Upregulation of MMPs by soluble E‐cadherin in human lung tumor cells

Abstract

Loss of E-cadherin/catenin mediated cell-cell adhesion and overexpression of matrix metalloproteinases (MMPs) are largely involved in tumor invasion. It has been recently shown that high levels of a soluble 80 kDa fragment of E-cadherin, resulting from a cleavage by MMPs, are found in serum and in urine from cancer patients. Additionally, this soluble E-cadherin (sE-CAD) promotes cell invasion into chick heart and into collagen type I gels. The aim of our study was to examine the mechanism of sE-CAD-induced cell invasion. Since MMPs play a crucial role in invasion, we looked for induction of MMPs by sE-CAD in noninvasive human lung tumor cells 16HBE. An induction of MMP-2, MMP-9 and MT1-MMP expression was observed both at the mRNA and at the protein level in the presence of sE-CAD (in conditioned medium form or in E-cadherin HAV peptide form). No induction of MMP-1, -3 and -7 or variation of the levels of their inhibitors, TIMP-1 and TIMP-2, were detected. The biologic relevance of the sE-CAD-induced MMP upregulation was tested by demonstrating that sE-CAD promotes in vitro cell invasion in a modified Boyden chamber assay. These data provide new insight into mechanisms of tumor invasion by ectodomain shedding of the cell-cell adhesion molecule E-cadherin. © 2003 Wiley-Liss, Inc. Key words: cancer progression; soluble E-cadherin; MMPs; cell invasionTumor cell invasion in the surrounding host tissue is a key event of the metastatic progression. This process requires dispersion of tumor cells from the primary tumor and infiltration of the stromal compartment.Tumor cell dispersion largely relies on the loss of homotypic cell-cell adhesion. The E-cadherin/catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Modifications in the expression or function of this complex result in a decrease of adhesive properties of the complex and, thus, E-cadherin is considered as an important invasion suppressor. 1-3 Indeed, several in vitro studies have shown a strong correlation between the defect of E-cadherin/catenin complex expression at the level of the cell surface and loss of both an epithelial phenotype and enhanced cell invasiveness. 4 -9 In addition, many in vivo studies have described a correlation between loss of E-cadherin or catenin expression or dysfunction of the complex and dedifferentiation, malignancy, tumor aggressiveness, metastasis, or a poor survival rate in several types of cancer including breast, gastric, liver, bladder, prostate, lung and colon carcinomas. 1,2,10 -12 Invasion through basement membranes and interstitial extracellular matrix requires the action of proteolytic enzymes. Among these enzymes, matrix metalloproteinases (MMPs) are able to degrade almost all of the extracellular matrix (ECM) components. Most MMPs are secreted as latent proenzymes that are extracellularly activated through proteolytic cleavage. The MMP activity is inhibited by TIMPs (tissue inhibitors of metalloproteinases), their major physiologic specific inhibitors...

Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E‐cadherin

“…[32][33][34][35] In a similar fashion, cultured BxPC-3 pancreatic cancer cells, which produce high levels of E-cadherin (data not shown), also constitutively release sE-CAD. Because neither the KLK7 transcript nor hK7 protein could be detected in BxPC-3 cells by RT-PCR or Western analysis (data not shown), respectively, the constitutive release of sE-CAD from this cell line must be dependent on the action of another protease(s) or mechanism.…”

MT1-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells

“…Motility and invasion of numerous cancer cell types is prevented by expression of the tumour-suppressor E-cadherin. Through its sequestration of the transcriptional co-activator b-catenin, E-cadherin inhibits Tcf/LEF transcriptional activation of numerous targets that contribute to a motile, invasive phenotype, including MT1 (Ara et al, 2000;Takahashi et al, 2002;Nawrocki-Raby et al, 2003a, b;Hazan et al, 2004;Hlubek et al, 2004;Munshi and Stack, 2006).…”

“…The inability of SKOV-3 and OVCAR-3 cells to invade 3-D collagen gels may relate to their E-cadherin expression (Kokenyesi et al, 2003). That MT1 expression is upregulated through b-catenin signalling may explain the reported inverse correlation between E-cadherin and MT1 expression (Ara et al, 2000;Takahashi et al, 2002;Nawrocki-Raby et al, 2003a, b;Hazan et al, 2004;Hlubek et al, 2004;Munshi and Stack, 2006). Therefore, we analysed cadherin expression to determine whether E-cadherin was associated with the absence of MT1 and cell invasion in SKOV-3 and OVCAR-3 cells.…”

“…Therefore, the impact of MT1 expression on motility, in addition to collagen I degradation, was evaluated. As elevated E-cadherin is known to suppress invasive behaviour of cancer cells and to negatively regulate MMP expression, including that of MT1 (Ara et al, 2000;Takahashi et al, 2002;Nawrocki-Raby et al, 2003a, b;Hazan et al, 2004;Hlubek et al, 2004;Munshi and Stack, 2006), we also assessed cadherin expression in these cell lines.…”

Nectin-4, a New Serological Breast Cancer Marker, Is a Substrate for Tumor Necrosis Factor-α-converting Enzyme (TACE)/ADAM-17

“…Overexpression of Nectin-4 does not alter the epithelial architecture of Madin-Darby canine kidney cell cysts embedded in a Matrigel matrix (data not shown). Recently, it has been shown that the E-cadherin-shed form was able to increase protease expression and invasive properties of lung tumor cells in vitro (43). Because Nectins are involved in leukocyte transmigration and diapedesis through endothelial cells, we can speculate that soluble Nectin-4 could take part in the process of tumor cell migration and invasion (7).…”