(1) Excess dietary (30 microg/g) retinoic acid (RA) specifically inhibited carcinoma formation (100%) in the two-stage model (DMBA-TPA) of skin carcinogenesis in SENCAR mice. Papilloma formation in these mice was not inhibited compared to groups fed RA at subphysiological (0.3 microg) and physiological levels (3 microg/g diet). The provitamin A compound beta-carotene at high dietary concentration (600 microg/g) enhanced papilloma yield, but inhibited carcinoma yield compared to groups fed diets of 6 and 60 microg/g. These data suggest that dietary retinoids and carotenoids inhibit the conversion step from papilloma to carcinoma in mouse skin. (2) In an analysis of benign and malignant skin tumors induced by chemical carcinogens or oncogene transduction, we found that the integrin receptors alpha3beta1 and `5~1 as well as the non-integrin 67LR are sequentially down-regulated in the progression from benign to malignant, while alpha6beta4 is the predominant receptor expressed in the carcinomas. The changes in matrix receptors are linked to appearance of keratin 13 in suprabasal regions, but always in `6~4 negative cells. The predominance of alpha6beta4 in the proliferating cells during progression is associated with decreased expression of keratin 13 in carcinomas. (3) Studies in hamster tracheal epithelium showed that the expression of the laminin binding protein 67LR decreased as the epithelium changed from pseudostratified to stratified. In contrast, immunofluorescence studies did not show a decrease either in the `6 integrin subunit, which was localized in the basal aspect of basal cells, or in laminin. Functional assays demonstrated that tracheal cells obtained from RA- tracheas displayed reduced attachment to laminin compared to RA+ cells. (4) Transglutaminases function in programmed cell death. RA induced TG activity and cell adhesion in NIH-3T3 cells but failed to stimulate the low basal TG of v-Ha-ras cells which also display very poor adhesiveness. These data would suggest that v-Ha-ras interferes with apoptosis and renders the cells refractory to RA and that TG may be involved in cell adhesiveness.
