Effects of dietary retinoic acid on skin papilloma and carcinoma formation in female SENCAR mice

Abstract

Previously we have shown that dietary retinoids are essential for papilloma formation induced by either an initiation-promotion or a complete skin carcinogenesis protocol. The present study was conducted to further determine the effect of dietary retinoic acid (RA) on papilloma formation and the conversion of papillomas to carcinomas. Skin tumors were induced in 3 week old female SENCAR mice by an initiation-promotion protocol with one application of 20 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA), followed by 20 weekly applications of 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice were fed RA at one of the three doses: 0.3 (nutritionally marginal dose), 3 (near physiological) and 30 (pharmacological) micrograms/g of diet. Mice fed 30 micrograms of RA/g of diet had the same survival rate as the other two groups despite a lower body weight and all three groups had similar papilloma incidence, which reached 100% at age 18 weeks. Mice fed 3 micrograms of RA/g of diet had the highest papilloma yield (approximately 14 papillomas/mouse) of all groups and it peaked between weeks 18 and 38 of age. These papillomas later regressed such that mice from all three groups had about the same papilloma yield at week 44 of age. Mice fed 30 micrograms of RA/g of diet failed to develop any visible carcinoma, while mice fed 0.3 or 3 micrograms/g showed 1.9% conversion of papillomas to carcinomas. Therefore, dietary RA at 30 micrograms/g of diet inhibited the conversion of papillomas to carcinomas without affecting papilloma incidence. In addition, dietary RA at 30 and 0.3 micrograms/g of diet lowered papilloma yield.

In vivo long‐term effects of retinoic acid exposure in utero on induced hyperplastic epidermal foci in murine skin

“…RA and its analogues (retinoids) are used in the therapy of dermatological 5,6 and neoplastic diseases, 7 although their clinical usefulness is limited by their proven teratogenic potential 8–10 . Retinoids have been shown to be effective in the prevention of skin cancer 7 in different animal models, following either topical application 11 or oral administration 12,13 . However, there appears to be nothing known about the in vivo long‐term effects on skin carcinogenesis after prenatal RA exposure in mice.…”

“…[8][9][10] Retinoids have been shown to be effective in the prevention of skin cancer 7 in different animal models, following either topical application 11 or oral administration. 12,13 However, there appears to be nothing known about the in vivo long-term effects on skin carcinogenesis after prenatal RA exposure in mice.…”

Retinoid Receptors and Keratinocytes

“…Studies in mouse models as well as in vitro culture systems show that the proliferation of tumor cells is more sensitive to RA than of normal cells (Fountzilas, 1994). Dietary RA inhibits malignant conversion of skin papillomas to carcinomas induced by a two-stage carcinogenesis protocol in mice (De Luca et al, 1993). Long-term oral administration of 13-cis-RA reduced tumor formation in patients with Xeroderma pigmentosum (Kraemer et al, 1988).…”

Lutein, a Nonprovitamin A, Activates the Retinoic Acid Receptor to Induce HAS3-Dependent Hyaluronan Synthesis in Keratinocytes

“…7) It has been reported that high doses of -carotene substantially reduced the malignant conversion of papillomae to carcinomas as well as retinoic acid. 8,9) Because both provitamin A carotenoids and retinoids are used as potential protective agents in tumor formation, the molecular mechanisms of the action of carotenoids is probably mediated at least in part by retinoic acid.Topical treatments of retinoic acid have been found to be beneficial to photodamaged skin. 10,11) Retinoic acid inhibits UV-caused loss of procollagen synthesis, 12) the induction of matrix metalloproteinases, 13) and the tortuosity of elastic fibers.…”

“…7) It has been reported that high doses of -carotene substantially reduced the malignant conversion of papillomae to carcinomas as well as retinoic acid. 8,9) Because both provitamin A carotenoids and retinoids are used as potential protective agents in tumor formation, the molecular mechanisms of the action of carotenoids is probably mediated at least in part by retinoic acid.…”