Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors.
Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors.
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DOI：
10.1053/j.gastro.2011.07.037
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发表时间：
2011-11
期刊：
影响因子：
29.4
通讯作者：
Ellis LM
中科院分区：
文献类型：
--
作者：
Gaur P;Sceusi EL;Samuel S;Xia L;Fan F;Zhou Y;Lu J;Tozzi F;Lopez-Berestein G;Vivas-Mejia P;Rashid A;Fleming JB;Abdalla EK;Curley SA;Vauthey JN;Sood AK;Yao JC;Ellis LM
转移性胃肠道神经内分泌肿瘤(NETs)往往对化疗无效。肿瘤干细胞(CSCs)可导致多种恶性肿瘤的化疗耐药。我们试图在手术标本和网状细胞系中鉴定胃肠神经内分泌干细胞(N-CSCs)，并表征新的N-CSC治疗靶点。使用Aldeflor试验评估人类胃肠道网络中的CSCs。对原代网状细胞进行体外球化试验。人中肠类癌细胞株CNDT2.5用于体外(球体形成)和体内(致瘤性测定)CSC研究。用Western blotting检测N-CSC蛋白的表达。在体内，系统地以Src为靶点的siRNA注射。用Aldeflor法检测，乙醛脱氢酶阳性(ALDH+)细胞占19例患者细胞的5.8%±1.4%(平均值±扫描电子显微镜)。虽然许多原代细胞系未能生长，但CNDT96ALDH+细胞在非贴壁条件下形成球体，而ALDH−细胞不形成球体。CNDT2.5ALDH+细胞形成球体，而ALDH−细胞不形成球体。在体内，ALDH+CNDT2.5细胞产生更多的肿瘤，潜伏期比ALDH−或假分选细胞短。与非CSCs相比，ALDH+细胞中激活的Src、Erk、Akt和mTOR的表达增加。在体内，ALDH+肿瘤的抗Src siRNA治疗使肿瘤质量减少了91%。CSCs存在于神经内分泌肿瘤(Net)中，体外球体形成和体内致瘤性分析证实了这一点。SRC在N-CSCs中被激活，是胃肠道Net潜在的治疗靶点。
Metastatic gastrointestinal neuroendocrine tumors (NETs) are frequently refractory to chemotherapy. Chemoresistance in various malignancies has been attributed to cancer stem cells (CSCs). We sought to identify gastrointestinal neuroendocrine CSCs (N-CSCs) in surgical specimens and a NET cell line and to characterize novel N-CSC therapeutic targets. Human gastrointestinal NETs were evaluated for CSCs using the Aldefluor assay. In vitro sphere-forming assay was performed on primary NET cells. CNDT2.5, a human midgut carcinoid cell line, was used for in vitro (sphere-formation) and in vivo (tumorigenicity assays) CSC studies. N-CSC protein expression was characterized using Western blotting. In vivo, systemic siRNA administration targeted Src. Using the Aldefluor assay, aldehyde dehydrogenase–positive (ALDH+) cells comprised 5.8% ± 1.4% (mean ± SEM) of cells from 19 patient samples. Though many primary cell lines failed to grow, CNDT96 ALDH+ cells formed spheres in anchorage-independent conditions, whereas ALDH− cells did not. CNDT2.5 ALDH+ cells formed spheres, whereas ALDH− cells did not. In vivo, ALDH+ CNDT2.5 cells generated more tumors, with shorter latency than ALDH− or sham-sorted cells. Compared with non-CSCs, ALDH+ cells demonstrated increased expression of activated Src, Erk, Akt, and mTOR. In vivo, anti-Src siRNA treatment of ALDH+ tumors reduced tumor mass by 91%. CSCs are present in neuroendocrine tumors (NETs), demonstrated by in vitro sphere-formation and in vivo tumorigenicity assays. Src was activated in N-CSCs and represents a potential therapeutic target in gastrointestinal NETs.
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影响因子：
5.7
作者：
Keysar SB;Jimeno A
通讯作者：
Jimeno A
影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
4.8
作者：
Krishnamurthy, P;Ross, DD;Schuetz, JD
通讯作者：
Schuetz, JD
影响因子：
20.3
作者：
Konig, Heiko;Holyoake, Tessa L.;Bhatia, Ravi
通讯作者：
Bhatia, Ravi
DOI：
10.1093/jnci/djm279
发表时间：
2008-01-16
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Gray, Michael J.;Van Buren, George;Ellis, Lee M.
通讯作者：
Ellis, Lee M.