Two-Stage Tumorigenesis of Dermal Melanocytes in the Back Skin of the Syrian Golden Hamster Using Systemic Initiation with 7, 12-Dimethylbenz(a)anthracene and Topical Promotion with 12-O-Tetradecanoylphorbol-13-acetate

Abstract

Tumor formation in terms of a two-stage mechanism after initiation with 7,12-dimethylbenz(a)anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) has been investigated in the Syrian golden hamster. Forty hamsters were initiated intragastrically by two applications of DMBA (50 mg/kg body weight each), followed by repeated topical promotion with 20 nmol TPA. In comparison with the corresponding control groups (no treatment, DMBA initiation only, and TPA treatment only), a clear-cut two stage mechanism was observed to operate in the perifollicular dermal melanocytes, leading to the early appearance of a high incidence of benign melanomas. Upon transplantation to normal hosts, these tumors rapidly underwent malignant growth and developed pigmented metastases in several organs. The morphology of melanoma formation resembled that described for DMBA-mediated melanocytic carcinogenesis in hamsters. The effect of TPA alone consisted of both a reactivation of nonfunctional melanocytes and an enhanced proliferation of the perifollicular melanocytic population. Thus, like epithelial two-stage carcinogenesis, pigmentary cell tumor promotion seems to be linked to a hyperplasia of the target cell under consideration.

Although evidence for two-stage carcinogenesis also exists for some internal organs (i.e., esophagus, forestomach, liver), the dorsal epidermis did not show morphological alterations worth mentioning, despite the relatively high amounts of TPA applied. Even epidermal hyperplasia, normally the consequence of TPA application to mammalian skin, could scarcely be observed. Consistent with the view of an interdependence of hyperplastic and promoting capacity of phorbol esters, no tumors developed in the dorsal epidermis. In accordance with recent findings on two-stage carcinogenesis mechanisms in various organs of different animal species, melanocytic two-stage carcinogenesis in the hamster not only strengthens the general validity of the principle but also provides an excellent model for the study of melanotic tumors closely resembling those of humans.