestinal O‐glycans developed typical colonic cancers, it was indeed dependent on colitis rather than aberrant O‐glycosylation 50. In addition, several studies showed that direct deletion of Cosmc in pancreatic cancer cell lines induces classical oncogenic features, which is also in agreement with our findings 35, 51.…”

A Systematic Review on the Implications of O-linked Glycan Branching and Truncating Enzymes on Cancer Progression and Metastasis

“…Altogether, this study provides a unique model system to address the role of glycosylation in context of the microbiota or the immune system towards different stages of cancer. The same group later studied the role of DKO mice on tumor progression in the small intestine, specifically the duodenum [44]. The spontaneous duodenal tumor occurrence increased in DKO mice as compared to the wild type mice.…”

Prominent members of the human gut microbiota express endo-acting O-glycanases to initiate mucin breakdown

“…Finally, CRC is the second and fourth deadliest type of cancer in western countries and globally, respectively, and is exacerbated by a ‘Western’ lifestyle, so is likely to become an increasing problem 34,35 . Alterations in the synthesis, secretion and composition of O-glycans in the mucosal surface of the colon have been linked to causation and exasperation of UC and CRC 1,36–41 .…”