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

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 integral receptors α3β1, α5β1, α6β4, the Mr 67,000 laminin receptor (67LR) laminin-binding protein, and the secreted matrix protein laminin are strictly regulated during differentiation of mouse epidermis. While a604 and α5β1 are polarized to the basal surface of basal cells in contact with the basement membrane, α3β1 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 α3β1 and α5β1 as well as the non-integrin 67LR are sequentially down-regulated in the progression from benign to malignant, while α6β4 is the predominant receptor expressed in the carcinomas. Tumor expression of α6β4 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 α6β4 negative cells. The predominance of α6β4 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.