Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression.

PURPOSE

Carcinoma-associated fibroblasts (CAFs) in tumor stroma play an important role in tumor progression and have been associated with a poor prognosis in oral squamous cell carcinoma (OSCC). However, how CAFs influence OSCC malignancy and whether normalizing CAFs inhibits cancer progression remain unclear.

EXPERIMENTAL DESIGN

The relationship between the expression of Galectin-1 (Gal-1) and alpha-smooth muscle actin (α-SMA, a CAF marker) in OSCC patient samples and primary cultured CAFs was examined by quantitative real-time PCR, Western blotting, and immunofluorescence. To examine the effect of Gal-1 on CAF activation and CAF-mediated tumor invasion and migration in vitro, Gal-1 expression was knocked down by small hairpin RNA. Finally, cancer cells and CAFs were coimplanted into SCID mice to evaluate the effect of Gal-1 on CAF-modulated tumor progression in vivo.

RESULTS

Gal-1 expression is positively associated with α-SMA in the stroma of OSCC specimens. Gal-1 knockdown decreases activated CAF characteristics, resulting in a decrease in α-SMA expression and extracellular matrix protein production. Notably, blocking Gal-1 expression significantly inhibits CAF-conditioned medium-induced tumor cell migration and invasion, possibly by reducing the production of monocyte chemotactic protein-1 (MCP-1/CCL2). MCP-1 induces the migration of OSCC cells by binding to the receptor CCR2; adding an MCP-1 antibody to CAF-conditioned medium that inhibits the interaction between MCP-1 and CCR2 abolishes migration. Finally, we found that Gal-1 knockdown in CAFs significantly reduces CAF-augmented tumor growth and metastasis in vivo.

CONCLUSIONS

Our findings demonstrate that Gal-1 regulates CAF activation and indicate that targeting Gal-1 in CAFs inhibits OSCC metastasis by modulating MCP-1 expression.