A human colon cancer cell capable of initiating tumour growth in immunodeficient mice
A human colon cancer cell capable of initiating tumour growth in immunodeficient mice
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DOI：
10.1038/nature05372
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发表时间：
2007-01-04
期刊：
影响因子：
64.8
通讯作者：
Dick, John E.
中科院分区：
文献类型：
--
作者：
O'Brien, Catherine A.;Pollett, Aaron;Dick, John E.
从遗传学角度来看，结肠癌是人们了解最为透彻的肿瘤之一（1 - 3），然而它仍然是癌症相关死亡的第二大常见原因，这表明其一些癌细胞未被当前的疗法根除（4，5）。尚未确定的是，是否每个结肠癌细胞都具有引发和维持肿瘤生长的潜力，还是肿瘤呈层级结构，以至于只有一部分细胞——癌症干细胞——具有这种潜力（6，7）。在此，我们利用在免疫缺陷的NOD/SCID小鼠中进行肾包膜移植来鉴定一种人类结肠癌起始细胞（CC - IC）。纯化实验证实所有的CC - IC均为CD133阳性；构成肿瘤大部分的CD133阴性细胞无法引发肿瘤生长。通过极限稀释分析我们计算得出，在5.7×10⁴个未分选的肿瘤细胞中有1个CC - IC，而在262个CD133阳性细胞中有1个CC - IC，这意味着富集倍数超过200倍。CD133阳性群体中的CC - IC能够自我维持，并且在连续移植时能够分化并重新建立肿瘤异质性。结肠癌干细胞与肿瘤主体细胞不同，这一鉴定结果为人类结肠癌的层级结构提供了有力支持，并且它们的存在表明，治疗策略要想有效，就必须针对癌症干细胞。
Colon cancer is one of the best-understood neoplasms from a genetic perspective(1-3), yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies(4,5). What has yet to be established is whether every colon cancer cell possesses the potential to initiate and sustain tumour growth, or whether the tumour is hierarchically organized so that only a subset of cells - cancer stem cells - possess such potential(6,7). Here we use renal capsule transplantation in immunodeficient NOD/SCID mice to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133(+); the CD133(-) cells that comprised the majority of the tumour were unable to initiate tumour growth. We calculated by limiting dilution analysis that there was one CC-IC in 5.7 x 10(4) unfractionated tumour cells, whereas there was one CC-IC in 262 CD133(+) cells, representing >200-fold enrichment. CC-ICs within the CD133(+) population were able to maintain themselves as well as differentiate and reestablish tumour heterogeneity upon serial transplantation. The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem cells.