Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine
Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine
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DOI：
10.1158/0008-5472.can-16-3192
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发表时间：
2017-07-01
期刊：
影响因子：
11.2
通讯作者：
Seno, Hiroshi
中科院分区：
文献类型：
--
作者：
Goto, Norihiro;Ueo, Taro;Seno, Hiroshi
癌症干细胞（CSC）作为治疗靶点已经引起了人们的关注;然而，CSC靶向治疗可能会破坏正常组织的稳态，因为许多CSC分子也由正常干细胞（NSC）表达。在这里，我们证明了干细胞转录因子Hes 1在肠道中的NSC-specific和CSC-specific作用使特定癌症治疗的可行性成为可能。Hes 1在神经干细胞和肠道肿瘤中表达上调。成年小鼠肠道的谱系追踪实验显示，Lgr 5（+）或Bmi 1（+）神经干细胞中Hes 1的缺失导致自我更新的丧失，但不会扰乱体内平衡。此外，在Lgr 5（+）NSC中，Hes 1的缺失和β-连环蛋白的稳定性限制了肿瘤的形成并延长了宿主的生存期。值得注意的是，在来源于已建立的肠道肿瘤的Lgr 5（+）或Dclk 1（+）肿瘤干细胞中，Hes 1缺失引发了立即凋亡，降低了肿瘤负荷。我们的研究结果显示了Hes 1如何在NSC和CSC中发挥不同的作用，其中Hes 1的破坏导致肿瘤消退而不干扰正常的干细胞稳态，临床前验证Hes 1作为癌症治疗靶点。(C)2017年AACR。
Cancer stem cells (CSC) have attracted attention as therapeutic targets; however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here, we demonstrate that NSC-specific and CSC-specific roles of the stem cell transcription factor Hes1 in the intestine enable the feasibility of a specific cancer therapy. Hes1 expression was upregulated in NSCs and intestinal tumors. Lineage-tracing experiments in adult mouse intestine revealed that Hes1 deletion in Lgr5(+) or Bmi1(+) NSCs resulted in loss of self-renewal but did not perturb homeostasis. Furthermore, in Lgr5(+) NSC, deletion of Hes1 and beta-catenin stabilization limited tumor formation and prolonged host survival. Notably, in Lgr5(+) or Dclk1(+) tumor stem cells derived from established intestinal tumors, Hes1 deletion triggered immediate apoptosis, reducing tumor burden. Our results show how Hes1 plays different roles in NSCs and CSCs, in which Hes1 disruption leads to tumor regression without perturbing normal stem cell homeostasis, preclinically validating Hes1 as a cancer therapeutic target. (C) 2017 AACR.