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First published online 3 January 2006
doi: 10.1242/jcs.02738
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Research Article |
1 Division of Cancer Biology and Tissue Engineering, Department of Oral and Maxillofacial Pathology, School of Dental Medicine, Tufts University, 55 Kneeland Street, Boston, MA 02111, USA
2 German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3 Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA
Author for correspondence (e-mail: jonathan.garlick{at}tufts.edu)
Accepted 5 October 2005
Much remains to be learned about how cell-cell and cell-matrix interactions are coordinated to influence the earliest development of neoplasia. We used novel 3D human tissue reconstructs that mimic premalignant disease in normal epidermis, to directly investigate how loss of E-cadherin function directs conversion to malignant disease. We used a genetically tagged variant of Ha-Ras-transformed human keratinocytes (II-4) expressing dominant-interfering E-cadherin fusion protein (H-2kd-Ecad). These cells were admixed with normal human keratinocytes and tumor cell fate was monitored in 3D reconstructed epidermis upon transplantation to immunodeficient mice. Tumor initiation was suppressed in tissues harboring control- and mock-infected II-4 cells that lost contact with the stromal interface. By contrast, H-2kd-Ecad-expressing cells persisted at this interface, thus enabling incipient tumor cell invasion upon in vivo transplantation. Loss of intercellular adhesion was linked to elevated cell surface expression of 
2, 3 and ß1 integrins and increased adhesion to laminin-1 and Types I and IV collagen that was blocked with ß1-integrin antibodies, suggesting that invasion was linked to initial II-4 cell attachment at the stromal interface. Collectively, these results outline a novel aspect to loss of E-cadherin function that is linked to the mutually interdependent regulation of cell-cell and cell-matrix adhesion and has significant consequences for the conversion of premalignancy to cancer.
Key words: E-cadherin, Integrin, Squamous cell carcinoma, 3D cultures, Premalignant
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