Impaired Glycosylation of Gastric Mucins Drives Gastric Tumorigenesis and Serves as a Novel Therapeutic Target.

BACKGROUND & AIMS: Gastric cancer is often accompanied by a loss of mucin 6 (MUC6), but its pathogenic role in gastric carcinogenesis remains unclear. METHODS: Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1flox/flox, Cosmcflox/flox, and A4gnt-/- mice were also used. Histology, DNA and RNA, proteins, and sugar chains were analyzed by whole-exon DNA sequence, RNA sequence, immunohistochemistry, lectin-binding assays, and liquid chromatography-mass spectrometry analysis. Gastric organoids and cell lines were used for in vitro assays and xenograft experiments. RESULTS: Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on mitogen-activated protein kinase activation, mediated by Golgi stress-induced up-regulation of Golgi phosphoprotein 3. Glycomic profiling revealed aberrant expression of mannose-rich N-linked glycans in gastric tumors, detected with banana lectin in association with lack of MUC6 expression. We identified a precursor of clusterin as a binding partner of mannose glycans. Mitogen-activated protein kinase activation, Golgi stress responses, and aberrant mannose expression are found in separate Cosmc- and A4gnt-deficient mouse models that lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer. CONCLUSIONS: We propose that Golgi stress responses and aberrant glycans are important drivers of and promising new therapeutic targets for gastric cancer.

Non-Helicobacter pylori Gastric Microbiome Modulates Prooncogenic Responses and Is Associated With Gastric Cancer Risk.

Background and Aims: Although Helicobacter pylori is the most important bacterial carcinogen in gastric cancer (GC), GC can emerge even after H. pylori eradication. Studies suggest that various constituents of the gastric microbiome may influence GC development, but the role of individual pathogens is unclear. Methods: Human gastric mucosal samples were analyzed by 16SrRNA sequencing to investigate microbiome composition and its association with clinical parameters, including GC risk. Identified bacteria in the stomach were cocultured with gastric epithelial cells or inoculated into mice, and transcriptomic changes, DNA damage, and inflammation were analyzed. Bacterial reads in GC tissues were examined together with transcriptomic and genetic sequencing data in the cancer genome atlas dataset. Results: Patients after Helicobacter pylori eradication formed 3 subgroups based on the microbial composition revealed by 16SrRNA sequencing. One dysbiotic group enriched with Fusobacterium and Neisseria species was associated with a significantly higher GC incidence. These species activated prooncogenic pathways in gastric epithelial cells and promoted inflammation in mouse stomachs. Sugar chains that constitute gastric mucin attenuate host-bacteria interactions. Metabolites from Fusobacterium species were genotoxic, and the presence of the bacteria was associated with an inflammatory signature and a higher tumor mutation burden. Conclusion: Gastric microbiota in the dysbiotic stomach is associated with GC development after H. pylori eradication and plays a pathogenic role through direct host-bacteria interaction.

Texture and color enhancement imaging in magnifying endoscopic evaluation of colorectal adenomas.

BACKGROUND: Olympus Corporation has developed texture and color enhancement imaging (TXI) as a novel image-enhancing endoscopic technique. AIM: To investigate the effectiveness of TXI in identifying colorectal adenomas using magnifying observation. METHODS: Colorectal adenomas were observed by magnified endoscopy using white light imaging (WLI), TXI, narrow band imaging (NBI), and chromoendoscopy (CE). This study adopted mode 1 of TXI. Adenomas were confirmed by histological examination. TXI visibility was compared with the visibility of WLI, NBI, and CE for tumor margin, and vessel and surface patterns of the Japan NBI expert team (JNET) classification. Three expert endoscopists and three non-expert endoscopists evaluated the visibility scores, which were classified as 1, 2, 3, and 4. RESULTS: Sixty-one consecutive adenomas were evaluated. The visibility score for tumor margin of TXI (3.47 ± 0.79) was significantly higher than that of WLI (2.86 ± 1.02, P < 0.001), but lower than that of NBI (3.76 ± 0.52, P < 0.001), regardless of the endoscopist's expertise. TXI (3.05 ± 0.79) had a higher visibility score for the vessel pattern of JNET classification than WLI (2.17 ± 0.90, P < 0.001) and CE (2.47 ± 0.87, P < 0.001), but lower visibility score than NBI (3.79 ± 0.47, P < 0.001), regardless of the experience of endoscopists. For the visibility score for the surface pattern of JNET classification, TXI (2.89 ± 0.85) was superior to WLI (1.95 ± 0.79, P < 0.01) and CE (2.75 ± 0.90, P = 0.002), but inferior to NBI (3.67 ± 0.55, P < 0.001). CONCLUSION: TXI provided higher visibility than WLI, lower than NBI, and comparable to or higher than CE in the magnified observation of colorectal adenomas.

TXI (Texture and Color Enhancement Imaging) for Serrated Colorectal Lesions.

BACKGROUND AND AIM: Olympus Corporation released the texture and color enhancement imaging (TXI) technology as a novel image-enhancing endoscopic technique. We investigated the effectiveness of TXI in the imaging of serrated colorectal polyps, including sessile serrated lesions (SSLs). METHODS: Serrated colorectal polyps were observed using white light imaging (WLI), TXI, narrow-band imaging (NBI), and chromoendoscopy with and without magnification. Serrated polyps were histologically confirmed. TXI was compared with WLI, NBI, and chromoendoscopy for the visibility of the lesions without magnification and for that of the vessel and surface patterns with magnification. Three expert endoscopists evaluated the visibility scores, which were classified from 1 to 4. RESULTS: Twenty-nine consecutive serrated polyps were evaluated. In the visibility score without magnification, TXI was significantly superior to WLI but inferior to chromoendoscopy in the imaging of serrated polyps and the sub-analysis of SSLs. In the visibility score for vessel patterns with magnification, TXI was significantly superior to WLI and chromoendoscopy in the imaging of serrated polyps and the sub-analysis of SSLs. In the visibility score for surface patterns with magnification, TXI was significantly superior to WLI but inferior to NBI in serrated polyps and in the sub-analysis of SSLs and hyperplastic polyps. CONCLUSIONS: TXI provided higher visibility than did WLI for serrated, colorectal polyps, including SSLs.