The Initiating and Promoting Elements in Tumor Production

Abstract

Benzpyrene brings about neoplastic changes in rabbit epidermis much sooner than has been supposed. The long interval that elapses before visible growths appear is due in the main to the relatively slight power of the carcinogen to encourage multiplication of the cells it renders neoplastic. Yet some slight power of this sort it has. Methylcholanthrene has somewhat more but not nearly so much as tar. It may initiate neoplastic changes within less than 17 days, as compared with less than 10 days for tar, but tumors due to it do not ordinarily appear until months after those called forth by tarring. All three agents give rise to growths of essentially the same kinds, but most of those due to benzpyrene and methlycholanthrene remain for a long while small, dry, and indolent whereas many of the tar tumors are fleshy, vigorous, and rapidly enlarging,—differences wholly consequent on differences in the ability to promote growth. Such ability is an important element in the effectiveness of carcinogens. Tar and the polycyclic hydrocarbons cause many more cells to become tumor cells than give rise to visible growths. Benzpyrene is as effective in initiating neoplastic changes when dissolved in mineral oil as when in benzene, yet no tumors result from it until months after the benzene solution has given rise to them, the reason being that when in oil it is almost devoid of influence to encourage cell proliferation. Benzene itself has a very slight influence of the sort. Solvents may determine not only whether carcinogens initiate neoplastic change but may condition to a crucial degree the influence of these agents to encourage tumor formation. Rabbit epidermis is much more responsive to carcinogenic influences than that of the mouse, as measured in terms of time taken to elicit benign neoplasms. Even benzene will call forth these growths from rabbit skin. In appraising the relative responsiveness to carcinogens of various animal species it is essential to reckon in terms of cells of identical type.

The Life and Progression of Induced Skin Tumors in Mice

“…The horn seen grossly was of keratin and debris. These conical tumors have not been previously described, though they are similar to the " papillomes invagines " seen by Bang (1922) in tarred mice, and to the " frill horns " and " carcinomatoids" described by Rous and Kidd (1939) and by Friedewald and Rous (1944) in tarred and in benzpyrene painted rabbits.…”

Ethylnitrosourea Induces Neoplasia in Zebrafish (Danio rerio)

“…Progression from non-dysplastic papillomas to dysplastic papillomas to malignant skin tumors has been studied in the mouse (Berenblum, 1954;Berenblum and Shubik, 1949;Boutwell, 1964;DiGiovanni, 1992;Friedewald and Rous, 1944;Yuspa, 1998). In SENCAR mouse skin, ENU functions as a tumor initiator at lower doses, but as a complete carcinogen at higher doses (O'Connell et al, 1987).…”

The Role of Croton Oil Applications, Associated with a Single Painting of a Carcinogen, in Tumour Induction of the Mouse's Skin

“…Thus, Mottram's second stage (" Specific Cellular Reaction ") corresponds to the " Precarcinogenic Action " of Berenblum (1941b; and also to the "Initiating Process " of Friedewald and Rous (1944), while his third stage (" Developing Factor ") corresponds to Berenblum's " Epicarcinogenic Action " and Friedewald and Rous's " Promoting Process." (See Table of (a) whether a single application of a carcinogen is indeed adequate antecedent treatment to allow the " developing " effect of croton oil to be manifested; and (b) whether there is in fact an initial, non-specific, hyperplasia-producing, " sensitizing factor," operating prior to the specific carcinogenic action.…”