The advantages of epidermis of mice for the study of carcinogenesis have been briefly described. Since the epidermis of other species responds to the potent carcinogen, 9, 10-dimethyl-1, 2-benzanthracene (40), a comparison of the carcinogenic process in a variety of animals is possible. Many constituents of this tissue in the mouse have been quantitatively determined to ascertain the mechanism by which this tissue becomes carcinomatous. Of the minerals studied, the levels of iron, copper, zinc, and calcium were less in hyperplastic epidermis and in the carcinoma than in normal epidermis, but some experiments suggest that the drop in calcium, and perhaps other constituents, may be associated with altered cell types rather than with a change specific for pre-malignant epidermis. Investigations with radiocalcium suggest an alteration in the calcium binding complex at the cell surface of the transplantable squamous-cell carcinoma. Coman's studies indicate that the decreased adhesiveness of squamous carcinoma cells, which have a low calcium content, may play a role in the formation of metastasis.

The sebaceous glands appear to be important structures in the response of mice to methylcholanthrene, since the skin of new-born mice in which these structures are rudimentary do not respond to this carcinogen. Furthermore, adult skin treated with this carcinogen loses its sebaceous glands concomitantly with a drop in the content of phospholipid, total lipid, and cholesterol. Repeated application of the carcinogen leaves the epidermal cells without secretions from these glands and in a new chemical environment. Whether the disappearance of the sebaceous glands in other species is a prerequisite to cancer formation has not yet been decisively answered. In the total lipid of the epidermis during carcinogenesis there is a lipid-like substance which undergoes alteration at the onset of malignancy.

Of the water-soluble vitamins studied, pyridoxine, choline, inositol, and p-aminobenzoic acid increased in the carcinoma, while the biotin and ascorbic acid levels were not appreciably changed from that in epidermis. The rise in the level of choline and inositol may be associated with the increased amount of phospholipid in the tumor.

Mouse epidermis is characterized by a low activity of succinic dehydrogenase, cytochrome oxidase, and apyrase. In late hyperplastic epidermis only cytochrome oxidase is increased significantly, and this is the only cellular component found to date which changes prior to malignancy. In the carcinoma, the activity of apyrase, succinic dehydrogenase, and arginase are markedly increased, while that of cytochrome oxidase and cytochrome c are decreased.

The assay of twelve amino acids in the epidermis undergoing carcinogenesis revealed that their distribution in the carcinoma was quite similar to that found in hyperplastic epidermis, but the sum of the amino acids in these two stages of carcinogenesis was significantly increased over that of normal epidermis. Hyperplastic epidermis had larger amounts of free amino acids than did normal epidermis, while the carcinoma showed an over-all decrease in these constituents.

A survey of the many constituents determined in the epidermis of mice undergoing carcinogenesis reveals some very interesting changes from normal epidermis to the hyperplastic state and from the latter to the carcinoma. However, in hyperplastic epidermis it has been found that with but one exception, cytochrome oxidase in late hyperplasia, all the components change abruptly from the normal to and throughout the precancerous epidermis and abruptly from the latter to the carcinoma. As has been pointed out previously, all chemical analysis of hyperplastic epidermis represents pooled samples of large areas of treated epidermis, so that chemical alterations arising in the few actual premalignant areas are diluted with cells of the former. Only when procedures become available for ascertaining the actual epidermal foci which will give rise to carcinomas will it be possible to determine chemical alterations critical to the problem of neoplasia of epidermis. So even in a tissue such as epidermis, in which the experimental conditions for carcinogenesis can be rigidly controlled, assessment of chemical changes due to alterations in cell types from those characteristics of real pre-malignancy are most difficult to evaluate. Such conditions must certainly exist to an even greater degree in other organs or tissues where criteria for the pre-malignant state are even more difficult to establish and assess.

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