Proliferative Responses of the Skin to External Stimuli

Abstract

The skin, in particular the epidermis, offers unique opportunities to investigate the induction and control of cellular proliferation and tissue homeostasis both under in vivo and in vitro conditions. Moreover, it represents one of the most feasible model systems for experimental cancer research. As the primary border of the body, the skin has important protective and defensive functions. A general response to external injury consists of a thickening of the epithelial layer (epidermal hyperplasia) combined with an inflammatory reaction. This hyperplastic transformation of the skin is a critical condition of skin tumor development (i.e., conversion and promotion) and of the wound response. It is believed to be due to a transformation of keratinocytes into an activated state characterized by an increased rate of proliferation and the ability to release a series of growth factors and other cytokines that coordinate the defense reaction (e.g., hyperproliferation, recruitment of leukocytes, activation of the immune system) along autoand paracrine feedback loops. The initial and probably later phases of this response depend critically on a local release of eicosanoids such as prostaglandins and lipoxygenase-generated factors. A unique reaction seen upon phorbol ester treatment of mouse skin is a strong induction of the enzyme 8-lipoxygenase, which might be involved in skin tumor development by catalyzing the generation of clastogenic metabolites thought to play a role in the conversion stage.Hyperplasia may be considered to be the result of an imbalance between the rates of cell gain and cell loss. Therefore, hyperplastic transformation has to be distinguished from another response of skin to external stimuli where the homeostatic equilibrium is maintained (i.e., no hyperplasia develops in spite of strong hyperproliferation). This balanced hyperproliferation as induced by mild stimuli (pressure, phorbol ester 4-O-methyl-TPA) is neither accompanied by inflammatory reactions nor by the symptoms of keratinocyte activation. It may simply be due to an increased rate of cell-cycle traverse in the proliferative tissue compartment. In contrast, the prostaglandin-dependent activation of keratinocytes leading to hyperplastic transformation resembles in many aspects (such as, for instance, the activation of cell -cycle-related genes) the Go-S transition of cells in vitro. The control of proliferative homeostasis in normal epidermis is an unresolved problem. It is not known whether the rate of cell proliferation adapts automatically to the rate of terminal differentiation or whether this adaption is regulated by local factors such as the elusive chalones or other inhibitory signals like transforming growth factor [B.The same is true for stimulatory growth factors such as epidermal growth factor and transforming growth factor-a whose fimction may be that of wound hormones rather than of homeostatic regulators of normal tissue regeneration.

Selective Cyclooxygenase-2 Inhibition Does Not Alter Keratinocyte Wound Responses in the Mouse Epidermis after Abrasion

“…From these data, COX-2 induced prostaglandin E 2 has been postulated to play a role in the development of skin cancer (Buckman et al, 1998). Consistent with this hypothesis, suppression of tumor development with a selective COX-2 inhibitor has been observed in mouse models of skin tumorigenesis (Marks and Furstenburger, 1993;MullerDecker et al, 1998a,b). In contrast to the data obtained in mouse models of skin cancer (Marks and Furstenburger, 1993;Muller-Decker et al, 1998a,b), we demonstrated that keratinocyte proliferation and differentiation following mild epidermal injury by abrasion were unaffected by inhibition of COX-2 or both COX isoforms.…”

“…Consistent with this hypothesis, suppression of tumor development with a selective COX-2 inhibitor has been observed in mouse models of skin tumorigenesis (Marks and Furstenburger, 1993;MullerDecker et al, 1998a,b). In contrast to the data obtained in mouse models of skin cancer (Marks and Furstenburger, 1993;Muller-Decker et al, 1998a,b), we demonstrated that keratinocyte proliferation and differentiation following mild epidermal injury by abrasion were unaffected by inhibition of COX-2 or both COX isoforms. Furthermore, the epidermis became hyperplastic and returned to a normal, quiescent state with a similar time course in all treatment groups.…”

“…Furthermore, prostaglandin E 2 has been shown to regulate calcium-induced keratinocyte differentiation resulting in enhanced cornified envelope formation in vitro that was reversed by indomethacin (Evans et al, 1993). Taken together, these data have led some investigators to suggest that prostaglandin E 2 modulates keratinocyte proliferation and differentiation (Marks and Furstenburger, 1993;Scholz et al, 1995;Muller-Decker et al, 1998b).…”

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

“…2A, Right). The presence of infiltrating cells following incision was greatest between 24 h and 3 d, with the cellular immune response largely resolved between 7 and 10 d. Wound closure was observed by 2-3 d, along with a characteristic thickening of the epidermis at the site of injury (22,23). Some immune cells were still present within the dermal and, to a lesser extent, hypodermal layers 10 d after injury (the endpoint for incisional wounds).…”

Cell Proliferation and Chemical Carcinogenesis: Symposium Overview

“…In experimental studies of skin carcinogenesis, stimulation of epidermal cell proliferation alone is not a reliable predictor of tumor promotion; hyperplastic transformation with keratinocyte activation and the release of growth factors are critical for tumor development (20). A stochastic-based mathematical model of skin tumor promotion predicts that initiated cells may not exhibit a growth advantage over normal cells (21).…”