Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations.
Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations.
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DOI：
10.1158/1541-7786.mcr-12-0634-t
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发表时间：
2013-06
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影响因子：
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通讯作者：
Minna JD
中科院分区：
文献类型：
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作者：
Sato M;Larsen JE;Lee W;Sun H;Shames DS;Dalvi MP;Ramirez RD;Tang H;DiMaio JM;Gao B;Xie Y;Wistuba II;Gazdar AF;Shay JW;Minna JD
我们使用来自几个个体的CDK 4/hTERT永生化的正常人支气管上皮细胞（HBECs），通过引入常见肺癌致癌变化（p53、KRAS、MYC）的组合并遵循HBECs向完全恶性的逐步转化来研究肺癌发病机制。该模型表明：（1）五种遗传变异的组合（CDK 4、hTERT、sh-p53、KRASV 12和c-MYC）足以使HBEC完全致瘤转化; 2）转化的HBEC的遗传上相同的克隆在肿瘤生长、组织学和分化方面表现出明显的差异; 3）来自不同个体的HBEC在它们对通过这些致瘤操作的转化的敏感性方面不同; 4）HBEC的完全恶性转化需要高水平的KRASV 12，然而需要p53功能的先前丧失以防止癌基因诱导的衰老; 5）c-MYC的过表达极大地增强恶性，但仅在sh-p53+ KRASV 12的情况下; 6）亲本HBEC在含血清培养基中的生长诱导分化，而致癌性操作的HBEC在血清中的生长增加体内致瘤性，降低肿瘤潜伏期，产生更多未分化肿瘤，并诱导上皮向间质转化（EMT）; 7）HBEC的致癌转化导致对标准化疗双联体的敏感性增加; 8）通过比较致瘤性克隆与非致瘤性克隆而得到的mRNA标记可预测肺癌患者的结果。总的来说，我们的研究结果表明，该HBEC模型系统可用于研究致癌突变的影响，其表达水平，以及恶性转化中血清来源的环境效应，同时还提供临床可翻译的应用，如发展预后特征和药物反应表型。
We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, MYC) and followed the stepwise transformation of HBECs to full malignancy. This model demonstrated that: 1) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRASV12, and c-MYC) is sufficient for full tumorigenic conversion of HBECs; 2) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; 3) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 4) high levels of KRASV12 are required for full malignant transformation of HBECs, however prior loss of p53 function is required to prevent oncogene-induced senescence; 5) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 6) growth of parental HBECs in serum-containing medium induces differentiation while growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); 7) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; 8) an mRNA signature derived by comparing tumorigenic vs. non-tumorigenic clones was predictive of outcome in lung cancer patients. Collectively, our findings demonstrate this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes.