Membrane Type 1 Matrix Metalloproteinase Induces Epithelial-to-Mesenchymal Transition in Prostate Cancer

Abstract

By mining DNA microarray data bases at GenBank TM , we identified up-regulation of membrane type 1 matrix metalloproteinase (MT1-MMP) in human primary and metastatic prostate cancer specimens as compared with nonmalignant prostate tissues. To explore the role of up-regulated MT1-MMP in early stage cancer progression, we have employed a three-dimensional cell culture model. Minimally invasive human prostate cancer cells (LNCaP) were transfected with MT1-green fluorescent protein (GFP) chimeric cDNA as compared with GFP cDNA, and morphologic and phenotypic changes were characterized. GFP-expressing LNCaP cells formed multicellular spheroids with cuboidal-like epithelial morphology, whereas MT1-GFP-expressing cells displayed a fibroblast-like morphology and a scattered growth pattern in type I collagen gels. Cell morphologic changes were accompanied by decreased epithelial markers and enhanced mesenchymal markers, consistent with epithelial-to-mesenchymal transition. MT1-MMP-induced morphologic change and cell scattering were abrogated by target inhibition of either the catalytic domain or the hemopexin domain. We further demonstrated that MT1-MMP-induced phenotypic changes were dependent upon up-regulation of Wnt5a, which has been implicated in epithelial-to-mesenchymal transition. We conclude that MT1-MMP plays an important role in early cancer dissemination by converting epithelial cells to migratory mesenchymal-like cells.Most human cancers are epithelial in origin. Carcinoma progression is often accompanied by the loss of an epithelial phenotype and the acquisition of a fibroblastic or mesenchymal phenotype (epithelial-to-mesenchymal transition (EMT) 2 ).This transition has emerged as a critical step in the conversion of early stage cancer to invasive and metastatic cancer (1, 2). Turning an epithelial cell into a mesenchymal cell requires alterations in morphology, cellular architecture, adhesion, and migration. A molecular hallmark of EMT is the decrease or loss of expression of the adherens junction protein, E-cadherin, resulting in loss of cell-cell association and change of cell morphology. Decreased levels of E-cadherin and cytokeratins and acquisition of mesenchymal proteins like fibronectin and vimentin are indicative of a switch toward a mesenchymal dedifferentiated phenotype; these phenotypic changes result in enhanced cell motility and invasiveness (3). Enhanced production and activation of matrix metalloproteinases (MMPs), especially membrane type 1 MMP (MT1-MMP), have been described in most types of carcinoma, including commonly occurring prostate and breast cancer (4). High levels of MMPs in cancer tissues have been correlated with poor prognosis. MMPs have been linked with EMT through both autocrine and/or paracrine pathways (5). Secreted MMPs (e.g. MMP-2, -3, -9, and -28) have been associated with cancer cell EMT through various mechanisms (6 -8). Although MT1-MMP is capable of cleaving E-cadherin in transfected breast cancer cells (9), the effect of this cleavage on EMT has not been characte...

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

“…This in turn enables the mechanical changes necessary to drive proliferative and invasive responses (27). In certain model systems including studies in prostate cancer cells (42), MT1-MMP expression has even been shown to promote epithelial-mesenchymal transition, demonstrated by cells that display a more fibroblast-like, scattered growth pattern compared with controls (43). Significantly, the in vivo expression of MT1-MMP has been associated with increased SCC progression and invasion.…”

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

“…It has been shown that Wnt5a is upregulated at the transcriptional level in PCa by hypomethylation in the 5 0 -untranslated region and that three CpG sites were consistently methylated in normal tissues but not in primary PCa (Wang et al, 2007). It was also reported that membrane type 1-MMP is upregulated in PCa species and that membrane type 1-MMP-induced phenotypic changes are dependent on the expression of Wnt5a (Cao et al, 2008). It is intriguing to speculate Figure 4 Wnt5a stimulates cell migration and invasion by activating protein kinase C (PKC).…”

EMT, the cytoskeleton, and cancer cell invasion

“…Several reports demonstrate that the colocalization and cooperation of β1-integrin and MT1-MMP1 is necessary for cancer cell invasion into a collagen matrix and that both MT1-MMP and β 1 -integrins have important roles in EMT [119][120][121][122][123]. The localization of MT1-MMP to β 1 -integrins is an exocytic event dependent on the activity of the GTPase Rab8 [124].…”