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Matrix Metalloproteinase–induced Fibrosis and Malignancy in Breast and Lung

¹ Mayo Clinic Cancer Center, Jacksonville, Florida

Correspondence and requests for reprints should be addressed to Derek Radisky, Ph.D., Mayo Clinic Cancer Center, Griffin Cancer Research Building, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: radisky.derek{at}mayo.edu

ABSTRACT

Fibrosis is a pathological condition in which tissue structure is disrupted by production of excess extracellular matrix (ECM), and chronic tissue fibrosis is associated with tumor development. Myofibroblasts are the principal mediators of fibrosis, producing abundant ECM as well as inflammatory and angiogenic factors. Myofibroblasts are also abundant in tumor stroma, where they facilitate tumor growth and progression. Matrix metalloproteinases (MMPs), enzymes that degrade and remodel the ECM, are believed to play a critical role in the development of fibrotic tissue, though the mechanism by which this occurs is unclear. Expression of MMP-3 in mammary epithelial cells of transgenic mice stimulates development of fibrosis and subsequent tumor formation. We have recently determined that exposure of mammary epithelial cells to MMP-3 induces a specialized form of epithelial–mesenchymal transition in which the cells acquire myofibroblast-like characteristics and that this process is dependent upon the generation of cellular reactive oxygen species (ROS). New data from culture models in which MMPs are inducibly expressed in human lung cell lines, and transgenic mouse models in which MMPs are inducibly expressed in lung alveolar epithelial cells, suggest that similar processes likely exist in the lung.

Key Words: matrix metalloproteinases • epithelial–mesenchymal transition • breast • fibrosis