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...

Tumor progression may be controlled by various fragments derived from noncollagenous 1 (NC1) C-terminal domains of type IV collagen. We demonstrated previously that a peptide sequence from the NC1 domain of the ␣3(IV) collagen chain inhibits the in vitro expression of matrix metalloproteinases in human melanoma cells through RGD-independent binding to ␣ v ␤ 3 integrin. In the present paper, we demonstrate that in a mouse melanoma model, the NC1 ␣3(IV)-(185-203) peptide inhibits in vivo tumor growth in a conformation-dependent manner. The decrease of tumor growth is the result of an inhibition of cell proliferation and a decrease of cell invasive properties by down-regulation of proteolytic cascades, mainly matrix metalloproteinases and the plasminogen activation system. A shorter peptide comprising the seven N-terminal residues 185-191 (CNYYSNS) shares the same inhibitory profile. The three-dimensional structures of the CNYYSNS and NC1 ␣3(IV)-(185-203) peptides show a ␤-turn at the YSNS (188 -191) sequence level, which is crucial for biological activity. As well, the homologous MNYYSNS heptapeptide keeps the ␤-turn and the inhibitory activity. In contrast, the DNYYSNS heptapeptide, which does not form the ␤-turn at the YSNS level, is devoid of inhibitory activity. Structural studies indicate a strong structure-function relationship of the peptides and point to the YSNS turn as necessary for biological activity. These peptides could act as potent and specific antitumor antagonists of ␣ v ␤ 3 integrin in melanoma progression.Tumor growth and metastasis require cross-talk between tumor cells and host stromal cells as well as interactions between tumor cells and the environmental extracellular matrix (ECM), 1 especially basement membranes (1). Basement membranes are thin layers of a specialized ECM which not only provide a supporting structure for various cell types but also largely influence their physiologic behavior. Basement membrane components can also regulate neovascularization, an important process of tumor growth (2, 3). During tumor invasion, the reinforced interactions of tumor cells with basement membranes lead to a sequential proteolytic degradation of their components (4).The degradation of basement membrane macromolecules involves various proteolytic cascades, such as matrix metalloproteinases (MMPs) and the plasminogen activation system. MMPs are a large family of at least 25 members of zinccontaining endopeptidases that degrade ECM macromolecules. Among them, gelatinase A (MMP-2), gelatinase B (MMP-9), and stromelysin (MMP-3) have widely been shown to play a crucial role in the degradation of basement membranes during melanoma progression (5-7). MMPs are secreted as inactive zymogens. Their activation, a major step of tumor invasion, results from an imbalance between levels of tissue inhibitors of metalloproteinases (TIMPs) and the MMP activators, such as urokinase, plasmin, or membrane-type MMPs (MT-MMPs). MT-MMPs constitute a new subgroup of MMPs containing an additional domain for anchorage to th...

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