In vivo long-term effects of retinoic acid exposure in utero on induced tumours in adult mouse skin

• Published in: Veterinary dermatology 2014-12, Vol.25 (6), p.538-e94
• Main Authors: García-Fernández, Rosa A., Pérez-Martínez, Claudia, García-Iglesias, Maria J.
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Acetic acid; Animals; Anthracene; Antineoplastic Agents - therapeutic use; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - prevention & control; Cell differentiation; Cell proliferation; Drug Administration Schedule; Epidermis; Female; Intrauterine exposure; Keratin; Keratoacanthoma - chemically induced; Keratoacanthoma - prevention & control; Male; Medical research; Mice; Oral administration; Papilloma; Papilloma - chemically induced; Papilloma - prevention & control; Pregnancy; Retinoic acid; Retinoids; Skin cancer; Skin Neoplasms - chemically induced; Skin Neoplasms - prevention & control; Tetradecanoylphorbol Acetate; Topical application; Treatment Outcome; Tretinoin - therapeutic use; Tumors
• ISSN: 0959-4493; 1365-3164
• DOI: 10.1111/vde.12149

Background Retinoic acid (RA) and its analogues (retinoids) are promising agents in skin cancer prevention following either topical application or oral administration. However, long‐term in vivo effects of RA on chemically induced hyperplastic epidermal foci in adult mouse skin have also been described, casting some doubt with regard to its chemopreventive activity. Hypothesis/Objectives To characterize chemically induced skin tumours and to investigate the in vivo long‐term action and preventive effect of RA on adult mouse skin carcinogenesis. Animals Fifty‐six adult Naval Medical Research Institute mice, exposed (n = 28) or not exposed (n = 28) to RA in utero. Methods Mice were treated with a standard two‐stage skin carcinogenesis protocol, which included an initiating application of 7,12‐dimethylbenz(a)anthracene followed by promotion with 12‐O‐tetradecanoylphorbol 13‐acetate. Results Retinoic acid administered to pregnant mice showed a long‐term inhibitory action on cell differentiation and development of chemically induced tumours on the adult skin of their offspring, as well as a stimulatory effect on cell proliferation and expression of an early marker of malignant progression (keratin 13). Conclusions and clinical importance The results suggest that RA exposure in utero confers long‐lasting effects on adult mouse skin carcinogenesis. These include chemopreventive activity (reduced number of tumours), as well as enhancement of squamous papilloma progression, which appears to be due to enhanced keratinocyte proliferation and suppression of epidermal maturation. The clinical significance of these findings is not known for other routes of RA administration at this time. Résumé Contexte L'acide rétinoïque (RA) et ses analogues (rétinoïdes) sont des agents prometteurs de la prévention des cancers cutanés suite à une application topique ou à une administration orale. Cependant, les effets à long terme in vivo de l' RA sur des foyers d'hyperplasie épidermique induits chimiquement sur la peau de souris adulte ont également été décrits, laissant des doutes sur leur activité chimiopréventive. Hypothèses/Objectifs Définir les tumeurs cutanées chimio‐induites et identifier l'action à long terme in vivo et l'effet préventif de l'RA sur la carcinogénèse de la peau de souris adulte. Sujets Cinquante‐six souris adultes de l'Institut de Recherche Médical Naval, exposées (n = 28) ou non exposées (n = 28) à l' RA in utero. Méthodes Les souris ont été traitées avec un