Matrix metalloproteinase-induced epithelial–mesenchymal transition: Tumor progression at Snail's pace

Matrix metalloproteinases (MMPs) are enzymes that digest components of the extracellular matrix (ECM) as well as cell surface receptors for soluble factors and junctional proteins involved in cell–cell and cell–ECM interactions. MMPs are involved in many physiological processes that require tissue remodeling but are also expressed in nearly all tumors, where they stimulate tumor growth, invasion, and metastasis. Previous studies have shown that expression of stromelysin-1/MMP-3 in the mammary glands of transgenic mice causes the production of invasive carcinomas; our recent investigations provide insight into how MMPs can promote the development of such tumors. We show that exposing mouse mammary epithelial cells to MMP-3 stimulates epithelial–mesenchymal transition (EMT), a phenotypic alteration in which epithelial cells acquire invasive mesenchymal characteristics. EMT is a necessary component of embryonic development, but acquisition of EMT characteristics by cancer cells facilitates invasion and metastasis. MMP-3-induced EMT involves induction of Snail, a transcription factor long studied for its role in physiological EMT but which is increasingly recognized as a factor involved in tumor progression and malignancy. In this review, we examine how MMPs and Snail function in tumor progression and how identification of an MMP-Snail signaling axis provides insight into new anticancer therapeutic strategies.