Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis.
Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis.
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DOI：
10.1158/0008-5472.can-08-4418
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Boman BM
中科院分区：
文献类型：
--
作者：
Huang EH;Hynes MJ;Zhang T;Ginestier C;Dontu G;Appelman H;Fields JZ;Wicha MS;Boman BM
尽管癌症起源于干细胞（SC）的概念在科学上越来越被接受，但干细胞促进肿瘤发生和发展的机制在很大程度上是未知的。对于结直肠癌（CRC），由于缺乏从正常和恶性结肠中识别和分离SC的特异性标记物，对这一问题的研究一直受到阻碍。因此，我们研究了醛脱氢酶1 （ALDH1）作为识别结肠SC并在癌症进展过程中跟踪它们的可能标记物。免疫染色显示ALDH1+细胞稀疏且局限于SCs所在的正常隐窝底部。在从正常上皮到突变（APC）上皮到腺瘤的过程中，ALDH1+细胞数量增加，并向隐窝上游分布。CD133+和CD44+细胞在正常隐窝中数量更多，分布更广，在肿瘤发生过程中也表现出类似的变化。基于ALDH酶活性的流式细胞术分离癌细胞（Aldefluor法），并将这些细胞植入非肥胖糖尿病-严重联合免疫缺陷小鼠(a)产生异种移植肿瘤（Aldefluor -细胞没有），(b)在植入25个细胞后产生肿瘤，(c)产生剂量依赖性肿瘤。使用第二标记物（CD44+或CD133+）进一步分离癌细胞，仅根据肿瘤启动能力适度增加富集。因此，ALDH1似乎是在结直肠癌发展过程中识别、分离和跟踪人类结肠SC的特异性标记物。这些发现也支持了我们最初的假设，即从隐窝动力学的数学模型中得出的，即进行性结肠SC过剩发生在结肠肿瘤发生过程中，并驱动结直肠癌的发展。
Although the concept that cancers originate from stem cells (SC) is becoming scientifically accepted, mechanisms by which SC contribute to tumor initiation and progression are largely unknown. For colorectal cancer (CRC), investigation of this problem has been hindered by a paucity of specific markers for identification and isolation of SC from normal and malignant colon. Accordingly, aldehyde dehydrogenase 1 (ALDH1) was investigated as a possible marker for identifying colonic SC and for tracking them during cancer progression. Immunostaining showed that ALDH1+ cells are sparse and limited to the normal crypt bottom, where SCs reside. During progression from normal epithelium to mutant (APC) epithelium to adenoma, ALDH1+ cells increased in number and became distributed farther up the crypt. CD133+ and CD44+ cells, which are more numerous and broadly distributed in normal crypts, showed similar changes during tumorigenesis. Flow cytometric isolation of cancer cells based on enzymatic activity of ALDH (Aldefluor assay) and implantation of these cells in nonobese diabetic–severe combined immunodeficient mice (a) generated xenograft tumors (Aldefluor− cells did not), (b) generated them after implanting as few as 25 cells, and (c) generated them dose dependently. Further isolation of cancer cells using a second marker (CD44+ or CD133+ serially) only modestly increased enrichment based on tumor-initiating ability. Thus, ALDH1 seems to be a specific marker for identifying, isolating, and tracking human colonic SC during CRC development. These findings also support our original hypothesis, derived previously from mathematical modeling of crypt dynamics, that progressive colonic SC overpopulation occurs during colon tumorigenesis and drives CRC development.