Abstract
Retinoic acid (RA) was topically applied to the skin of Sencar mice during the promotion phase of specific tumor induction protocols that produce papillomas at low (12-O-tetradecanoylphorbol-13-acetate promoted, TPA) or high (mezerein-promoted) risk for premalignant progression and malignant conversion. RA consistently reduced the yield of papillomas and carcinomas in both protocols, but the frequency of malignant conversion in papillomas that emerged during RA treatment was not reduced. When TPA was reapplied after cessation of RA treatment, the number of papillomas increased 2-fold, suggesting that RA had not eliminated initiated cells. In vitro, RA prevented the emergence of transformed keratinocytes in an assay that mimics malignant conversion, suggesting that RA can suppress conversion if applied during the stage of premalignant progression. Examination of tumor markers at weeks 14 and 22 of the tumor-induction experiments in vivo indicated that papillomas evolving during RA treatment exhibited a phenotype of high progression risk, even in the TPA-promoted groups. In the majority of these tumors, the α6β4 integrin and retinoid X receptor a transcripts were detected suprabasally, indicating an advanced state of premalignant progression. RA-treated tumors also expressed higher levels of transcripts for transforming growth factor (TGF)-β1 and localized TGF-β1 peptide in the basal portions of the tumor fronds. Because up-regulated expression of TGF-β1 suppresses papilloma formation, these studies suggest a mechanism whereby RA can prevent papilloma eruption via a TGF-β intermediate, but papillomas resistant to RA may have altered TGF-β signaling and progress to carcinomas at an increased frequency.