Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Oncogene. 2014 Jan 30;33(5):665-70. doi: 10.1038/onc.2012.611. Epub 2013 Jan 14.
A gene signature specific for intestinal stem cells (ISCs) has recently been shown to predict relapse in colorectal cancer (CRC) but the tumorigenic role of individual signature genes remains poorly defined. A prominent ISC-signature gene is the cancer stem cell marker CD44, which encodes various splice variants comprising a diverse repertoire of adhesion and signaling molecules. Using Lgr5 as ISC marker, we have fluorescence-activated cell sorting-purified ISCs to define their CD44 repertoire. ISCs display a specific set of CD44 variant isoforms (CD44v), but remarkably lack the CD44 standard (CD44s) isoform. These CD44v also stand-out in transformed human ISCs isolated from microadenomas of familial adenomatous polyposis patients. By employing knock-in mice expressing either CD44v4-10 or CD44s, we demonstrate that the CD44v isoform, but not CD44s, promotes adenoma initiation in Apc(Min/+)mice. Our data identify CD44v as component of the ISCs program critical for tumor initiation, and as potential treatment target in CRC.
最近已经证实，一种特定于肠干细胞（ISCs）的基因特征可预测结直肠癌（CRC）的复发，但个别特征基因的致瘤作用仍未得到明确界定。ISCs 特征基因中的一个突出代表是癌症干细胞标志物 CD44，它编码了各种剪接变体，包含一系列不同的粘附和信号分子。我们使用 Lgr5 作为 ISC 标志物，通过荧光激活细胞分选（FACS）纯化 ISC 以定义其 CD44 谱。ISCs 显示出一组特定的 CD44 变体同工型（CD44v），但显著缺乏 CD44 标准（CD44s）同工型。这些 CD44v 也在从家族性腺瘤性息肉病患者的微腺瘤中分离出的转化人 ISC 中突出显示。通过使用表达 CD44v4-10 或 CD44s 的基因敲入小鼠，我们证明 CD44v 同工型而非 CD44s 可促进 Apc(Min/+)小鼠的腺瘤起始。我们的数据表明，CD44v 是 ISCs 程序的重要组成部分，对于肿瘤起始至关重要，并且可能成为 CRC 的潜在治疗靶点。
