Yamasaki H
IARC Sci Publ. 1980(27):91-111.
The potent tumour promoters in mouse skin, phorbol esters and their congeners, inhibit various types of cell differentiation in cell culture systems. There is a good correlation between the tumour-promoting activity of these plant diterpenes and their inhibitory effect on cell differentiation systems. Such findings reinforce the 'aberrant differentiation' theory of carcinogenesis and support Berenblum's (1954b) speculation that tumour promoters may act by interfering with the maturation of initiated cells. FLC are one of the best-defined differentiation systems; and in these, one can see the reversible inhibition of spontaneous and induced differentiation by tumour promoters. Furthermore, clones of FLC have been isolated that are completely resistant to tumour promoter-mediated inhibition of differentiation yet retain the capacity to differentiate normally in response to various inducers. In an attempt to elucidate the mechanism by which tumour promoters inhibit cell differentiation and to obtain a possible clue as to the mechanism of tumour promotion, these variant clones were characterized and compared with tumour promoter-sensitive clonal FLC. The possible relevance of these finding to mouse skin two-stage carcinogenesis is discussed, and is proposed that initiation may be caused by mutagenic actions of carcinogens, whereas unbalanced differentiation triggered by phorbol esters may play a crucial role in the promotion step.
小鼠皮肤中的强效肿瘤促进剂佛波酯及其同系物，在细胞培养系统中可抑制多种类型的细胞分化。这些植物二萜的肿瘤促进活性与其对细胞分化系统的抑制作用之间存在良好的相关性。此类发现强化了致癌作用的“异常分化”理论，并支持了贝伦布卢姆（1954b）的推测，即肿瘤促进剂可能通过干扰起始细胞的成熟发挥作用。扁平上皮细胞（FLC）是定义最明确的分化系统之一；在这些系统中，可以观察到肿瘤促进剂对自发和诱导分化的可逆抑制作用。此外，已分离出对肿瘤促进剂介导的分化抑制完全耐药但仍保留对各种诱导剂正常分化能力的FLC克隆。为了阐明肿瘤促进剂抑制细胞分化的机制，并获取有关肿瘤促进机制的可能线索，对这些变异克隆进行了表征，并与对肿瘤促进剂敏感的克隆性FLC进行了比较。讨论了这些发现与小鼠皮肤两阶段致癌作用的可能相关性，并提出引发可能是由致癌物的诱变作用引起的，而佛波酯引发的分化失衡可能在促进阶段起关键作用。
