Centre de Recherche des Cordeliers, Equipe Labellisée Par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
Metabolomics and Cell Biology Platforms, Villejuif, France.
Oncoimmunology. 2023 Jul 21;12(1):2237354. doi: 10.1080/2162402X.2023.2237354. eCollection 2023.
Formyl peptide receptor-1 (FPR1) is a pattern recognition receptor that is mostly expressed by myeloid cells. In patients with colorectal cancer (CRC), a loss-of-function polymorphism (rs867228) in the gene coding for FPR1 has been associated with reduced responses to chemotherapy or chemoradiotherapy. Moreover, rs867228 is associated with accelerated esophageal and colorectal carcinogenesis. Here, we show that dendritic cells from mice exhibit reduced migration in response to chemotherapy-treated CRC cells. Moreover, mice are particularly susceptible to chronic ulcerative colitis and colorectal oncogenesis induced by the mutagen azoxymethane followed by oral dextran sodium sulfate, a detergent that induces colitis. These experiments were performed after initial co-housing of mice and wild-type controls, precluding major Fpr1-driven differences in the microbiota. Pharmacological inhibition of Fpr1 by cyclosporin H also tended to increase intestinal oncogenesis in mice bearing the mutation, and this effect was reversed by the anti-inflammatory drug sulindac. We conclude that defective FPR1 signaling favors intestinal tumorigenesis through the modulation of the innate inflammatory/immune response.
甲酰肽受体 1（FPR1）是一种模式识别受体，主要由髓样细胞表达。在结直肠癌（CRC）患者中，编码 FPR1 的基因中的功能丧失性多态性（rs867228）与对化疗或放化疗的反应降低有关。此外，rs867228与食管和结直肠癌的加速发生有关。在这里，我们表明，对化疗处理的 CRC 细胞的反应中， 小鼠的树突状细胞的迁移减少。此外， 小鼠特别容易受到诱变剂氧化偶氮甲烷（azoxymethane）诱导的慢性溃疡性结肠炎和结直肠肿瘤发生的影响，随后是口服葡聚糖硫酸钠（dextran sodium sulfate），这是一种诱导结肠炎的清洁剂。这些实验是在 小鼠和野生型对照最初共同饲养之后进行的，排除了主要由 Fpr1 驱动的微生物群差异。环孢素 H 对 Fpr1 的药理学抑制也倾向于增加携带 突变的小鼠的肠道肿瘤发生，而这种作用被抗炎药舒林达逆转。我们得出结论，FPR1 信号传导的缺陷通过调节先天炎症/免疫反应有利于肠道肿瘤发生。
