Tumor-promoting phorbol esters cause a stable reduction of dermal collagen in mouse skin

Chronic treatment with the tumor-promoting phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) causes permanently increased levels of active collagenolytic enzymes in the dermis and leads to a stable reduction of dermal collagen content. Non-promoting skin mitogens like the Ca-ionophore A 23187 or the 4-O-methylether of TPA, while being active stimulators of collagenolytic enzymes, do not support chronic collagen degradation throughout the experimental period. On the other hand, TPA-induced collagen degradation is not necessarily influenced by inhibition of tumor promotion. Fluocinolone acetonid (FA), an inhibitor preventing not only tumor development but also chronic inflammation and the establishment of a stationary hyperplasia, has been compared with retinoic acid (RA) which has no influence on either the inflammatory reaction or hyperplasia. While FA inhibited the dermal effects of TPA almost completely, RA at a dose that prevented tumor development by 80% had no effect whatsoever in this respect. Therefore, we conclude that both epidermal proliferation and inflammation are accompanied by collagenolytic reactions in the dermis. During chronic treatment sustained collagenolysis correlates with inflammation and/or the establishment of a stationary hyperplasia. Like these it can be regarded as a necessary but insufficient condition of tumor promotion (second stage).