Ben-Porath Ittai, Thomson Matthew W, Carey Vincent J, Ge Ruping, Bell George W, Regev Aviv, Weinberg Robert A
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Nat Genet. 2008 May;40(5):499-507. doi: 10.1038/ng.127.
Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell-like phenotypes shown by many tumors.
癌细胞具有一些与正常干细胞相似的特征。然而，目前尚不清楚这些表型上的相似性是否反映了共同分子途径的活性。在此，我们分析了与胚胎干细胞（ES细胞）特征相关的基因集在各种人类肿瘤类型表达谱中的富集模式。我们发现，组织学上低分化的肿瘤表现出通常在ES细胞中富集的基因的优先过表达，同时伴有多梳蛋白调控基因的优先抑制。此外，Nanog、Oct4、Sox2和c-Myc的激活靶点在低分化肿瘤中比在高分化肿瘤中更频繁地过表达。在乳腺癌中，这种类似ES细胞的特征与高级别雌激素受体（ER）阴性肿瘤相关，这些肿瘤通常为基底样亚型，且临床预后较差。ES细胞特征也存在于低分化的胶质母细胞瘤和膀胱癌中。我们鉴定出了一组在低分化肿瘤中高表达的与ES细胞相关的转录调节因子。我们的结果揭示了与ES细胞特征相关的基因和肿瘤组织病理学特征之间以前未知的联系，并支持了这些基因促成许多肿瘤所表现出的干细胞样表型的可能性。
