Fusobacterium nucleatum is implicated in the acceleration of colorectal cancer (CRC), yet the mechanisms by which this bacterium modulates the tumor microenvironment remain understudied. Here we show that binding and cellular invasion of CRC cells selectively induces the secretion of the pro-inflammatory and metastatic cytokines IL-8 and CXCL1, which we then show induces robust migration of HCT116 cancer cells. Next, we demonstrate that cytokine signaling by cancer cells is largely driven by invasion coordinated by the surface adhesin Fap2. By contrast, we show that F. nucleatum induced secretion of CCL3, CXCL2, and TNFα cytokines from neutrophils and macrophages is Fap2 independent. Finally, we show that inhibiting F. nucleatum host-cell binding and entry using galactose sugars, neutralizing membrane antibodies, and deletion of the fap2 gene, lead to attenuated cytokine secretion and cellular migration. As elevated IL-8 and CXCL1 levels in cancer have been associated with increased metastatic potential and cell seeding, poor prognosis, and enhanced recruitment of tumor-associated macrophages and fibroblasts within tumor microenvironments, these data show that F. nucleatum directly and indirectly modulates immune and cancer cell signaling and migration. In conclusion, as viable F. nucleatum were previously shown to migrate within metastatic CRC cells, 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-induced signaling that drives metastasis and cancer cell seeding.
Cancer Cell Seeding Following Manipulation: An Ancient Concern According to the Traditional Iranian Medicine
