Identification of Cancer Stem Cells in Human Gastrointestinal Carcinoid and Neuroendocrine Tumors

被引:69
作者
Gaur, Puja [1 ]
Sceusi, Eric L. [1 ]
Samuel, Shaija [2 ]
Xia, Ling [2 ]
Fan, Fan [2 ]
Zhou, Yunfei [2 ]
Lu, Jia [2 ]
Tozzi, Federico [1 ]
Lopez-Berestein, Gabriel [3 ]
Vivas-Mejia, Pablo [3 ]
Rashid, Asif [4 ]
Fleming, Jason B. [1 ]
Abdalla, Eddie K. [1 ]
Curley, Steven A. [1 ]
Vauthey, Jean-Nicolas [1 ]
Sood, Anil K. [5 ]
Yao, James C. [6 ]
Ellis, Lee M. [1 ,2 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77230 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77230 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77230 USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77230 USA
[5] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77230 USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77230 USA
基金
美国国家卫生研究院;
关键词
Carcinoid Tumors; Cancer Stem Cells; Src Family Kinase Inhibitor PP2; Neuroendocrine Tumors; ENDOTHELIAL GROWTH-FACTOR; BREAST-CANCER; COLORECTAL-CANCER; RETINOIC ACID; RESISTANCE; LEUKEMIA; CHEMOTHERAPY; INHIBITION; RECEPTOR; SURVIVAL;
D O I
10.1053/j.gastro.2011.07.037
中图分类号
R57 [消化系及腹部疾病];
学科分类号
100201 [内科学];
摘要
BACKGROUND & AIMS: Metastatic gastrointestinal neuroendocrine tumors (NETs) frequently are 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. METHODS: Human gastrointestinal NETs were evaluated for CSCs using the Aldefluor (Stemcell Technologies, Vancouver, Canada) assay. An 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 short interfering RNA administration targeted Src. RESULTS: By using the Aldefluor assay, aldehyde dehydrogenase-positive (ALDH+) cells comprised 5.8% +/- 1.4% (mean +/- standard error of the mean) of cells from 19 patient samples. Although 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 mammalian target of rapamycin (mTOR). In vivo, anti-Src short interfering RNA treatment of ALDH+ tumors reduced tumor mass by 91%. CONCLUSIONS: CSCs are present in NETs, as shown 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.
引用
收藏
页码:1728 / 1737
页数:10
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