Fibronectin Matrix Remodeling in the Regulation of the Inflammatory Response within the Lung: An Early Step in Lung Cancer Progression

Abstract : Changes in tissue mechanics as well as increased tissue inflammation have been identified as contributory factors to the development of malignancies. These pathologies are characterized by extensive remodeling of extracellular matrix and increased tissue rigidity. Recent studies have shown that increased tissue rigidity is associated with the unfolding of the Type III domains of extracellular matrix fibronectin. During the previous funding year, we have addressed the hypothesis that changes in secondary structure of fibronectin present in the extracellular matrix drives chronic inflammation within the lung microenvironment. We found that a peptide representing a partially unfolded intermediate of the first Type III repeat of fibronectin (FnIII-1c) induced the expression of cytokines, CXCL1-3, IL-8 and TNF-alpha, by lung fibroblast cells. The increase in IL-8 expression was dependent on Toll-like receptor 2 and NFkB immunohistochemistry of squamous cell carcinoma of the lung revealed extensive stromal staining for IL-8 and fibronectin fibrils which were co-aligned with myofibroblasts. These data suggest that unfolding of FnIII domains secondary to myofibroblast-generated tension induces cytokine expression by stromal fibroblasts. These data implicate changes in fibronectin secondary structure in response to increased tissue rigidity as part of a feed forward mechanism driving chronic inflammation within the lung microenvironment.