Mechanism of Experimental Tumorigenesis. VI. Ultrastructural Alterations in Mouse Epidermis Caused by Locally Applied Carcinogen and Dipole-Type Tumor Promoter2

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Abstract
An electron microscopic study of the effect of locally applied 7,12-dimethylbenz[a]anthracene (DMBA) and 3-methylcholanthrene (MCA) on the inter-follicular epidermis (IFE) of the back of the mouse was made. The pattern appeared to agree with that seen with the light microscope. Thus in light and electron microscopy, the hyperplastic response of the IFE that was caused by DMBA and MCA was totally different from and opposite to that of a locally applied dipole-type tumor promoter. Characteristic effects were: (a) abnormalities in cell surface-to-cell surface contact in which combined light and electron microscopy indicate disturbances in detachment of epidermal cells; (b) development of new patterns in the cytoplasm of nucleated cells; (c) accumulation of electron-dense inclusion bodies within mitochondria—the most characteristic and most regularly occurring change; (d) disturbances in keratinization; (e) an increase in nucleo/cytoplasmic ratio; and (f) variabilities in degree and quality of the changes in different places of the treatment area. When the skin was exposed to effective or prolonged doses of carcinogen, all these alterations were pronounced and the changes were easily reproducible. There was neither a reversion of the epidermal cells to normal basal cells nor to less-differentiated cell types; instead new cell types developed. Since related patterns were also evident in light microscopy on paraffin sections, the changes had arisen intra vitam. The nature and pattern of the alterations, by DMBA, by MCA, and by dipole-type tumor promoters, may clarify the regression mechanism of benign, regularly formed skin papillomas.