Tough D F, Haliotis T, Chow D A
Department of Immunology, University of Manitoba, Winnipeg, Canada.
Int J Cancer. 1992 Feb 1;50(3):423-30. doi: 10.1002/ijc.2910500317.
Changes in the natural resistance phenotype were examined for the 2H1, 10T 1/2 cells expressing the activated human H-ras oncogene under the transcriptional regulation of the zinc-inducible mouse metallothionein-I promoter. Culture of the cells in 50 microM ZnSO4 induced an increase in ras protein p21 levels which were maximal within 1 day. Natural-antibody (NAb) binding was significantly increased following 2 days of cell culture in ZnSO4 and continued to increase up to 4 days. The increased NAb binding returned to uninduced levels within 2 days following the removal of added zinc ions from the culture medium. The cells also exhibited a significant increase in natural killer (NK) cell sensitivity following 2 days in ZnSO4. This was maintained as long as the zinc was in the medium, but returned to uninduced levels within 1 day following its removal. The results show that NAb binding and susceptibility to NK cells increased following ras oncogene expression in 10T 1/2 cells and that both parameters were regulated by p21 expression. Repeated i.v. administration of whole-serum NAb prior to tumor inoculation reduced the number of early tumors following s.c. injection of Zn(++)-induced 2Hl cells into Zn(++)-treated C3H/HeN mice, consistent with an in vivo role for NAb in the defense against ras-transformed cells. In contrast, small but statistically significant reductions in NAb binding were observed following v-H-ras transformation of NIH 3T3 cells or v-src transformation of 10T 1/2. The data argue for an NAb- and NK-cell-susceptible phase of ras-induced tumor development which is a prerequisite for these mediators to contribute to a first line of defense against incipient neoplasia, and suggest that characteristics of the recipient cell and the transforming oncogene are important in determining the natural resistance phenotype.
在锌诱导的小鼠金属硫蛋白-I启动子的转录调控下，对表达活化的人H-ras癌基因的2H1、10T 1/2细胞的天然抗性表型变化进行了检测。在50 microM硫酸锌中培养细胞可诱导ras蛋白p21水平升高，在1天内达到最大值。在硫酸锌中培养细胞2天后，天然抗体（NAb）结合显著增加，并持续增加至4天。从培养基中去除添加的锌离子后2天内，增加的NAb结合恢复到未诱导水平。在硫酸锌中培养2天后，这些细胞对自然杀伤（NK）细胞的敏感性也显著增加。只要锌存在于培养基中，这种敏感性就会维持，但在去除锌后1天内恢复到未诱导水平。结果表明，10T 1/2细胞中ras癌基因表达后，NAb结合和对NK细胞的敏感性增加，并且这两个参数均受p21表达的调节。在肿瘤接种前重复静脉注射全血清NAb，可减少将锌离子诱导的2H1细胞皮下注射到经锌处理的C3H/HeN小鼠后早期肿瘤的数量，这与NAb在体内对ras转化细胞的防御作用一致。相比之下，在NIH 3T3细胞v-H-ras转化或10T 1/2细胞v-src转化后，观察到NAb结合有小幅但具有统计学意义的降低。数据表明，ras诱导的肿瘤发展存在一个NAb和NK细胞敏感阶段，这是这些介质有助于对早期肿瘤形成进行一线防御的先决条件，并表明受体细胞和转化癌基因的特征在决定天然抗性表型方面很重要。
