Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration
Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration
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DOI：
10.1126/scisignal.aba9157
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发表时间：
2020-07-21
影响因子：
7.3
通讯作者：
Slade, Daniel J.
中科院分区：
文献类型：
--
作者：
Casasanta, Michael A.;Yoo, Christopher C.;Slade, Daniel J.
具核梭杆菌与加速结直肠癌（CRC）有关，并在患者活检的转移性CRC细胞中发现。在这里，我们发现大肠癌细胞和共培养的免疫细胞的细菌入侵诱导差异细胞因子分泌，这可能有助于大肠癌转移。我们使用了一种改良的半乳糖激酶无标记基因缺失方法，发现F。nucleatum通过细菌表面粘附素Fap 2侵入培养的HCT 116 CRC细胞。反过来，Fap 2依赖性侵袭诱导促炎细胞因子IL-8和CXCL 1的分泌，这些细胞因子与CRC进展相关，并促进HCT 116细胞迁移。F. nucleatum感染的HCT 116细胞引起幼稚细胞迁移，这通过从条件培养基中耗尽CXCL 1和IL-8来阻断。抑制F.使用半乳糖、L-精氨酸、中和膜蛋白抗体或fap 2缺失的具核宿主细胞结合和进入。F.核质还诱导肿瘤微环境中免疫细胞的动员。然而，在中性粒细胞和巨噬细胞中，细菌诱导的细胞因子分泌是Fap 2独立的。因此，我们的研究结果表明，F。nucleatum直接和间接调节免疫和癌细胞信号传导和迁移。由于肿瘤中IL-8和CXCL 1产生的增加与转移潜能和细胞接种的增加、预后不良以及肿瘤相关巨噬细胞和成纤维细胞的募集增强有关，我们建议通过疫苗接种或新型半乳糖苷化合物抑制宿主细胞结合和侵袭可能是减少F.核相关的CRC转移。
Fusobacterium nucleatum is implicated in accelerating colorectal cancer (CRC) and is found within metastatic CRC cells in patient biopsies. Here, we found that bacterial invasion of CRC cells and cocultured immune cells induced a differential cytokine secretion that may contribute to CRC metastasis. We used a modified galactose kinase markerless gene deletion approach and found that F. nucleatum invaded cultured HCT116 CRC cells through the bacterial surface adhesin Fap2. In turn, Fap2-dependent invasion induced the secretion of the proinflammatory cytokines IL-8 and CXCL1, which are associated with CRC progression and promoted HCT116 cell migration. Conditioned medium from F. nucleatum-infected HCT116 cells caused naive cells to migrate, which was blocked by depleting CXCL1 and IL-8 from the conditioned medium. Cytokine secretion from HCT116 cells and cellular migration were attenuated by inhibiting F. nucleatum host-cell binding and entry using galactose sugars, L-arginine, neutralizing membrane protein antibodies, or fap2 deletion. F. nucleatum also induces the mobilization of immune cells in the tumor microenvironment. However, in neutrophils and macrophages, the bacterial-induced secretion of cytokines was Fap2 independent. Thus, our findings show that F. nucleatum both directly and indirectly modulates immune and cancer cell signaling and migration. Because increased IL-8 and CXCL1 production in tumors is associated with increased metastatic potential and cell seeding, poor prognosis, and enhanced recruitment of tumor-associated macrophages and fibroblasts, we propose that inhibition of host-cell binding and invasion, potentially through vaccination or novel galactoside compounds, could be an effective strategy for reducing F. nucleatum-associated CRC metastasis.