Pathogenetics Unit, National Institutes of Health, Bethesda, Maryland 20892, USA.
Am J Pathol. 2013 Feb;182(2):529-39. doi: 10.1016/j.ajpath.2012.10.028. Epub 2012 Dec 3.
The classic tumor clonal evolution theory postulates that cancers change over time to produce unique molecular subclones within a parent neoplasm, presumably including regional differences in gene expression. More recently, however, this notion has been challenged by studies showing that tumors maintain a relatively stable transcript profile. To examine these competing hypotheses, we microdissected discrete subregions containing approximately 3000 to 8000 cells (500 to 1500 μm in diameter) from ex vivo esophageal squamous cell carcinoma (ESCC) specimens and analyzed transcriptomes throughout three-dimensional tumor space. Overall mRNA profiles were highly similar in all 59 intratumor comparisons, in distinct contrast to the markedly different global expression patterns observed in other dissected cell populations. For example, normal esophageal basal cells contained 1918 and 624 differentially expressed genes at a greater than twofold level (95% confidence level of <5% false positives), compared with normal differentiated esophageal cells and ESCC, respectively. In contrast, intratumor regions had only zero to four gene changes at a greater than twofold level, with most tumor comparisons showing none. The present data indicate that, when analyzed using a standard array-based method at this level of histological resolution, ESCC contains little regional mRNA heterogeneity.
经典的肿瘤克隆进化理论假设，癌症会随着时间的推移而发生变化，在母肿瘤中产生独特的分子亚克隆，推测包括基因表达的区域差异。然而，最近的研究挑战了这一观点，这些研究表明肿瘤保持相对稳定的转录谱。为了检验这些相互竞争的假说，我们从离体食管鳞癌（ESCC）标本中微切割了包含大约 3000 到 8000 个细胞（500 到 1500μm 直径）的离散亚区，并分析了整个三维肿瘤空间的转录组。在 59 个肿瘤内比较中，所有比较的总体 mRNA 谱都非常相似，与在其他分离细胞群体中观察到的明显不同的全局表达模式形成鲜明对比。例如，与正常分化的食管细胞和 ESCC 相比，正常食管基底细胞中分别有 1918 个和 624 个差异表达基因（置信水平为 95%，假阳性率<5%），差异表达倍数大于两倍。相比之下，肿瘤内区域只有零到四个基因发生了两倍以上的变化，大多数肿瘤比较都没有。本数据表明，当使用标准的基于阵列的方法在这种组织学分辨率水平上进行分析时，ESCC 中区域 mRNA 异质性很小。
