F4/80+Ly6Chigh Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis
F4/80+Ly6Chigh Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis
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F4/80 Ly6Chigh 巨噬细胞导致结肠炎中的细胞可塑性和癌症发生
DOI：
10.1053/j.gastro.2023.01.002
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发表时间：
2023
期刊：
影响因子：
29.4
通讯作者：
Asfaha Samuel
中科院分区：
文献类型：
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作者：
Shin Alice E.;Tesfagiorgis Yodit;Larsen Frederikke;Derouet Mathieu;Zeng Peter Y.F.;Good Hayley J.;Zhang Liyue;Rubinstein Mara R.;Han Yiping W.;Kerfoot Steven M.;Nichols Anthony C.;Hayakawa Yoku;Howlett Christopher J.;Wang Timothy C.;Asfaha Samuel
背景与目的结直肠癌是癌症死亡的主要原因，慢性炎症是其主要危险因素。尽管结肠炎与癌症之间存在联系，但炎症导致结直肠癌的机制尚不清楚。方法为了研究不同形式的炎症是否构成相同的癌症风险，我们比较了几种结肠炎小鼠模型(葡聚糖硫酸钠[DSS]、2，4，6-三硝基苯磺酸、4-乙氧亚甲基-2-苯并恶唑-5-酮、罗氏柠檬酸杆菌、核梭杆菌和阿霉素)导致结肠癌的能力。我们试图在偶氮甲烷依赖和Dclk1/APCfl/fl鼠结肠炎相关癌症模型中将结肠炎的严重性和炎症特征与肿瘤发生的风险相关联。结果在两种结肠炎相关癌症小鼠模型中，DSS结肠炎可重复地导致结肠肿瘤。相比之下，所有其他形式的结肠炎并不会导致癌症。与与肿瘤发生无关的结肠炎相比，DSS结肠炎的特点是CD11b+F4/80+Ly6巨噬细胞和CD11b+Ly6G+中性粒细胞显著增加。有趣的是，CD11b+F4/80+Ly6巨噬细胞的去除抑制了肿瘤的发生，而CD11b+Ly6G+中性粒细胞的去除对肿瘤的发生没有影响。结论CD11b+F4/80+LY6巨噬细胞是结肠炎相关癌发生的重要细胞因子。结论CD11b+F4/80+LY6巨噬细胞是结肠炎相关癌发生的关键介质。针对这些细胞的新疗法的开发可能为结肠炎相关癌症提供有效的预防策略。
Background & AimsColorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to colorectal cancer is not well understood.MethodsTo investigate whether different forms of inflammation pose the same risk of cancer, we compared several murine models of colitis (dextran sodium sulfate [DSS], 2,4,6-trinitrobenzene sulfonic acid, 4-ethoxylmethylene-2-phenyloxazol-5-one,Citrobacter rodentium,Fusobacterium nucleatum, and doxorubicin) with respect to their ability to lead to colonic tumorigenesis. We attempted to correlate the severity of colitis and inflammatory profile with the risk of tumorigenesis in both azoxymethane-dependent andDclk1/APCfl/flmurine models of colitis-associated cancer.ResultsDSS colitis reproducibly led to colonic tumors in both mouse models of colitis-associated cancer. In contrast, all other forms of colitis did not lead to cancer. When compared with the colitis not associated with tumorigenesis, DSS colitis was characterized by significantly increased CD11b+F4/80+Ly6Chighmacrophages and CD11b+Ly6G+neutrophils. Interestingly, depletion of the CD11b+F4/80+Ly6Chighmacrophages inhibited tumorigenesis, whereas depletion of CD11b+Ly6G+neutrophils had no effect on tumorigenesis. Furthermore, the macrophage-derived cytokines interleukin-1β, tumor necrosis factor–α, and interleukin-6 were significantly increased in DSS colitis and promoted stemness of Dclk1+tuft cells that serve as the cellular origin of cancer.ConclusionsWe have identified CD11b+F4/80+Ly6Chighmacrophages as key mediators of cancer initiation in colitis-associated cancer. Development of new therapies that target these cells may provide an effective preventative strategy for colitis-associated cancer.