CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors
CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors
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DOI：
10.1172/jci34401
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发表时间：
2008-06-01
影响因子：
15.9
通讯作者：
Rafii, Shahin
中科院分区：
文献类型：
--
作者：
Shmelkov, Sergey V.;Butler, Jason M.;Rafii, Shahin
结肠癌干细胞被认为源自罕见的假定CD133(+)肠干细胞群。最近的出版物表明一小部分结肠癌细胞表达 CD133，并且只有这些 CD133(+) 癌细胞能够引发肿瘤。然而，CD133(+)肿瘤起始细胞在介导结肠癌转移中的确切作用仍不清楚。因此，为了在时间和空间上追踪成年小鼠和肿瘤发生过程中 CD133 的表达，我们构建了敲入 lacZ 报告小鼠 (CD133(lacZ/+))，其中 lacZ 的表达由内源性 CD133 启动子驱动。使用该模型和免疫染色，我们发现结肠中的CD133表达不仅限于干细胞；相反，CD133 在成年小鼠和人类的分化结肠上皮上普遍表达。使用 Il10(-/-)CD133(lacZ) 小鼠（其中结肠慢性炎症导致腺癌），我们证明 CD133 在全域结肠肿瘤细胞上表达，这些细胞表达上皮细胞粘附分子 (EpCAM)。类似地，CD133在人原发性结肠癌上皮细胞中广泛表达，而CD133(-)群体主要由基质细胞和炎症细胞组成。相反，CD133 表达并不能识别人类转移性结肠癌中的整个上皮细胞和肿瘤起始细胞群。事实上，CD133(+)和CD133(-)转移性肿瘤亚群在体外培养物中形成菌落球，并且能够在NOD/SCID系列异种移植模型中长期发生肿瘤。此外，转移性CD133(-)细胞形成更具侵袭性的肿瘤，并表达癌症起始细胞的典型表型标志物，包括CD44(CD44(+)CD24(-))，而CD133(+)部分由CD44(低)CD24(+)细胞组成。总的来说，我们的数据表明CD133表达并不局限于肠干细胞或癌症起始细胞，并且在转移转变过程中，CD133(+)肿瘤细胞可能产生更具侵袭性的CD133(-)亚群，该亚群也能够在NOD/SCID小鼠中引发肿瘤。
Colon cancer stem cells are believed to originate from a rare population of putative CD133(+) intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133(+) cancer cells are capable of tumor initiation. However, the precise contribution of CD133(+) tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133(lacZ/+)), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10(-/-)CD133(lacZ) mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133(-) population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133(+) and CD133(-) metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133(-) cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44(+)CD24(-)), whereas the CD133(+) fraction is composed of CD44(low)CD24(+) cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133(+) tumor cells might give rise to the more aggressive CD133(-) subset, which is also capable of tumor initiation in NOD/SCID mice.