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Cell migration requires precise control, which is altered or lost when tumor cells become invasive and metastatic. Although the integrity of cell-cell contacts, such as adherens junctions, is essential for the maintenance of functional epithelia, they need to be rapidly disassembled during migration. The transmembrane cell adhesion protein E-cadherin and the cytoplasmic catenins are molecular elements of these structures. Here we demonstrate that epithelial cell migration is accompanied by tyrosine phosphorylation of ␤-catenin and an increase of its free cytoplasmic pool. We show further that the protein-tyrosine phosphatase LAR (leukocyte common antigen related) colocalizes with the cadherincatenin complex in epithelial cells and associates with ␤-catenin and plakoglobin. Interestingly, ectopic expression of protein-tyrosine phosphatase (PTP) LAR inhibits epithelial cell migration by preventing phosphorylation and the increase in the free pool of ␤-catenin; moreover, it inhibits tumor formation in nude mice. These data support a function for PTP LAR in the regulation of epithelial cell-cell contacts at adherens junctions as well as in the control of ␤-catenin signaling functions. Thus PTP-LAR appears to play an important role in the maintenance of epithelial integrity, and a loss of its regulatory function may contribute to malignant progression and metastasis.The cadherins represent a family of transmembrane receptors that mediate homophilic, Ca 2ϩ -dependent cell-cell adhesion. In epithelial cells, the members of this family, such as the classical E-, N-, and P-cadherins, are primarily found at the adherens junctions of adjacent cells (1). ␤-Catenin as well as plakoglobin (␥-catenin) associate directly with the highly conserved cytoplasmic domain of classical cadherins in a mutually exclusive manner (2, 3). The cadherin-catenin complex is linked via ␣-catenin either directly (4) or indirectly to the actin filament network via the actin-binding proteins ␣-actinin or vinculin (5, 6). The association of the cadherin-catenin complex with the cytoskeleton is essential for tight cell-cell interaction.Nevertheless, cadherin/catenin-mediated cell-cell contacts have to be highly dynamic because, particularly during embryonic development or wound healing, adherens junctions have to be rapidly disassembled and reassembled (7). Down-regulation of cadherins results in the separation of neighboring cells, a phenomenon that is observed during embryonic development at the epithelial-mesenchymal transition (EMT) 1 of forming mesoderm (8) as well as in tumor cells, allowing their invasion and dissemination throughout the body (9). During epithelialmesenchymal transition, cells transiently lose their epithelial features and acquire a fibroblastoid morphology (10). The critical importance of an intact cadherin-catenin complex is underscored by the observation that down-regulation of any of its components resulting in the loss of the tumor-suppressive actions of adherens junctions correlates with tumor invasion and metastasis (11...

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The first bioengineered, autologous, dermo-epidermal skin grafts are presently undergoing clinical trials; hence, it is reasonable to envisage the next clinical step at the forefront of plastic and burn surgery, which is the generation of autologous skin grafts that contain vascular plexuses, preformed in vitro. As the importance of the blood, and particularly the lymphatic vascular system, is increasingly recognized, it is attractive to engineer both human blood and lymphatic vessels in one tissue or organ graft. We show here that functional lymphatic capillaries can be generated using three-dimensional hydrogels. Like normal lymphatics, these capillaries branch, form lumen, and take up fluid in vitro and in vivo after transplantation onto immunocompromised rodents. Formation of lymphatic capillaries could be modulated by both lymphangiogenic and anti-lymphangiogenic stimuli, demonstrating the potential usefulness of this system for in vitro testing. Blood and lymphatic endothelial cells never intermixed during vessel development, nor did blood and lymphatic capillaries anastomose under the described circumstances. After transplantation of the engineered grafts, the human lymphatic capillaries anastomosed to the nude rat's lymphatic plexus and supported fluid drainage. Successful preclinical results suggest that these skin grafts could be applied on patients suffering from severe skin defects.

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