CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance.
CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance.
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DOI：
10.1158/1078-0432.ccr-14-0011
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发表时间：
2014-08-01
期刊：
影响因子：
--
通讯作者：
Yoon SS
中科院分区：
文献类型：
--
作者：
Yoon C;Park DJ;Schmidt B;Thomas NJ;Lee HJ;Kim TS;Janjigian YY;Cohen DJ;Yoon SS
胃癌（GC）可能含有一小部分具有癌症干细胞（CSC）特性的细胞，包括化疗（CT）抗性。Hedgehog（HH）通路是肿瘤发生过程中可被CSC破坏的关键发育通路。在这里，我们研究HH信号在CD 44（+）GC细胞中的作用。检查GC细胞系、肿瘤异种移植物和患者肿瘤。GC细胞系AGS、MKN-45和NCI-N87生长为球状体或分选为CD 44（+），发现HH途径蛋白上调。使用Smo shRNA或维莫德吉（维斯）的HH抑制减少了球状体形成和集落形成。CD 44（+）细胞与CD 44（+）细胞相比，对5-氟尿嘧啶和顺铂CT也有耐药性，这种耐药性在体外和用Smo shRNA或维斯的异种移植物中被逆转。CD 44（+）细胞也具有显著更多的迁移、侵袭和锚定非依赖性生长，这些特性都可以被HH抑制剂阻断。分析了来自一项II期试验的临床肿瘤样本的CD 44表达，该试验用于晚期GC或CT，有或没有维斯。在单独CT组中，CD 44高表达与生存率下降相关，而在CT加维斯组中，CD 44高表达与生存率提高相关。HH信号转导维持CD 44（+）GC细胞中的CSC表型和恶性转化表型，并且HH抑制可以阻断CD 44（+）细胞中的CT抗性。GC是一种异质性疾病，CT与HH抑制相结合的策略可能仅在具有高CD 44水平的亚组中有效。
Gastric cancers (GC) may harbor a small subset of cells with cancer stem cell (CSC) properties including chemotherapy (CT) resistance. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here we examine the role of HH signaling in CD44(+) GC cells. GC cell lines, tumor xenografts, and patient tumors were examined. GC cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smo shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared to unselected cells, were also resistant to 5-fluorouracil and cisplatin CT, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial for advanced GC of CT with or without VIS were analyzed for CD44 expression. In the CT alone group, high CD44 expression was associated with decreased survival, while in the CT plus VIS group, high CD44 expression was associated with improved survival. HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) GC cells, and HH inhibition can block CT resistance in CD44(+) cells. GC is a heterogeneous disease, and the strategy of combining CT with HH inhibition may only be effective in the subset with high CD44 levels.