A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro.
A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro.
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DOI：
10.1158/0008-5472.can-08-4210
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Watkins DN
中科院分区：
文献类型：
--
作者：
Daniel VC;Marchionni L;Hierman JS;Rhodes JT;Devereux WL;Rudin CM;Yung R;Parmigiani G;Dorsch M;Peacock CD;Watkins DN
癌症治疗的临床前研究的传统方法依赖于使用以血清为基础的培养基中维持的已建立的细胞系。小细胞肺癌(SCLC)尤其如此，手术切除的组织很少。最近的注意力集中在需要更好的模型来保持癌症干细胞群体的完整性，以及三维肿瘤-间质相互作用。在这里，我们描述了一种原代小细胞肺癌异种移植模型，在该模型中，从化疗初期患者获得的支气管内肿瘤标本在免疫缺陷小鼠体内连续繁殖。同时，从每一株异种移植物中提取在常规组织培养条件下生长的细胞系，传代6个月，然后重新种植以产生二次异种移植物。使用Affymetrix平台，我们分析了原代异种移植、异种移植衍生细胞系和二次异种移植中的基因表达，并将这些数据与对无关的初级小细胞肺癌样本和实验室模型的类似分析进行了比较。与正常肺相比，原发肿瘤、异种移植瘤和细胞系表现出小细胞肺癌特有的基因表达特征。比较异种移植模型中的基因表达，发现了一组在原发小细胞肺癌和异种移植中表达的肿瘤特异性基因，这些基因在向组织培养的转变过程中丢失，当肿瘤重新建立为二次异种移植时，这些基因没有恢复。基因表达的这种变化可能是许多癌细胞培养系统的共同特征，对使用这种模型进行临床前药物开发具有功能意义。
Traditional approaches to the preclinical investigation of cancer therapies rely on the use of established cell lines maintained in serum-based growth media. This is particularly true of small cell lung cancer (SCLC), where surgically resected tissue is rarely available. Recent attention has focused on the need for better models that preserve the integrity of cancer stem cell populations, as well as three-dimensional tumor-stromal interactions. Here we describe a primary xenograft model of SCLC in which endobronchial tumor specimens obtained from chemo-naive patients are serially propagated in vivo in immunodeficient mice. In parallel, cell lines grown in conventional tissue culture conditions were derived from each xenograft line, passaged for 6 months, and then re-implanted to generate secondary xenografts. Using the Affymetrix platform, we analyzed gene expression in primary xenograft, xenograft-derived cell line, and secondary xenograft, and compared these data to similar analyses of unrelated primary SCLC samples and laboratory models. When compared to normal lung, primary tumors, xenografts and cell lines displayed a gene expression signature specific for SCLC. Comparison of gene expression within the xenograft model identified a group of tumor-specific genes expressed in primary SCLC and xenografts that was lost during the transition to tissue culture, and that was not regained when the tumors were re-established as secondary xenografts. Such changes in gene expression may be a common feature of many cancer cell culture systems, with functional implications for the use of such models for preclinical drug development.