Lichti U, Yuspa S H
Ciba Found Symp. 1985;113:77-89. doi: 10.1002/9780470720943.ch6.
Retinoids are physiological regulators of growth and differentiation for a number of epithelial tissues. In several of these, retinoids also act as pharmacological anticarcinogens. Retinoids are most effective as anticarcinogens in the post-initiation portion of carcinogenesis. In mouse skin, retinoids are inhibitors of phorbol ester-mediated tumour promotion and can cause regression of pre-existing benign tumours. Studies in vivo and in vitro have indicated that phorbol ester-mediated skin tumour promotion results from selective clonal expansion of initiated cells. We have proposed that the biological basis for selection resides in the induction of terminal differentiation in subpopulations of keratinocytes while other keratinocytes, including initiated cells, are stimulated to proliferate. Terminal differentiation is accelerated by phorbol esters through the induction of epidermal transglutaminase and consequent cornification. Retinoids inhibit terminal differentiation of keratinocytes. Retinoids also induce transglutaminase in epidermis, but they inhibit cornification. Recent results suggest a biochemical basis for this paradox. The phorbol ester-induced transglutaminase is primarily particulate but the retinoid-induced enzyme is cytosolic. The induced enzymes differ in kinetic parameters, thermal stability and in elution from ion-exchange columns. Induction of the retinoid enzyme is associated with suppression of the induction of transglutaminase by phorbol esters. The retinoid-induced epidermal transglutaminase could interfere with normal or promoter-induced differentiation by inappropriately cross-linking precursor proteins before their assembly at the cell periphery. This could explain one aspect of the inhibitory action of retinoids on tumour promotion.
类视黄醇是多种上皮组织生长和分化的生理调节剂。在其中一些组织中，类视黄醇还可作为药理学上的抗癌剂。类视黄醇在致癌作用的启动后阶段作为抗癌剂最为有效。在小鼠皮肤中，类视黄醇是佛波酯介导的肿瘤促进作用的抑制剂，并且可导致已存在的良性肿瘤消退。体内和体外研究表明，佛波酯介导的皮肤肿瘤促进作用源于起始细胞的选择性克隆扩增。我们提出，选择的生物学基础在于角质形成细胞亚群中终末分化的诱导，而其他角质形成细胞，包括起始细胞，则被刺激增殖。佛波酯通过诱导表皮转谷氨酰胺酶并随之发生角质化来加速终末分化。类视黄醇抑制角质形成细胞的终末分化。类视黄醇还可诱导表皮中的转谷氨酰胺酶，但它们抑制角质化。最近的结果提示了这一矛盾现象的生化基础。佛波酯诱导的转谷氨酰胺酶主要存在于微粒体中，而类视黄醇诱导的酶则存在于胞质溶胶中。诱导的酶在动力学参数、热稳定性以及从离子交换柱上的洗脱情况方面存在差异。类视黄醇酶的诱导与佛波酯对转谷氨酰胺酶诱导的抑制作用相关。类视黄醇诱导的表皮转谷氨酰胺酶可能通过在其组装到细胞周边之前不适当地交联前体蛋白来干扰正常的或启动子诱导的分化。这可以解释类视黄醇对肿瘤促进作用的抑制作用的一个方面。
