CD34 expression by hair follicle stem cells is required for skin tumor development in mice
CD34 expression by hair follicle stem cells is required for skin tumor development in mice
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DOI：
10.1158/0008-5472.can-06-3128
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Tennant, Raymond W.
中科院分区：
文献类型：
--
作者：
Trempus, Carol S.;Morris, Rebecca J.;Tennant, Raymond W.
细胞表面标记物CD 34标记小鼠毛囊隆突细胞，其具有干细胞的属性，包括静止和多能性。使用CD 34基因敲除（KO）小鼠，我们测试了CD 34可能参与小鼠肿瘤发展的假设，因为毛囊干细胞被认为是小鼠皮肤癌变两阶段模型中致癌物的主要靶点。在用200 nmol 7，12-二甲基苯并（a）蒽（DMBA）开始后，用12-O-十四酰基佛波醇-13-乙酸酯（TPA）促进小鼠20周。在这些条件下，CD 34 KO小鼠未能发生乳头状瘤。将DMBA的起始剂量增加至400 nmol导致CD 34 KO小鼠中的肿瘤发展，尽管与野生型（WT）品系相比具有增加的潜伏期和较低的肿瘤产量。DNA加合物分析DMBA启动的CD 34 KO小鼠的角质形成细胞显示，DMBA被代谢活化成致癌的二醇环氧化物在200和400 nmol。长期暴露于TPA显示，CD 34 KO皮肤发展并持续表皮增生。然而，CD 34 KO毛囊通常保持在休止期，而不是过渡到生长期生长，证实了在毛囊内的溴脱氧尿苷标记的隆突干细胞的保留。在TPA处理的WT小鼠的毛囊间基底细胞中发现了毛囊祖细胞标记物MTS 24的独特定位，而染色仍然限于CD 34 KO小鼠的毛囊，这表明祖细胞在品系之间不同地迁移到表皮中。这些数据表明，CD 34是TPA诱导的小鼠毛囊干细胞活化和肿瘤形成所必需的。
The cell surface marker CD34 marks mouse hair follicle bulge cells, which have attributes of stem cells, including quiescence and multipotency. Using a CD34 knockout (KO) mouse, we tested the hypothesis that CD34 may participate in tumor development in mice because hair follicle stem cells are thought to be a major target of carcinogens in the two-stage model of mouse skin carcinogenesis. Following initiation with 200 nmol 7,12-dimethylbenz(a)anthracene (DMBA), mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Under these conditions, CD34KO mice failed to develop papillomas. Increasing the initiating dose of DMBA to 400 nmol resulted in tumor development in the CD34KO mice, albeit with an increased latency and lower tumor yield compared with the wild-type (WT) strain. DNA adduct analysis of keratinocytes from DMBA-initiated CD34KO mice revealed that DMBA was metabolically activated into carcinogenic diol epoxides at both 200 and 400 nmol. Chronic exposure to TPA revealed that CD34KO skin developed and sustained epidermal hyperplasia. However, CD34KO hair follicles typically remained in telogen rather than transitioning into anagen growth, confirmed by retention of bromodeoxyuridine-labeled bulge stem cells within the hair follicle. Unique localization of the hair follicle progenitor cell marker MTS24 was found in interfollicular basal cells in TPA-treated WT mice, whereas staining remained restricted to the hair follicles of CD34KO mice, suggesting that progenitor cells migrate into epidermis differently between strains. These data show that CD34 is required for TPA-induced hair follicle stem cell activation and tumor formation in mice.