Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma (original) (raw)

2012, Experimental cell research

Co-culture of periodontal ligament (PDL) fibroblasts and SCC-25 oral squamous carcinoma cells (OSCC), results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs). Paracrin circuits between CAFs and OSCC cells were hypothesized to regulate the gene expression of matrix remodeling enzymes in their co-culture, which was performed for 7 days, followed by analysis of the mRNA/protein expression and activity of metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and other relevant genes. Interleukin1-β, transforming growth factor-β1, fibronectin and αvβ6 integrin have shown to be involved in the regulation of the MMP and TIMP gene expression in co-culture of CAFs and tumor cells. In addition, these cells also cooperated in activation of MMP pro-enzymes. It is particularly interesting that the fibroblast-produced inactive MMP-2 has been activated by the tumor-cell-produced membrane-type 1 matrix metalloproteinase (MT1-MMP). The crosstalk between cancer- and the surrounding fibroblast stromal-cells is essential for the fine tuning of cancer cells invasivity.Summary of the suggested mechanism for the regulation of MMPs and TIMPs in the paracrine interplay between SCC-25 cells and fibroblasts. MMP-9 showed a tumor specific expression, regulated presumably by the fibronectin ITGA5B6 pathway. The ITGA5 was inducible in both SCC-25 and PDL fibroblasts in co-culture, but ITGB6 expression was tumor (SCC-25) specific. Based on a previous report [41], MMP-9 might be activated in the interaction with CD-44, and according to our gelatinase assay results, it remains bound with the tumor cells (A). The results of this study suggest that MMP-2 is secreted in its pro- (inactive-) form by CAFs surrounding the tumor cells, and at a lower extent also by the tumor cells themselves. Activation of MMP-2 either requires MT1-MMP localized on the SCC-25 cancer cells [31], or integrins, where the involvement of αv integrins (ITGA5) is expected (A).MMPs-1, 3 and TIMPs-1, 3 are produced in the PDL fibroblasts, and their expression might be regulated by inflammatory cytokines, including IL1-β produced by SCC-25 cells. The expression of TIMP-1 and TIMP-3 is 20–70-times higher than that of MMPs-1 and 3. The gene expression of MMP-1; 2, TIMP-1 and TIMP-3 was reduced by dexamethasone (DEX) (B).