Research ArticleHost-Microbe Interactions

Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration

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Science Signaling  21 Jul 2020:
Vol. 13, Issue 641, eaba9157
DOI: 10.1126/scisignal.aba9157

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Moved to metastasize by gut microbiota

Bacterial dysbiosis in the gut, particularly an increase in Fusobacterium nucleatum, is associated with colorectal cancer (CRC). Casasanta et al. found that CRC cell–resident F. nucleatum promotes proinflammatory cytokine secretion that stimulates tumor cell migration and invasion. Gene deletion revealed that F. nucleatum infection of HCT116 CRC cells required a membrane adhesin protein that did not mediate bacterial infection of immune cells. Infected CRC cells secreted the cytokines IL-8 and CXCL1 that promoted the invasive motility of infected and noninfected cells. The findings suggest that preventing F. nucleatum invasion of tumor cells may reduce bacterial-associated gut inflammation and metastatic progression in CRC patients.

Abstract

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 naïve 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.

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