Yuspa S H, Lichti U, Morgan D, Hennings H
Curr Probl Dermatol. 1980;10:171-91. doi: 10.1159/000396289.
Studies of tumor induction on mouse skin have provided insight into the basis biology of chemical carcinogenesis, but molecular mechanisms have been more difficult to elucidate. Mouse epidermal cell cultures have proven to be a valuable model for performing mechanistic studies. Previous data have indicated that such cultures proliferate and differentiate in a manner highly analogous to epidermis in vivo. In addition, carcinogen metabolism, DNA repair, and responses to tumor promoters are quite similar in mouse skin in vivo and in vitro. Recent data have extended these observations toward defining the biological characteristics of initiated cells and elucidating the mechanism of action of promoters and antipromoters. When mouse epidermis is cultured under conditions of low extracellular Ca++, proliferation is enhanced and terminal differentiation is inhibited. Addition of Ca++ induces terminal differentiation. If cells are treated with carcinogens under low Ca++ conditions and subsequently switched to standard Ca++, cell colonies which do not terminally differentiate evolve. Such colonies continue to synthesize keratin, are subculturable, and may represent preneoplastic cells. In other experiments, epidermal cells derived from mouse skin treated with carcinogens in vivo also demonstrate prolonged in vitro survival and subculturability while controls have a limited lifespan. Such studies suggest that biological alterations can be detected in epidermal cells exposed to carcinogens well before and the phenotypic expression of neoplasia. Exposure of epidermal cells to phorbol-ester tumor promoters induces ornithine decarboxylase (ODC). This induction is enhanced by corticosteroids and markedly inhibited by retinoids. Ultraviolet light also induces ODC in epidermal cells, but kinetic studies suggest that the early pathway of induction (afferent to the nucleus) is different from that of phorbol esters. The later pathways (efferent from the nucleus-i.e., transcription and translation) appear to be similar. Retinoids have only a minor suppressive effect on ODC induction by UV while corticosteroids enhance UV induction to the same extent as seen with phorbol esters These results suggest that the site of retinoids is in the afferent pathway while steroids act on the efferent pathway.
对小鼠皮肤肿瘤诱发的研究为化学致癌作用的基础生物学提供了深入见解，但分子机制却更难阐明。事实证明，小鼠表皮细胞培养是进行机制研究的宝贵模型。先前的数据表明，此类培养物的增殖和分化方式与体内表皮高度相似。此外，致癌物代谢、DNA修复以及对肿瘤启动子的反应在体内和体外的小鼠皮肤中颇为相似。最近的数据扩展了这些观察结果，有助于定义起始细胞的生物学特性，并阐明启动子和抗启动子的作用机制。当小鼠表皮在低细胞外钙离子浓度条件下培养时，增殖增强而终末分化受到抑制。添加钙离子会诱导终末分化。如果在低钙离子浓度条件下用致癌物处理细胞，随后切换到标准钙离子浓度，不会终末分化的细胞集落就会形成。此类集落持续合成角蛋白，可传代培养，可能代表肿瘤前体细胞。在其他实验中，体内经致癌物处理的小鼠皮肤来源的表皮细胞在体外也表现出延长的存活期和可传代性，而对照细胞的寿命有限。此类研究表明，在接触致癌物的表皮细胞中，早在肿瘤形成的表型表达之前就能检测到生物学改变。表皮细胞暴露于佛波酯肿瘤启动子会诱导鸟氨酸脱羧酶（ODC）。皮质类固醇会增强这种诱导作用，而视黄酸则会显著抑制。紫外线也会在表皮细胞中诱导ODC，但动力学研究表明，早期诱导途径（传入细胞核）与佛波酯不同。后期途径（传出细胞核，即转录和翻译）似乎相似。视黄酸对紫外线诱导ODC的作用仅有轻微抑制，而皮质类固醇对紫外线诱导的增强程度与对佛波酯的相同。这些结果表明，视黄酸作用于传入途径，而类固醇作用于传出途径。
