Abrogation of E-Cadherin-Mediated Adhesion Induces Tumor Cell Invasion in Human Skin-Like Organotypic Culture

The role of cell–cell adhesion in the transition from premalignancy to invasive cancer is not well understood. The purpose of this study was to determine how abrogation of E-cadherin-mediated adhesion influenced early neoplastic progression in tissues that mimic human, premalignant disease. To accom...

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Bibliographic Details
Published in:Journal of investigative dermatology 2003-11, Vol.121 (5), p.1182-1190
Main Authors: Margulis, Alexander, Andriani, Frank, Fusenig, Norbert, Hashimoto, Koji, Hanakawa, Yasushi, Garlick, Jonathan A.
Format: Article
Language:English
Subjects:
adherens junctions
basement membrane
Basement Membrane - pathology
Cadherins - physiology
Cell Adhesion
Cells, Cultured
Collagen Type IV - analysis
E-cadherin
Humans
Laminin - analysis
Neoplasm Invasiveness
Organ Culture Techniques
organotypic culture
Signal Transduction
Skin - pathology
tumor cell invasion
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Summary:The role of cell–cell adhesion in the transition from premalignancy to invasive cancer is not well understood. The purpose of this study was to determine how abrogation of E-cadherin-mediated adhesion influenced early neoplastic progression in tissues that mimic human, premalignant disease. To accomplish this, E-cadherin function was abrogated in a human cell line representing an early stage in the transformation process (HaCaT-II-4 cells) that was grown in three-dimensional, organotypic cultures with intact basement membrane. Before modification, this cell line showed a paucity of cell adhesion structures by ultrastructural and immunohistochemical analysis, whereas immunoblot studies demonstrated that expression and association of E-cadherin and catenins were not diminished when compared with normal keratinocytes. To further reduce functional E-cadherin, II-4 cells were infected with a dominant-negative, recombinant adenovirus, expressing E-cadherin lacking an extracellular domain (AdECadEC). AdECadEC infection resulted in loss of endogenous E-cadherin and completely disrupted II-4 cell adhesion, as seen by loss of β-catenin from II-4 cell junctions in monolayer culture. In three-dimensional cultures, AdECadEC-infected cells demonstrated disruption of tissue architecture, loss of cell–cell adhesion, and the invasion of individual tumor cells into the stroma. The induction of this invasive phenotype was associated with loss of basement membrane integrity, as seen by degradation of type IV collagen and laminin 5. These studies showed that loss of E-cadherin-mediated adhesion enabled acquisition of an invasive phenotype, suggesting that maintenance of intercellular adhesion and tissue organization plays a crucial part in suppressing the incipient stages of squamous cell cancer progression.
ISSN:0022-202X
1523-1747
DOI:10.1046/j.1523-1747.2003.12523.x