Label-retaining liver cancer cells are relatively resistant to sorafenib.
Label-retaining liver cancer cells are relatively resistant to sorafenib.
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DOI：
10.1136/gutjnl-2012-303261
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发表时间：
2013-12
期刊：
影响因子：
24.5
通讯作者：
Avital I
中科院分区：
文献类型：
--
作者：
Xin HW;Ambe CM;Hari DM;Wiegand GW;Miller TC;Chen JQ;Anderson AJ;Ray S;Mullinax JE;Koizumi T;Langan RC;Burka D;Herrmann MA;Goldsmith PK;Stojadinovic A;Rudloff U;Thorgeirsson SS;Avital I
晚期肝细胞癌的标准治疗方法是索拉非尼，大多数患者在6个月内病情恶化。标记保留癌细胞(LRCC)代表了肿瘤干细胞(CSC)的一个新亚群。目的是测试LRCC是否对索拉非尼耐药。我们检测了索拉非尼治疗前后人肝癌来源的LRCC和非LRCC。人肝细胞癌来源的LRCC对索拉非尼具有相对耐药性。经索拉非尼治疗后，LRCC在肝癌细胞系中的比例增加，而普通癌细胞的生长受到抑制。我们发现，与非LRCC相比，LRCC显示出更好的生存能力和毒性，并减少了细胞凋亡。我们发现，经索拉非尼治疗后，LRCC上调了CSC标志物乙醛脱氢酶1家族、无翅型MMTV整合位点家族、细胞存活和增殖基因，下调了凋亡、细胞周期停滞、细胞黏附和干细胞分化基因。伴随这一现象的是，在LRCC中，索拉非尼靶蛋白、细胞外信号调节蛋白和v-akt小鼠-胸腺瘤-病毒癌基因同源物(AKT)的特定亚型的激活不均匀，而在非LRCC中则不是。提出了索拉非尼治疗LRCC的分子路径图。我们的结果表明，肝癌来源的LRCC对索拉非尼具有相对耐药性。由于LRCC可以产生只有10个细胞的肿瘤，我们的数据表明这些细胞在疾病复发中具有潜在的作用。对这一现象的进一步研究可能会为癌症生物学、癌症复发和耐药性提供新的见解，对开发基于靶向LRCC的新型癌症治疗具有重要意义。
The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib. We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib. LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-aktmurine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed. Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.
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