Growth Stimulation and Tumor Promotion in Skin

Abstract

Stimulation of epidermal growth in adult mouse skin can be induced by chemical agents, such as phorbol esters and other skin mitogens, or by mechanical means, such as skin massage and skin wounding. It leads to different kinds of epidermal hyperproliferation, according to interference with mechanisms of endogenous growth control (G1 chalone) and to mediation by endogenous regulatory factors (prostaglandins). Certain phorbol esters and skin wounding induce epidermal hyperproliferation and, in addition, a metaplastic process. Another property of these metaplasiogenic mitogens is their tumor-promoting efficacy in mouse skin, which has been initiated by a carcinogen in a subthreshold dose. Tailor-made phorbol esters allow the subdivision of the process of tumor promotion into two stages. In the first--probably irreversible--stage, a single application of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or wounding brings about the events critical and obligatory for promotion, whereas in the second--probably reversible--stage, repetitive applications of an "incomplete promoter" evoke epidermal hyperplasia necessary to make the tumors visible. Adult guinea pig epidermis in vivo, as well as primary cell cultures derived from adult guinea pig ear epidermis, responds to the proliferative effects of phorbol esters such as TPA along a similar sequence of biochemical events as mouse skin in vivo. The in vitro approach allows the study of the molecular events involved in the mechanism of action of phorbol esters in more detail.

The conversion stage of skin carcinogenesis

“…Wounding has, on the other hand, no tumorigenic effect in non-initiated skin (50). We have shown that single wounding can also replace TPA or MMS as a converting stimulus (24). These findings show that the role of exogenous tumor promoters such as phorbol esters and others can be entirely taken over by endogenous factors, most probably polypeptide growth factors and pro-inflammatory mediators involved in wound healing.…”

“…This result was confirmed by Slaga et al (22) using Sencar mice with TPA as a converting agent and mezerein as a propagating agent, as well as by Fiirstenberger et al (23) using NMRI mice with the two phorbol esters, TPA and RPA, as converting and propagating agents respectively. The introduction of the non-converting TPAderivative RPA (retinoylphorbol acetate) is based on a study showing that the introduction of conjugated double bonds into the long-chain fatty acid residue of a tumor-promoting phorbol ester results in a weakening of the converting effect without impairing the hyperplasiogenic potency (24). The almost complete lack of a converting effect of the semisynthetic RPA in NMRI mouse skin is thus the consequence of the polyunsaturated retinoyl residue rather than of an intrinsic retinoic acid activity, which could not be demonstrated for this phorbol ester (unpublished).…”

“…One possible explanation would be that the unsaturated structure scavenges active intermediates such as free radicals and active oxygen species which may play an essential role in the conversion process (see below). It must be emphasized that no qualitative difference exists between TPA and RPA in inducing hyperplastic transformation including the associated biochemical events mentioned above (15,16,(23)(24)(25)(26). In addition, both propagation and conversion are sensitive to several inhibitors (antipromoters) such as retinoic acid (27), steroidal (28) and non-steroidal antiphlogistica (29), cyclosporins (30), hydroxyurea (31), antioxidants (32), inhibitors of arachidonic acid metabolism (33) and protease inhibitors (34).…”

Gene Expression Architecture of Mouse Dorsal and Tail Skin Reveals Functional Differences in Inflammation and Cancer

“…To model epithelial response to inflammation, we treated dorsal skin of inbred FVB mice with the phorbol ester TPA, which results in edema and an influx of inflammatory cells into the skin (Furstenberger and Marks, 1983; Schlingemann et al, 2003). TPA treatment has been observed to induce differentiation of basal keratinocytes (Reiners and Slaga, 1983).…”

Transformation of differentiated rat hepatocytes with adenovirus and adenovirus DNA

“…Subsequent studies demonstrated that although transfection with a single oncogene is sufficient for transformation of NIH 3T3 cells, cooperation between two oncogenes is necessary for transformation of primary cells (39,43,48,52,61). The realization that transformation of primary cells by DNA involved multiple factors or multiple steps provides support for the concept of multistage progression in cancer (13) postulated from studies of chemically induced mouse skin tumors in vivo (7,15,26,27) and chemically induced transformation of cells in culture (36). Although primary cells by definition do not form stable cell lines, many primary cell types replicate.…”