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Cell Proliferation and Promoting Action in Skin Carcinogenesis¹

Department of Pathology, University of Toronto, School of Medicine, 100 College Street, Toronto, Ontario, M5G 1L5, Canada

The changes induced in the thickness, number of nucleated cell layers, and mitotic index of mouse interfollicular epidermis by various doses of ethylphenylpropiolate (EPP) or turpentine were measured and their promoting activity was tested. Doses of EPP or turpentine able to induce marked cell proliferation and hyperplasia of the epidermis were found to have minimal or no promoting activity. Experiments in which EPP or turpentine were applied to mouse skin [weekly after four weekly applications of a promoting dose of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or weekly 72 hr after treatment with TPA] show that, contrary to what would be expected if a summation of the effects of the promoter and the hyperplastic agents took place, EPP and turpentine have an inhibtory effect on the promoting activity of TPA. These findings show that induction of cell proliferation and hyperplasia of the epidermis is not sufficient to ensure skin tumor promotion or the growth of the tumor cells into clinical neoplasms and suggest that cellular events other than cell proliferation are required to enable the expression of neoplastic transformation.

A comparative study of the time sequence of the early histological changes induced in mouse interfollicular epidermis by turpentine, cantharidin, and a nonpromoting dose of TPA shows that, after treatment with a nonpromoting dose of these agents, the increase in the number of nucleated cell layers of interfollicular epidermis occurs only after the increase in the mitotic index, comparable to that observed with EPP. The time sequence of these changes is clearly different from that observed after treatment with a promoting dose of TPA, in which the increase in number of nucleated cell layers precedes the increase in mitotic index. It suggests that stimulation of cells of the upper layers of the epidermis and reversal of their differentiation induced by a promoting dose of TPA is not induced by these nonpromoting agents, and indicates that basic differences exist between the cellular reprogramming induced by promoting and nonpromoting agents.

¹ This work was supported by Grant-in-Aid MA-4340 of the Medical Research Council of Canada.

Received 11/28/72. Accepted 1/10/74.