Objectives: 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.
Materials and methods: 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.
Results: 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.
Conclusion: 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.
Keywords: CXCL1; Cancer-associated fibroblasts; IL-1β; Matrix metalloproteinase 1; Neoplasm invasiveness; Oral squamous cell carcinoma; Survival rate.
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