Fibroblasts and extracellular matrix differently modulate MMP activation by primary and metastatic head and neck cancer cells

Abstract

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.

Biomarkers of Epithelial-Mesenchymal Transition in Squamous Cell Carcinoma

“…IL-6 is overexpressed in HNSCC and is a biomarker of poor diseasespecific survival (Van Tubergen et al, 2011). Moreover, collagen I enhanced MMP-2 and MMP-9 secretion in both primary and metastatic cell lines (Koontongkaew et al, 2011). MMP-9 is a biomarker that contributes to invasion of HNSCC and is correlated with poor disease-specific survival (Mitra et al, 2008).…”

Mechanisms of Invasion in Head and Neck Cancer

“…[141][142][143] Integrin a v b6 is important to inducing protease expression. 142,144 Conversely, expression of specific ECM proteins, such as collagen I, 145 collagen XVI, 146,147 or laminin, 148 can enhance invasion. Binding of integrins to these matrix molecules triggers a signaling cascade, including integrin-linked kinase (ILK), 149 talin, 92,150 focal adhesion kinase (FAK), [151][152][153] and Src family members, 90,154 which then link to the MAP kinase and PI3 kinase pathways for stimulation of MMPs.…”

“…Binding of integrins to these matrix molecules triggers a signaling cascade, including integrin-linked kinase (ILK), 149 talin, 92,150 focal adhesion kinase (FAK), [151][152][153] and Src family members, 90,154 which then link to the MAP kinase and PI3 kinase pathways for stimulation of MMPs. 82,145,149,154 It is unclear why both growth factor signaling and adhesion signaling are needed for invasion-the connection between adhesion and growth factor signaling in invadopod formation is an active area of investigation. [155][156][157][158][159] MicroRNAs THAT REGULATE HNSCC INVASION MicroRNAs (miRNAs) are a class of gene-expression regulators that often have altered expression in various human cancers, including HNSCC.…”

The protective effect of p16INK4a in oral cavity carcinomas: p16Ink4A dampens tumor invasion—integrated analysis of expression and kinomics pathways

“…Although both RTKs and NRTKs have been associated with head and neck cancers, NRTKs are often linked with integrin signaling, well known for affecting migration/invasion. 68,69 Our integrated network modeling approach confirmed distinct signaling networks at work in these cell lines despite the very similar phenotype. Further evaluation of the signaling cascades at work within these model systems will help elucidate the mechanism by which p16 INK4a promotes better outcomes and may also reveal novel targets for therapeutic development.…”