Malejczyk J, Malejczyk M, Majewski S, Breitburd F, Luger T A, Jablonska S, Orth G
Department of Histology and Embryology, Warsaw Medical School, Poland.
Int J Cancer. 1994 Feb 15;56(4):593-8. doi: 10.1002/ijc.2910560421.
The aim of this study was to evaluate the relationship between tumorigenicity of cell sublines derived from weakly tumorigenic SKv-e and SKv-l keratinocytes harboring human papillomavirus type 16 (HPV16) and their susceptibility to autocrine growth limitation mediated by tumor necrosis factor-alpha (TNF-alpha). These sublines displayed different in vitro proliferative potential which correlated with tumorigenicity in nu/nu mice. Recombinant TNF-alpha inhibited in vitro growth of weakly tumorigenic parental SKv cell lines while it did not affect proliferation of their respective highly tumorigenic sublines. Resistance to TNF-alpha correlated with both increased in vitro proliferation and tumorigenicity. Anti-TNF-alpha antibodies (Ab) significantly increased in vitro proliferation of weakly tumorigenic parental SKv cells up to the levels of their highly tumorigenic sublines. Growth of highly tumorigenic SKv cells was not affected. On the other hand, proliferation of SKv cells was affected neither by transforming growth factor-beta (TGF-beta) nor by anti-TGF-beta Ab. All SKv cell sublines tested spontaneously released TNF-alpha, as evaluated by a specific radioimmunoassay; however, the levels of the endogenous cytokine were not related to their proliferative potential and tumorigenicity. An increased resistance to the anti-proliferative effect of TNF-alpha may be associated with decreased expression of TNF-alpha receptors (TNF-alpha R) inasmuch as evaluation of 125I-TNF-alpha binding and Northern-blot analysis of TNF-alpha R-specific mRNA showed that highly tumorigenic SKv cell sublines expressed significantly lower numbers of TNF-alpha R than their respective parental cells. These results show that an increased tumorigenicity of HPV16-harboring SKv keratinocytes may be, at least partially, due to escape from autocrine TNF-alpha-mediated growth limitation.
本研究的目的是评估源自携带人乳头瘤病毒16型（HPV16）的弱致瘤性SKv - e和SKv - l角质形成细胞的细胞亚系的致瘤性与其对肿瘤坏死因子-α（TNF-α）介导的自分泌生长限制的敏感性之间的关系。这些亚系表现出不同的体外增殖潜能，这与裸鼠中的致瘤性相关。重组TNF-α抑制弱致瘤性亲代SKv细胞系的体外生长，而不影响其各自高致瘤性亚系的增殖。对TNF-α的抗性与体外增殖增加和致瘤性均相关。抗TNF-α抗体（Ab）显著增加弱致瘤性亲代SKv细胞的体外增殖，直至其高致瘤性亚系的水平。高致瘤性SKv细胞的生长不受影响。另一方面，SKv细胞的增殖既不受转化生长因子-β（TGF-β）影响，也不受抗TGF-β Ab影响。通过特异性放射免疫测定评估，所有测试的SKv细胞亚系均自发释放TNF-α；然而，内源性细胞因子的水平与其增殖潜能和致瘤性无关。对TNF-α抗增殖作用的抗性增加可能与TNF-α受体（TNF-α R）表达降低有关，因为对125I - TNF-α结合的评估和TNF-α R特异性mRNA的Northern印迹分析表明，高致瘤性SKv细胞亚系表达的TNF-α R数量明显低于其各自的亲代细胞。这些结果表明，携带HPV16的SKv角质形成细胞致瘤性增加可能至少部分归因于逃避自分泌TNF-α介导的生长限制。
