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Extracellular Matrix Receptors and Mouse Skin Carcinogenesis: Altered Expression Linked to Appearance of Early Markers of Tumor Progression¹

Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Cancer Etiology [T. T., S. H. Y., A. G., L. M. D.] and Laboratory of Tumor Pathology [V. C., M. E. S.J, National Cancer Institute, and Laboratory of Developmental Biology, National Institute of Dental Research [Y. Y.], National Institutes of Health, Bethesda, Maryland 20892

Interaction of cells with the basement membrane is important for cell proliferation and differentiation. Disruption of the basement membrane is an early event during progression of benign tumors to cancer. Using the techniques of immunohistochemistry and immunofluorescence, we show that cell-matrix interactions via the cell surface integrin receptors 3ß1, 5ß1, 6ß4, the M_r 67,000 laminin receptor (67LR) lamininbinding protein, and the secreted matrix protein laminin are strictly regulated during differentiation of mouse epidermis. While 6ß4 and 5ß1 are polarized to the basal surface of basal cells in contact with the basement membrane, 3ß1 and the non-integrin 67LR are primarily detected in the cell periphery of suprabasal cells, where cell to cell contacts are found. Sequential changes in expression of matrix receptors occur following multistage carcinogenesis of mouse skin. In an analysis of benign and malignant skin tumors induced by chemical carcinogens or oncogene transduction, we found that 3ß1 and 5ß1 as well as the non-integrin 67LR are sequentially down-regulated in the progression from benign to malignant, while 6ß4 is the predominant receptor expressed in the carcinomas. Tumor expression of 6ß4 is not polarized and is dissociated from its colocalized normal partner bullous pemphigoid antigen, which remains restricted to the basement membrane. The changes in matrix receptors are linked to appearance of keratin 13 in suprabasal regions, but always in 6ß4 negative cells. The predominance of 6ß4 in the proliferating cells during progression is associated with decreased expression of keratin 13 in carcinomas. These results suggest that matrix interactions with its receptors are important determinants of ordered differentiation in normal skin and show characteristic alterations during carcinogenesis that parallel changes in differentiation of the tumors.

¹ This work was supported by a grant from Johnson & Johnson, Consumer Products corporation. T. T. is the recipient of a fellowship from the Israel Cancer Research Fund and the European Organization for Research and Treatment of Cancer.

² To whom requests for reprints should be addressed, at National Cancer Institute, Laboratory of Cellular Carcinogenesis and Tumor Promotion, Building 37, Room 3B25, Bethesda, MD 20892.

Received 12/ 4/91. Accepted 3/10/92.

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