Promotion of epidermal carcinogenesis by repeated damage to mouse skin

Abstract

Chemically induced epidermal carcinogenesis is usually divided into two stages: initiation, which involves the conversion of some epidermal cells into latent neoplastic cells; and promotion, which results in tumors. The hallmark of chemical promoters is epidermal hyperplasia. The hyperplasia caused by a strong promoter, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), differs morphologically from that caused by weak promoters, such as acetic acid and mezerin. The epidermal regeneration that follows abrasion results in a hyperplastic epidermis that resembles the effects of strong promoters. Repeated mechanical injuries are capable of enhancing papillomas and carcinomas in mouse skin initiated with 7,12-dimethylbenzanthracene (DMBA). Thus, a regenerative epidermal hyperplasia appears to be a precondition for tumor promotion. It is highly probable that many epidermal cells are initiated during the lifetime of man. In the work place, repeated mechanical injury could predispose to epidermal neoplasms.

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

“…In line with this scenario we found that TPA treatment can stimulate migration of Lgr5+ progeny to the IFE. TPA treatment induces a strong inflammatory and hyperproliferative response in mouse skin and is typically used for epidermal tumor promotion, and TPA has been shown to be as effective as deep skin wounding in promoting papilloma formation in mice (36). Although treatment with TPA can provide the important signals responsible for the migration of the potential tumor initiating cells, the key signals for HF cell migration into the wound are as of yet unclear.…”

Epithelial stem cells in vivo

“…The carcinogen LRCs may indeed be initiated cells, not necessarily because they retain carcinogen, but because they are stem cells affected before commitment to terminal differentiation (Lajtha, 1979;Buick & Poliak, 1984). Although the long-term presence of the adduct might possibly represent an enduring potential for the formation of initiated cells (Randerath et al 1983) in the murine skin system, the similar tumour responses at one week and one year after initiation (Boutwell, 1964-Roe et al 1972Stenback et al 1981;Van Duuren et al 1975;Loehrkeeta l. 1983;Hennings & Boutwell, 1970;Argyris, 1985a) suggest that the initiated state is established quickly and then maintained.…”

“…The consequences of tumour initiation are essentially irreversible and not expressed in the absence of promotion. The tumour responses are evoked whether promotion is begun one week or one year after the exposure to the carcinogen (Boutwell, 1964;Roe et al 1972;Stenbach et al 1981;Van Duuren et al 1975;Loehrke et al 1983;Hennings & Boutwell, 1970;Argyris, 1985a) and are surprisingly similar for a tissue such as the epidermis which is characterized by continuous turnover and cyclic growth and regression of the hair follicles (Hennings & Yuspa, 1985;Argyris, 1963;Potten, 1983;Iversen et al 1968;Leblond, 1964). Conceivably, any epidermal cell could become and remain initiated.…”

Keratinocyte stem cells: targets for cutaneous carcinogens

“…Argyris (24) suggests a follicular origin for papillomas and carcinomas, based on a model of epidermal abrasion that was found to be a tumor-promoting stimulus. The Argyris abrasion protocol entails removing the interfollicular epidermis but leaves the hair follicles undisturbed.…”