PROLIFERATIVE RESPONSES OF THE SKIN TO EXTERNAL STIMULI
PROLIFERATIVE RESPONSES OF THE SKIN TO EXTERNAL STIMULI
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DOI：
10.2307/3431849
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发表时间：
1993-12-01
影响因子：
10.4
通讯作者：
FURSTENBERGER, G
中科院分区：
文献类型：
--
作者：
MARKS, F;FURSTENBERGER, G
皮肤，特别是表皮，提供了独特的机会来研究在体内和体外条件下细胞增殖和组织动态平衡的诱导和控制。此外，它代表了实验癌症研究最可行的模型系统之一。皮肤作为人体的主要边界，具有重要的防护和防御功能。对外部损伤的一般反应包括上皮层增厚(表皮增生)和炎症反应。皮肤的这种增生性转化是皮肤肿瘤发展(即转化和促进)和伤口反应的关键条件。它被认为是由于角质形成细胞转变为激活状态，其特征是增殖速度加快，并能够释放一系列生长因子和其他细胞因子，这些细胞因子沿着自身和旁分泌反馈环协调防御反应(例如，过度增殖、白细胞募集、免疫系统激活)。这种反应的初始阶段和可能的后期阶段关键取决于局部释放二十烷类化合物，如前列腺素和脂氧合酶生成的因子。佛波酯处理小鼠皮肤的一个独特反应是强烈诱导8-脂氧合酶，该酶可能通过催化产生被认为在转化阶段发挥作用的碎裂代谢产物而参与皮肤肿瘤的发展。增生可能被认为是细胞增殖率和细胞损失率之间不平衡的结果。因此，必须将增生性转化与皮肤对外界刺激的另一种反应区分开来，在这种反应中，维持动态平衡(即，尽管强烈的过度增殖，但不会发生增殖)。温和刺激(压力、佛波酯4-O-甲基-TPA)诱导的这种平衡的过度增殖既不伴随炎症反应，也不伴随角质形成细胞激活的症状。这可能仅仅是由于细胞周期在增殖组织间隔室中穿行的速度增加所致。相反，前列腺素依赖的角质形成细胞激活导致的增生性转化在许多方面(如细胞周期相关基因的激活)与体外细胞的G(O)-S转变相似。如何控制正常表皮的增殖动态平衡是一个尚未解决的问题。目前尚不清楚细胞增殖速度是否会自动适应末端分化的速度，或者这种适应是否受到局部因素的调节，比如难以捉摸的查尔酮或其他抑制信号，如转化生长因子β。同样的情况也适用于刺激生长因子，如表皮生长因子和转化生长因子-α，它们的功能可能是伤口激素，而不是正常组织再生的动态平衡调节器。
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 auto- and 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 G(o)-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 beta. The same is true for stimulatory growth factors such as epidermal growth factor and transform ing growth factor-alpha whose function may be that of wound hormones rather than of homeostatic regulators of normal tissue regeneration.