Regeneration and the mechanism of epidermal tumor promotion

Abstract

Chemically induced epidermal carcinogenesis is often divided into two stages: initiation, which involves the conversion of some epidermal cells into latent neoplastic cells, and promotion, which allows the evolution of this neoplastic change into the formation of a neoplasm. The hallmark of epidermal tumor promotion is the transformation of the normal epidermis into a hyperplastic epidermis. A major unanswered question about epidermal tumor promotion is whether the epidermal hyperplasia that characterizes promoted skin is a regenerative epidermal hyperplasia resulting from damage produced by the promoter. The opinion currently held is that the epidermal hyperplasia produced by tumor promoters is not simply a regenerative epidermal hyperplasia and possesses characteristics which a regenerative hyperplasia does not have, enabling it to evolve into an epidermal neoplasm. The purpose of this review is to present recent evidence which strongly suggests that promoter-induced epidermal hyperplasia is a regenerative hyperplasia. Three principal lines of evidence are reviewed. The first demonstrates that an epidermal regenerative hyperplasia repeatedly produced by wounding or abrasion can promote epidermal carcinogenesis in the initiated skin of mice. The second line of evidence demonstrates that the epidermal hyperplasia produced by the application of 12-O-tetradecanoyl-phorbol-13-acetate (TPA), the most powerful and widely used promoter of skin carcinogenesis, is preceded by damage to the epidermis. This strongly suggests that the epidermal hyperplasia which ensues is a regenerative hyperplasia. Thirdly, evidence is presented which demonstrates that hyperplasia-producing agents which do not promote, produce an epidermal hyperplasia which is different from that produced by tumor promoters. Finally, the review discusses the evidence which suggests that the production of a hyperplasia may be the mechanism for tumor promotion in other organs, such as the liver, bladder, and intestine.

Haploinsufficiency for Odc Modifies Mouse Skin Tumor Susceptibility

“…treatment varied by Odc gene dosage. An epidermal hyperplastic response to TPA treatment, which is considered a necessary prerequisite for tumor promotion (15), was observed in Odc +/À mice but was less robust and of shorter duration than the response of wild-type mice. This was true for interfollicular epidermis, but especially so for hair follicles, the presumptive origin of most tumors in the initiation-promotion model (12).…”

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

“…The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).In this work, we have investigated skin proliferation and inflammation, before and after TPA application, in mice lacking TR␣1, TR␤, or both genes, comparing these responses with those of hypothyroid animals to distinguish the specific contributions of receptor expression and activation. We found that TRs and thyroid hormones are required for skin homeostasis after TPA treatment and that both receptor genes contribute to…”

“…The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).…”

A Method of Producing Carcinoma in Upper Aerodigestive Tree and Esophagus of the Syrian Golden Hamster Using Wounding and Instillation of N-Methylnitrosourea

“…In addition to the instillation of MNU, we added a wounding procedure. Wounding has long been thought to be a part of carcinogenesis (9) and has proved carcinogenic in mouse skin (9). In addition to the upper airway, our method also produced carcinoma of the esophagus as well as squamous carcinoma of the forestomach of the hamster.…”