Reciprocal activation of cancer-associated fibroblasts and oral squamous carcinoma cells through CXCL1

Crosstalk between cancer cells and carcinoma-associated fibroblasts (CAFs) is known to be involved in various aspects of tumor biology, including during invasion. Using oral squamous cell carcinoma (OSCC) cells as a model, we examined whether and how CAFs respond to inflammatory signals to influence cancer cell migration and invasion. Chemokine signatures within the human HNSCC datasets from The Cancer Genome Atlas (TCGA) were analyzed together with tissue assessment using immunohistochemical staining (IHC) and real-time PCR. A co-culture system was used to identify reciprocal effects exerted by CAFs and cancer cells upon one another. Recombinant CXCL1, CXCL1 neutralizing antibodies, and CXCR2 antagonist were used to confirm CXCL1/CXCR2 axis-mediated cell behaviors. Analysis of the TCGA dataset revealed that CXCL1 is associated with poor survival, and IHC demonstrated CXCL1 is highly expressed in OSCC stromal cells. Moreover, real-time PCR showed that in addition to CXCL1, IL-1β and CXCR2 are also highly expressed in OSCC and IL-1β mRNA levels positively correlate with CXCL1 expression. Furthermore, CAFs co-cultured with SAS, a poorly differentiated OSCC cell line, or stimulated with IL-1β exhibit increased CXCL1 secretion in an NF-κB-dependent manner. Treatment of SAS cells with CAF-conditioned medium or CXCL1 increased their invasion and migration capabilities, indicating a reciprocal activation between CAFs and cancer cells. Moreover, CXCL-1 upregulated matrix metalloprotease-1 (MMP-1) expression and activity in CAFs. The induction of IL-1β following CXCL1 stimulation of CAFs mediates cancer cell invasion, and there is a reciprocal dependency between CAFs and cancer cells in the OSCC microenvironment.