High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-FLI1 inhibition.
High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-FLI1 inhibition.
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DOI：
10.1371/journal.pone.0013943
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发表时间：
2010-11-11
期刊：
影响因子：
3.7
通讯作者：
Loeb DM
中科院分区：
文献类型：
--
作者：
Awad O;Yustein JT;Shah P;Gul N;Katuri V;O'Neill A;Kong Y;Brown ML;Toretsky JA;Loeb DM
癌症干细胞是能够自我更新和使大块肿瘤再生的化疗抗性群体，从而引起复发和患者死亡。尤文氏肉瘤是青少年和年轻人中第二常见的骨肿瘤形式，其临床模式与癌症干细胞模型一致-即使对于转移性疾病患者也很容易实现缓解，但复发仍然频繁，通常是致命的。我们已经从免疫缺陷小鼠中生长的人细胞系和人异种移植物中分离出尤文肉瘤细胞亚群，其表达高醛脱氢酶（ALDHhigh）活性，并富含克隆形成、球体形成和肿瘤起始。ALDHhigh细胞在体外对化疗具有抗性，但这可以通过ATP结合盒转运蛋白抑制剂维拉帕米克服。重要的是，这些细胞对YK-4-279不耐药，YK-4 -279是EWS-FLI 1的小分子抑制剂，其在体外和体内对尤文肉瘤细胞具有选择性毒性。尤文氏肉瘤含有ALDHhigh干细胞样的化疗耐药细胞群，这些细胞对EWS-FLI 1抑制保持敏感性。抑制EWS-FLI 1癌蛋白可能被证明是通过靶向在标准化疗中存活的尤文肉瘤干细胞来改善患者预后的有效手段。
Cancer stem cells are a chemotherapy-resistant population capable of self-renewal and of regenerating the bulk tumor, thereby causing relapse and patient death. Ewing's sarcoma, the second most common form of bone tumor in adolescents and young adults, follows a clinical pattern consistent with the Cancer Stem Cell model – remission is easily achieved, even for patients with metastatic disease, but relapse remains frequent and is usually fatal. We have isolated a subpopulation of Ewing's sarcoma cells, from both human cell lines and human xenografts grown in immune deficient mice, which express high aldehyde dehydrogenase (ALDHhigh) activity and are enriched for clonogenicity, sphere-formation, and tumor initiation. The ALDHhigh cells are resistant to chemotherapy in vitro, but this can be overcome by the ATP binding cassette transport protein inhibitor, verapamil. Importantly, these cells are not resistant to YK-4-279, a small molecule inhibitor of EWS-FLI1 that is selectively toxic to Ewing's sarcoma cells both in vitro and in vivo. Ewing's sarcoma contains an ALDHhigh stem-like population of chemotherapy-resistant cells that retain sensitivity to EWS-FLI1 inhibition. Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing's sarcoma stem cells that survive standard chemotherapy.
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影响因子：
11.2
作者：
Huang EH;Hynes MJ;Zhang T;Ginestier C;Dontu G;Appelman H;Fields JZ;Wicha MS;Boman BM
通讯作者：
Boman BM
影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
5.7
作者：
Feldmann G;Fendrich V;McGovern K;Bedja D;Bisht S;Alvarez H;Koorstra JB;Habbe N;Karikari C;Mullendore M;Gabrielson KL;Sharma R;Matsui W;Maitra A
通讯作者：
Maitra A
影响因子：
3.7
作者：
Cironi, Luisa;Riggi, Nicolo;Stamenkovic, Ivan
通讯作者：
Stamenkovic, Ivan
影响因子：
3.2
作者：
Miser, James S.;Goldsby, Robert E.;Grier, Holcombe E.
通讯作者：
Grier, Holcombe E.