Chronic 12-O-tetradecanoylphorbol-13-acetate treatment prevents restoration of collagen loss associated with its inflammatory effect on mouse skin.

The extracellular matrix of the dermis is subject to severe alterations during tumor promotion with phorbol esters in mouse skin. The metabolic changes also involve general stimulation of protein synthesis and most specifically an increase of collagen synthesis. During chronic treatment with the tumor promoting phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) increased protein synthesis was observed that did not occur during treatment with the non-promoting mitogens 4-O-methyl-TPA and Ca-ionophore A 23187. Relative collagen synthesis measured as the ratio of radioactivities in hydroxyproline and proline or as the proportion of total radioactivity in pepsin resistant material was elevated, too, but not sufficiently to substitute for TPA-induced collagen loss. In contrast collagen degradation caused by the non-promoting irritant A 23187 is followed by an immediate, substantial increase of collagen synthesis. When TPA treatment was discontinued after a few applications insufficient for tumor development rapid resynthesis of collagen took place. Therefore we assume that continued phorbol ester application not only caused connective tissue damage but also prevents the repair of that damage. This effect seems to be promoter specific and contributes to the disruption of dermal-epidermal interactions during tumor promotion.