Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria.
Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria.
Int J Cancer. 2020 Oct 15;147(8):2316-2326. doi: 10.1002/ijc.33028. Epub 2020 May 18.
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 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.
结直肠癌是一种多因素疾病，涉及遗传 DNA 突变、环境因素、肠道炎症和肠道微生物群。DNA 错配修复系统中的某些种系突变与林奇综合征肿瘤相关，包括右侧结直肠癌伴黏液表型和炎症浸润。此类肿瘤更常与细菌生物膜相关，这可能有助于疾病的发生和进展。炎症性肠病也与结直肠癌和肠道菌群失调有关。在此，我们提出了一个问题，即在错配修复缺陷的情况下，炎症是否会加重结直肠癌的发展。我们将 MSH2 小鼠与 IL-10 背景杂交，以研究炎症和黏膜细菌作为林奇综合征小鼠模型中肿瘤发生的驱动因素的重要性。在常规饲养和特定病原体无饲养条件下，我们发现双敲除小鼠的大肠肿瘤形成增加。这种增加主要是由于近端肿瘤的发展，这是林奇综合征中肿瘤发生的热点，并且与更高程度的炎症相关。此外，还观察到细菌侵入肿瘤隐窝的黏液中。炎症改变了粪便和黏膜微生物群组成，并与粪便中 Escherichia-Shigella 以及 Akkermansia、Bacteroides 和 Parabacteroides 属的富集相关。携带肿瘤的双敲除小鼠也表现出对 Escherichia-Shigella 和 Parabacteroides 的类似富集。Lactobacilli、Lachnospiraceae 和 Muribaculaceae 家族成员在炎症时被耗尽。总之，慢性炎症在错配修复缺陷下加重结肠肿瘤发生，并与微生物群组成的变化相关。
