Head and neck squamous cell carcinoma (HNSCC) is a complex tissue that contains tumor cells and the surrounding stroma, which is populated by different types of mesenchymal cells and the extracellular matrix (ECM). Collectively, they are referred to as the tumor microenvironment (TME). Recent studies have shown that TME has a more profound influence on the growth and metastasis of HNSCC than was previously appreciated. Because carcinoma-associated fibroblasts (CAFs) are frequently observed in the stroma of the tumor, this review focuses on the potential role of tumor-CAFs interactions in progression of HNSCC. Tumor-CAFs crosstalk enhances the production of growth factors, cytokines, chemokines, matrix metalloproteinases (MMPs), and inflammatory mediators, which eventually facilitates tumor growth. In fact, factors and cells that do not support tumor growth are usually down regulated or mitigated in TME. Therefore TME may determine the fate of the tumors at the site of invasion and metastasis. For tumor cells that survive at these sites, stromal activation may serve to establish a supportive tumor stroma, fostering the outgrowth of the metastatic cells. The concept of tumor-stromal interactions and microenvironmental niche has profound consequences in tumor growth and metastasis and therefore, it's understanding will open up new strategies for the diagnosis, prognosis and therapy of HNSCC.

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Three heat-cured and three autopolymerized acrylic denture bases with different mixing proportions and/or processing methods were investigated for the amount of residual monomer content and methyl methacrylate (MMA) released into saliva after incubation during the first and second 24 hours after processing. A corresponding range of concentrations of MMA was also used to test for cell cytotoxicity using a culture of human oral fibroblasts. The results showed that the amount of residual monomer was dependent not only on the type of polymerization but also on the amount of liquid in the mixture ratio and the processing method. The acrylic resin that had the lowest residual monomer also released the smallest amount of MMA but resins which have higher residual monomer may not necessarily release higher amounts of MMA. MMA, tested in the same range of concentration as the MMA found leached from acrylic resin in this study, was found to be toxic in the cell culture. Therefore, it is recommended that dentists attempt to reduce the amount of leachable substances before insertion of new dentures. In addition, it is recommended that dentists advise their patients not to wear newly made dentures overnight, as this may cause mucosal irritation from the potential accumulation of leachable substances.

We have recently gained a remarkable understanding of the mutational landscape of head and neck squamous cell carcinoma (HNSCC). However, the nature of the dysregulated signaling networks contributing to HNSCC progression is still poorly defined. Here, we have focused on the role of the family of mitogen activated kinases (MAPKs), extracellular regulated kinase (ERK), c-Jun terminal kinase (JNK) and p38 MAPK in HNSCC. Immunohistochemical analysis of a large collection of human HNSCC tissues revealed that the levels of the phosphorylated active form of ERK1/2 and JNK were elevated in less than 33% and 16% of the cases, respectively. Strikingly, however, high levels of active phospho-p38 were observed in most (79%) of hundreds of tissues analyzed. We explored the biological role of p38 in HNSCC cell lines using three independent approaches: treatment with a specific p38 inhibitor, SB-203580; a retro-inhibition strategy consisting in the use of SB-203580 combined with the expression of an inhibitor-insensitive mutant form of p38α; and short-hairpin RNAs (shRNAs) targeting p38α. We found that specific blockade of p38 signaling significantly inhibited the proliferation of HNSCC cells both in vitro and in vivo. Indeed, we observed that p38 inhibition in HNSCC cancer cells reduces cancer growth in tumor xenografts and a remarkable decrease in intratumoral blood and lymphatic vessels. We conclude that p38α functions as a positive regulator of HNSCC in the context of the tumor microenvironment, controlling cancer cell growth as well as tumor-induced angiogenesis and lymphangiogenesis.

A genetically related pair of human head and neck cancer (HNSCC) cell lines derived from the same patient at different stages of disease was used to investigate the role of extracellular matrix, integrin, and CXCL12-CXCR4 receptor interactions and their signal pathways in MMP-2 and MMP-9 activation and cell invasion. We found that collagen I enhanced MMP-2 and MMP-9 secretion in both primary and metastatic HNSCC cells. Collagen I acted through α(2)β(1) integrin to activate tyrosine kinases, protein kinase C, ERK1/2, and p38, which in turn activated MMP-2 and MMP-9 production. The signaling function was also involved in the enhancement of cell invasion. Experiments using cocultures between live and fixed cells demonstrated that direct contact between tumor and fibroblast cells was required to activate MMP-2 and MMP-9 secretion in both tumor cells and fibroblasts. The augmentation appears specific for MMP-2. Fibroblasts seem to be responsible for the increased MMP-2 in the coculture. In addition, fibroblast or tumor cell-conditioned media upregulated the secretion of MMP-2 and MMP-9 in HNSCC cells. These findings indicate that autocrine and paracrine factors are involved in the augmented secretion of MMPs in coculture. We also found that CXCL12-enhanced HNSCC cell invasion through paracrine-activated CXCR4, which triggered MMP-dependent cell invasion. Together, our results suggest that cell-matrix and cell-cell interactions including autocrine and paracrine factors play important roles in the invasive behavior of HNSCC via upregulation of MMP-2 and MMP-9.

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This study evaluates the effects of gingival fibroblasts, type I collagen and autocrine/paracrine elements on cytokine expression in paired primary and metastatic human squamous cell carcinoma (HNSCC) cell lines. Additionally, the effects of IL-1alpha, IL-1beta, IL-6, TNF-alpha, TGF-beta and HGF on MMPs and cell invasion were investigated. RT-PCR results indicated the presence of mRNAs for IL-1alpha, IL-1beta, IL-6, TNF-alpha, and TGF-beta in primary and metastatic HNSCC cell lines but high expression of cytokines was not a prerequisite for metastatic cancer cells. HGF mRNA was not detected in the cancer cell lines. Co-culturing of HNSCC cells with fibroblasts caused increases in cytokine expression. Type I collagen and conditioned media derived from HNSCC cells or fibroblasts enhanced cytokine expression in the cancer cells. Cytokines also enhanced MMP-2 and MMP-9 enzymatic activities as well as HNSCC cell invasion. Our findings suggest that the interactions between cancer cells, the extracellular matrix and fibroblasts, as mediated by cytokines, play important roles in the progression of HNSCC.