(1) Our work has shown that retinoid depletion inhibits skin tumorigenesis in female SENCAR mice in the two-stage model, using 7,12- dimethylbenz[a]anthracene (DMBA) as the initiator and 12-0-tetradecanoylphorbol-13-acetate (TPA) as the tumor promoter. We asked whether tumor formation by the complete tumorigenesis schedule also requires retinoic acid (RA). At week 9, 15% of mice fed the RA-- containing diet had developed skin tumors compared to 0% of mice fed the vitamin A-deficient diet. A tumorigenic response was observed upon switching the diet to the RA-containing one. We conclude that dietary retinoids are necessary for skin tumor formation in female SENCAR mice both by the two-stage and by the complete tumorigenesis schedules. (2) We have studied the distribution of a laminin binding protein of 37 kd (LBP) in normal mouse skin and in skin papillomas and carcinomas. In cultured keratinocytes, LBP is mainly cytoplasmic in basal cells and is found in the particulate fraction in differentiating cells. In vivo, LBP was found localized to the plasma membrane of differentiating epidermal cells mainly in the spinous and granular layers. A similar pattern was found in hyperplastic skin and in benign tumors either induced chemically or formed by grafting keratinocytes transfected with the v-ras(Ha) oncogene. In carcinomas LBP immunostaining was generally reduced and predominantly cytoplasmic. The data suggest a specific function for cell surface LBP in normal skin differentiation and an altered function in tumors. (3) RA induces differentiation of embryonal carcinoma cells (F9) in an irreversible manner. It also increases the production of extracellular matrix. Therefore, we investigated the effects of RA on F9 cell attachment to plastic, collagen and laminin. RA treatment enhanced F9 cell attachment to all three substrates. Moreover, laminin biosynthesis was markedly increased by RA, consistent with the finding by others that an RA-response element is present in the promoter sequence of the laminin gene. (4) We have characterized keratin gene expression under conditions of vitamin A-deficiency in hamster tracheal epithelium.
