Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations
Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations
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DOI：
10.1158/1541-7786.mcr-08-0035
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发表时间：
2008-07-01
影响因子：
5.2
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Ma, Stephanie;Chan, Kwok Wah;Guan, Xin-Yuan
最近我们在肝细胞癌（HCC）中的癌症干细胞（CSC）研究中的努力已经导致CD 133被鉴定为突出的HCC CSC标志物。这些发现是基于对细胞系和异种移植肿瘤进行的实验，其中检测到CD 133的表达水平高达65%。基于CSC理论，CSC被认为仅代表肿瘤质量的少数。这表明我们先前表征的CD 133 HCC CSC群体仍然是异质的，可能由具有不同致瘤潜力的细胞亚群组成。我们假设有可能通过额外的差异表达标记物来进一步富集CSC群体。使用二维PAGE方法，我们比较了从Huh 7和PLC 8024分离的CD 133（+）和CD 133（+）亚群之间的蛋白质谱，并鉴定了醛脱氢酶1A 1作为在CD 133（+）消减中优先表达的蛋白质之一。几种不同的ALDH亚型和ALDH酶活性在肝细胞系中的表达分析发现ALDH与CD 133表达呈正相关。双色流式细胞术分析发现大多数ALDH（+）为CD 133（+），但并非所有CD 133（+）HCC细胞均为ALDH（+）。随后对纯化亚群的研究发现，无论是在体外还是在体内，CD 133（+）ALDH（+）细胞的致瘤性均显著高于其CD 133（-）ALDH（+）或CD 133（-）ALDH（-）对应物。这些数据，结合我们以前的工作，揭示了在具有致瘤潜力的HCC中存在分级组织，其顺序为CD 133（+）ALDH（+）> CD 133（+）ALDH（-）> CD 133（-）ALDH（-）。ALDH，沿沿着CD 133表达，可以更特异地表征致瘤性肝CSC群体。
Recent efforts in our study of cancer stem cells (CSC) in hepatocellular carcinoma (HCC) have led to the identification of CD133 as a prominent HCC CSC marker. Findings were based on experiments done on cell lines and xenograft tumors where expression of CD133 was detected at levels as high as 65%. Based on the CSC theory, CSCs are believed to represent only a minority number of the tumor mass. This is indicative that our previously characterized CD133 HCC CSC population is still heterogeneous, consisting of perhaps subsets of cells with differing tumorigenic potential. We hypothesized that it is possible to further enrich the CSC population by means of additional differentially expressed markers. Using a two-dimensional PAGE approach, we compared protein profiles between CD133(+) and CD133(+) subpopulations isolated from Huh7 and PLC8024 and identified aldehyde dehydrogenase 1A1 as one of the proteins that are preferentially expressed in the CD133(+) subtraction. Analysis of the expression of several different ALDH isoforms and ALDH enzymatic activity in liver cell lines found ALDH to be positively correlated with CD133 expression. Dual-color flow cytometry analysis found the majority of ALDH(+) to be CD133(+), yet not all CD133(+) HCC cells were ALDH(+). Subsequent studies on purified subpopulations found CD133(+)ALDH(+) cells to be significantly more tumorigenic than their CD133(-)ALDH(+) or CD133(-)ALDH(-) counterparts, both in vitro and in vivo. These data, combined with those from our previous work, reveal the existence of a hierarchical organization in HCC bearing tumorigenic potential in the order of CD133(+)ALDH(+) > CD133(+)ALDH(-) > CD133(-)ALDH(-). ALDH, expressed along CD133, can more specifically characterize the tumorigenic liver CSC population.