DIFFERENTIAL-EFFECTS OF COMPLETE AND 2ND-STAGE TUMOR PROMOTERS IN NORMAL BUT NOT TRANSFORMED HUMAN AND MOUSE KERATINOCYTES
DIFFERENTIAL-EFFECTS OF COMPLETE AND 2ND-STAGE TUMOR PROMOTERS IN NORMAL BUT NOT TRANSFORMED HUMAN AND MOUSE KERATINOCYTES
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DOI：
10.1093/carcin/5.8.1071
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发表时间：
1984-01-01
期刊：
影响因子：
4.7
通讯作者：
GORMAN, PA
中科院分区：
文献类型：
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作者：
PARKINSON, EK;PERA, MF;GORMAN, PA
完整的肿瘤促进剂佛波醇，12-肉豆蔻酸酯，13-乙酸酯（PMA）诱导大多数正常培养的人和小鼠角质形成细胞的终末分化，但存在一个亚群，这是抵抗这种作用（PMRR）。比较了PMA与Mez和佛波醇、12-维甲酸酯、13-乙酸酯（PRA）对正常和转化的人和小鼠角质形成细胞终末分化能力的影响，试图阐明为什么后两种化合物是无效的完全肿瘤促进剂，但在2阶段促进方案中在PMA后给予时作为第2阶段促进剂是有效的。PMA和Mez在正常和转化的角质形成细胞培养物中以类似的方式增加皮质包膜形成，在正常角质形成细胞中诱导超过溶剂对照的20至25倍增加，但在SCC-27系（来源于人鳞状细胞癌的细胞系）中仅增加2倍。然而，虽然佛波醇酯对集落形成能力的影响的定量剂量反应研究揭示了一部分对PMA具有抗性的正常人和小鼠角质形成细胞，但没有正常角质形成细胞对Mez或PRA具有抗性。相反，来自乳头状瘤和鳞状细胞癌的细胞系显示出与所有3种化合物相似大小的耐药分数。此外，当Mez或PRA与PMA混合时，SCC-27系的存活率与单独用化合物处理培养物时相同，表明对PRA或Mez具有抗性的角质形成细胞也是PMAR亚群。一个非致瘤性亚克隆SCC-12（克隆F.2），以前显示具有所有已知的属性的转化角质形成细胞，除了有缺陷的终末分化悬浮培养响应PMA和Mez以类似的方式正常角质形成细胞，这表明PMAR亚群的第二阶段启动子的抗性需要在角质形成细胞终末分化程序的缺陷的表达。
The complete tumor promoter phorbol, 12-myristate, 13-acetate (PMA) induces terminal differentiation in the majority of normal cultured human and mouse keratinocytes but a subpopulation exists which is resistant to this effect (PMRR). The effects of PMA were compared with mezerein (Mez) and phorbol, 12-retinoate, 13-acetate (PRA) on the ability of normal and transformed human and mouse keratinocytes to terminally differentiate in an attempt to elucidate why the latter 2 compounds are inefficient complete tumor promoters but are effective as 2nd-stage promoters when given after PMA in the 2-stage promotion regimen. Both PMA and Mez increased cornified envelope formation in a similar way in normal and transformed keratinocyte cultures inducing a 20- to 25-fold increase over the solvent controls in normal keratinocytes but only a 2-fold increase in line SCC-27 (a cell line derived from a human squamous cell carcinoma). However, while quantitative dose response studies of the effect of phorbol esters on colony forming ability revealed a proportion of normal human and mouse keratinocytes which were resistant to PMA, no normal keratinocytes were resistant to Mez or PRA. In contrast, cell lines derived from papillomas and squamous cell carcinomas showed a resistant fraction of similar size with all 3 compounds. Furthermore, when Mez or PRA were mixed with PMA the survival of line SCC-27 was the same as when the cultures were treated with the compounds individually indicating that the keratinocytes which were resistant to PRA or Mez were also the PMAR subpopulation. A non-tumorigenic subclone of line SCC-12 (clone F.2), previously shown to possess all known properties of transformed keratinocytes except defective terminal differentiation in suspension culture responded to PMA and Mez in a similar way to normal keratinocytes, suggesting that resistance of the PMAR subpopulation to 2nd-stage promoters requires the expression of a defect in the keratinocyte terminal differentiation program.