1] M2iSH, UMR 1071 Inserm/University of Auvergne, Clermont-Ferrand, France [2] INRA USC 2018, Clermont-Ferrand, France [3] Centre Hospitalier Universitaire, Clermont-Ferrand, France.
Section of Microbiology, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK.
Lab Invest. 2015 Mar;95(3):296-307. doi: 10.1038/labinvest.2014.161. Epub 2014 Dec 29.
Intestinal dysbiosis has been reported in patients with colorectal cancer, and there is a high prevalence of Escherichia coli belonging to B2 phylogroup and producing a genotoxin, termed colibactin. Macrophages are one of the predominant tumor-infiltrating immune cells supporting key processes in tumor progression by producing protumoral factors such as cyclooxygenase-2 (COX-2). Here, we investigated whether B2 E. coli colonizing colon tumors could influence protumoral activities of macrophages. In contrast to commensal or nonpathogenic E. coli strains that were efficiently and rapidly degraded by macrophages at 24 h after infection, colon cancer-associated E. coli were able to resist killing by human THP-1 macrophages, to replicate intracellularly, and to persist inside host cells until at least 72 h after infection. Significant increases in COX-2 expression were observed in macrophages infected with colon cancer E. coli compared with macrophages infected with commensal and nonpathogenic E. coli strains or uninfected cells at 72 h after infection. Induction of COX-2 expression required live bacteria and was not due to colibactin production, as similar COX-2 levels were observed in macrophages infected with the wild-type colon cancer-associated E. coli 11G5 strain or a clbQ mutant unable to produce colibactin. Treatment of macrophages with ofloxacin, an antibiotic with intracellular tropism, efficiently decreased the number of intracellular bacteria and suppressed bacteria-induced COX-2 expression. This study provides new insights into the understanding of how tumor- infiltrating bacteria could influence cancer progression through their interaction with immune cells. Manipulation of microbes associated with tumors could have a deep influence on the secretion of protumoral molecules by infiltrating macrophages.
肠菌失调已在结直肠癌患者中报道，并且属于 B2 进化枝并产生遗传毒素的大肠杆菌，即肠菌素，其流行率很高。巨噬细胞是浸润肿瘤的主要免疫细胞之一，通过产生环氧化酶-2（COX-2）等促肿瘤因子来支持肿瘤进展的关键过程。在这里，我们研究了定植在结肠肿瘤中的 B2 大肠杆菌是否会影响巨噬细胞的促肿瘤活性。与在感染后 24 小时内被巨噬细胞有效且快速降解的共生菌或非致病性大肠杆菌菌株不同，与结肠癌相关的大肠杆菌能够抵抗人 THP-1 巨噬细胞的杀伤，在细胞内复制，并在感染后至少 72 小时内存在于宿主细胞内。与感染共生菌和非致病性大肠杆菌菌株或未感染细胞的巨噬细胞相比，感染结肠癌大肠杆菌的巨噬细胞在感染后 72 小时观察到 COX-2 表达显著增加。COX-2 表达的诱导需要活细菌，而不是由于肠菌素的产生，因为在感染野生型结肠癌相关大肠杆菌 11G5 株或不能产生肠菌素的 clbQ 突变体的巨噬细胞中观察到相似的 COX-2 水平。用具有细胞内趋向性的抗生素氧氟沙星处理巨噬细胞可有效减少细胞内细菌数量并抑制细菌诱导的 COX-2 表达。这项研究为了解浸润肿瘤的细菌如何通过与免疫细胞相互作用影响癌症进展提供了新的见解。与肿瘤相关的微生物的操纵可能会对浸润巨噬细胞分泌促肿瘤分子产生深远影响。
