Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development

Abstract

Matrix metalloproteinases (MMPs) are a family of more than 28 enzymes that were initially identified on the basis of their ability to cleave most elements of the extracellular matrix (ECM) but have subsequently been found to be upregulated in nearly every tumor type. As digestion of the ECM is essential for tumor invasion and metastasis, MMPs have been studied for their role in these later stages of tumor development. More recently, exposure to these enzymes has been found to impact cellular signaling pathways that stimulate cell growth at early stages of tumor progression. MMPs have also been found to cleave intracellular targets and so inducing mitotic abnormalities and genomic instability. Emerging evidence indicates that tumor-associated MMPs can also stimulate processes associated with epithelial-mesenchymal transition (EMT), a developmental process that is activated in tumor cells during cell invasion and metastasis. Investigations of potential therapeutic MMP inhibitors aimed at blocking the protumorigenic tissue alterations induced by MMPs have been complicated by the side effects associated with nonspecific inhibition of normal physiological processes; recent investigations have shown how delineation of the extracellular targets and intracellular signaling pathways by which MMP action on cancer cells can induce EMT provides insight into novel therapeutic targets. Here, we provide an overview of recent findings of MMP action in tumors and the mechanisms by which MMPs induce both phenotypic and genotypic alterations that facilitate tumor progression.

Stromelysin-1 (MMP-3) is a target and a regulator of Wnt1-induced epithelial-mesenchymal transition (EMT)

“…More recently, Orlichenko and Radisky, have shown a similar effect for MMP-9 but not MMP-2. 36 We did not observe changes in Snail expression in C57MG and C57MG/Wnt1 cells in the absence or presence of AG3340 (data not shown) suggesting therefore a different mechanism. 37,38 The mechanism by which MMP-3 regulates Wnt signaling in C57MG cells is presently unknown but currently investigated in our laboratory.…”

Podoplanin promotes cell migration via the EGF-Src-Cas pathway in oral squamous cell carcinoma cell lines

“…MMPs, which are secreted from both tumor and/or stroma cells, play a role in tumor invasion and metastasis by degrading the extracellular matrix (ECM) surrounding the tumor, especially the basement membranes (28). Emerging evidence indicates that MMPs can stimulate processes associated with EMT to enhance tumor cell invasion and metastasis potential (29). Most reports have suggested that predominant expression of MMP-2, -3 and -9 proteins is correlated with a poorer prognosis (30).…”

Curcumin blocks CCL2-induced adhesion, motility and invasion, in part, through down-regulation of CCL2 expression and proteolytic activity

“…As a class of proteins, MMP proteases have essential roles in the regulation of invasion, as well as important roles in motility and adhesion, through their ability to degrade extracellular matrix (ECM) proteins (33). While important in the healing response, MMP proteins are often de-regulated in cancers and can lead to increased invasion and metastasis (33). We observed, through zymography, that CCL2 increased MMP-9 activity, but not MMP-2 in PC-3 cells and this up-regulation was blocked by curcumin (Fig.…”