Crypt residing bacteria and proximal colonic carcinogenesis in a mouse model of Lynch syndrome. Issue 8 (18th May 2020)

• Record Type: Journal Article
• Authors: Lang, Michaela; Baumgartner, Maximilian; Rożalska, Aleksandra; Frick, Adrian; Riva, Alessandra; Jarek, Michael; Berry, David; Gasche, Christoph
• Is Part Of: International journal of cancer. Volume 147:Issue 8(2020)
• Page Start: 2316
• Page End: 2326
• Publication Date: 2020-05-18
• Subjects: colorectal cancer -- inflammatory bowel disease -- Lynch syndrome -- microbiota; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33028
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: Colorectal cancer is a multifactorial disease involving inherited DNA mutations, environmental factors, gut inflammation and intestinal microbiota. Certain germline mutations within the DNA mismatch repair system are associated with Lynch syndrome tumors including right‐sided colorectal cancer with mucinous phenotype and presence of an inflammatory infiltrate. Such tumors are more often associated with bacterial biofilms, which may contribute to disease onset and progression. Inflammatory bowel diseases are also associated with colorectal cancer and intestinal dysbiosis. Herein we addressed the question, whether inflammation can aggravate colorectal cancer development under mismatch repair deficiency. MSH2 loxP/loxP Vill‐cre mice were crossed into the IL‐10 −/− background to study the importance of inflammation and mucosal bacteria as a driver of tumorigenesis in a Lynch syndrome mouse model. An increase in large bowel tumorigenesis was found in double knockout mice both under conventional housing and under specific pathogen‐free conditions. This increase was mostly due to the development of proximal tumors, a hotspot for tumorigenesis in Lynch syndrome, and was associated with a higher degree of inflammation. Additionally, bacterial invasion into the mucus of tumor crypts was observed in the proximal tumors. Inflammation shifted fecal and mucosal microbiota composition and was associated with enrichment in Escherichia‐Shigella as well as Akkermansia, Bacteroides and Parabacteroides genera in fecal samples. Tumor‐bearing double knockout mice showed a similar enrichment for Escherichia‐Shigella and Parabacteroides . Lactobacilli, Lachnospiraceae and Muribaculaceae family members were depleted upon inflammation. In summary, chronic inflammation aggravates colonic tumorigenesis under mismatch repair deficiency and is associated with a shift in microbiota composition. Abstract : What's new? DNA mismatch repair deficiency and longstanding inflammatory bowel disease are predisposing factors for colorectal cancer. Greater knowledge of these factors is relevant particularly for understanding carcinogenesis in the proximal colon, a cancer hotspot in patients with Lynch syndrome. Here, using a novel double knockout mouse model (MSH2 loxP/loxP Vil‐cre x IL‐10) to investigate the combined role of inflammation and mucosal bacteria in Lynch syndrome, the authors show that proximal colonic tumorigenesis in mismatch repair‐deficient mice is aggravated under chronic inflammation. Proximal colon tumorigenesis was accompanied by bacterial invasion into tumor crypts. The findings shed light on colonic tumorigenesis mechanisms in MSH2 loxP/loxP Vil‐cre x IL‐10 mice.