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Epidermal Growth Control Mechanisms, Hyperplasia, and Tumor Promotion in the Skin¹

Institute of Biochemistry, German Cancer Research Center (Deutsches Krebstorschungszentrum), D-69 Heidelberg, Germany

In permanently renewing epithelia such as epidermis, the steady state between cell loss and cell gain is thought to be controlled by tissue-own and tissue-specific inhibitors of cell proliferation (chalones). In epidermis two chalone-like factors have been found, a G₁ chalone retarding the entry of cells into the phase of DNA replication and a G₂ chalone inhibiting the transition of cells from G₂ into mitosis. Both factors have been isolated from pigskin; they are probably glycoproteins. In contrast to the G₂ chalone, the G₁ chalone is resistant to heat and proteolytic enzymes and is most probably produced in keratinizing cells. From the purified G₁ chalone a dose of 0.05 to 0.1 µg injected i.p. into an adult mouse is sufficient to depress epidermal DNA synthesis to about 50%.

Studies on the response of mouse epidermis to mitogenic stimuli lead to the conclusion that the tissue can react in two different ways:

1. If the stimulus does not involve severe injury, only the flow of cell through the steady state of tissue homeostasis is accelerated (e.g., after gentle skin massage or chemical depilation). In this case hyperplasia is not observed or develops only slowly if the stimulus lasts for a longer period of time (functional hyperplasia, e.g., at body sites that suffer a strong wear and tear). Under these conditions the G₁ chalone mechanism is not disturbed.

2. The automatic response to any kind of severe injury (e.g., wounding, removal of the horny layer, treatment with mitogens such as the tumor-promoting phorbol esters or acetic acid) is not only compensatory growth but also a transient loss of susceptibility to G₁ chalone which is followed by a sudden development of a pronounced and long-lasting hyperplasia (hyperplastic transformation). In many aspects hyperplastically transformed epidermis resembles neonatal tissue.

In analogy to the hemopoietic system, it is proposed that the proliferative compartment of epidermis consists of different types of stem cells and that only already maturating stem cells are able to respond to G₁ chalone. During the hyperplastic transformation this stem cell pool is depopulated due to either hasty keratinization (e.g., after removal of the horny laryer) or dedifferentiation (as is discussed for the mechanism of action of tumor promoters). The result is a transient chalone-insensitive cell proliferation.

The concept of dedifferentiation as the driving force of tumor promotion is supported by investigations of effects of hyperplasiogenic and promoting agents on the epidermal adenosine cyclic 3':5'-monophosphate (cyclic AMP) system. The observations are not consistent with the assumption that epidermal cell proliferation is triggered by a fall in the epidermal level of cyclic AMP but favor the idea that cyclic AMP is involved in the expression of epidermal function. Provided that this is correct certain effects of different phorbol esters on epidermal cyclic AMP may be directly correlated to the "dedifferentiating" and promoting activity of the agent.

¹ Presented at the Conference "Early Lesions and the Development of Epithelial Cancer," October 21 to 23, 1975, Bethesda, Md. This work was supported by the Deutsche Forschungsgemeinschaft.