Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors.
Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors.
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DOI：
10.1053/j.gastro.2010.05.083
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发表时间：
2010-09
期刊：
影响因子：
29.4
通讯作者：
Ordog T
中科院分区：
文献类型：
--
作者：
Bardsley MR;Horváth VJ;Asuzu DT;Lorincz A;Redelman D;Hayashi Y;Popko LN;Young DL;Lomberk GA;Urrutia RA;Farrugia G;Rubin BP;Ordog T
胃肠道间质瘤(GIST)与Cajal间质细胞(ICC)相关，常含有激活Kit或PDGFRA突变。Kit/PDGFRA信号的抑制剂，如甲磺酸伊马替尼，可以增加转移性GIST的无进展生存率，但不能治愈。在小鼠模型中，我们研究了Kitlow成人ICC祖细胞是否可以代表GIST固有的Kit/PDGFRA耐药库。连续克隆扩增后分离KitlowCD44+CD34+细胞并进行鉴定。对自发转化细胞在裸鼠体内的致瘤潜能进行了研究。通过对KitK641E小鼠(GIST模型)、Kit信号转导缺陷小鼠和药理学研究KitlowCD44+CD34+细胞对Kit激活和阻断的反应性。单独分离的KitlowCD44+CD34+细胞具有克隆性，具有自我更新和分化为ICC的能力。在裸鼠体内，自发转化的细胞形成了表达GIST标记的恶性肿瘤。KitlowCD44+CD34+细胞在体外对Kit阻断具有抵抗力，包括伊马替尼，在Kit信号减弱的小鼠中正常出现。在KitK641E小鼠中，突变的ICC干细胞大量增殖，但仍对伊马替尼耐药。相比之下，致癌细胞靶向药物盐霉素阻止了KitlowCD44+CD34+细胞的增殖，并增加了它们对伊马替尼的敏感性。KitlowCD44+CD34+祖细胞是正常和增生性ICC的真正干细胞，并导致GIST。对Kit/PDGFRA抑制剂的耐药性是GIST固有的，这是由于天然的ICC干细胞缺乏对Kit的生存依赖，这种情况在获得致癌Kit突变后保持。癌症干细胞药物可能针对这些细胞。
Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating Kit or Pdgfra mutations. Inhibitors of Kit/Pdgfra signaling such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kitlow adult ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST. KitlowCd44+Cd34+ cells were isolated and characterized after serial clonal re-derivation. Tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The KitlowCd44+Cd34+ cells responsiveness to Kit activation and blockade was studied by enumerating them in KitK641E mice (a GIST model), in mice with defective Kit signaling, and pharmacologically. Single isolated KitlowCd44+Cd34+ cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The KitlowCd44+Cd34+ cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In KitK641E mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer-initiating cell-targeting drug salinomycin blocked the proliferation of KitlowCd44+Cd34+ cells and increased their sensitivity to imatinib. KitlowCd44+Cd34+ progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is due to the native ICC stem cells lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.
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影响因子：
8
作者：
Tuveson, DA;Willis, NA;Demetri, GD
通讯作者：
Demetri, GD
影响因子：
29.4
作者：
Lorincz, Andrea;Redelman, Doug;Ordog, Tamas
通讯作者：
Ordog, Tamas
影响因子：
3.7
作者：
Ördög, T;Redelman, D;Sanders, KM
通讯作者：
Sanders, KM
影响因子：
29.4
作者：
Huizinga JD;Zarate N;Farrugia G
通讯作者：
Farrugia G
影响因子：
2.5
作者：
Beckett, Elizabeth A. H.;Ro, Seungil;Ward, Sean M.
通讯作者：
Ward, Sean M.