Mechanism of Experimental Tumorigenesis. I. Epidermal Hyperplasia in Mouse Caused by Locally Applied Tumor Initiator and Dipole-Type Tumor Promotor2

Abstract

Laboratory-synthesized “membrane active agents,” Span 60 (sorbitan monostearate) and its ethylene oxide derivative, Tween 60 (polyoxyethylene sorbitan monostearate), and Tween 20 (polyoxyethylene sorbitan monolaurate), produced changes in skin on back of the mouse analogous to those caused by corresponding technical products. The degree of hyperplasia was correlated to the tumor-promoting property of the agent, or to its absence. The skin changes produced by a potent tumor promoter of Tween 60 type, which were analyzed histologically and histoquantitatively, differed from those caused by similarly applied carcinogens methylcholanthrene (MCA) and 9,10-dimethyl-1,2-benzanthracene (DMBA). A single application with MCA or DMBA immediately produced toxic alterations. Reparative hyperplasia set in only after the latter became quiescent. Continuous MCA or DMBA treatment caused cellular and nuclear atypia and severe disturbances in organization and differentiation, which increased progressively. Treatment with Tween 60 did not produce retrogressive alterations, but intense cell multiplication and high-degree hyperplasia commenced immediately. Continuous Tween 60 treatment caused neither cellular nor nuclear atypia, nor disturbances in organization; the amount of cells in differentiation increased significantly. Continuous treatment maintained the hyperplasia unchanged. After initial application of carcinogen, Tween 60 treatment evoked changes typical of carcinogens. Tween 20 (a weak tumor promoter) and Span 60 (an ineffectual compound) did not produce these alterations. The nature of tumor promotion after application of a pure dipole-type promoter is benign. Tumor promotion is not a phase of the carcinogenic process itself as these processes are contradictory. Tumor promotion is comparable to intense continuous reparative (“simple”) cell multiplication.