Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Department of Surgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Cancer Res. 2017 Jul 1;77(13):3442-3454. doi: 10.1158/0008-5472.CAN-16-3192. Epub 2017 May 23.
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 β-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. .
癌症干细胞（CSC）作为治疗靶点引起了关注；然而，CSC 靶向治疗可能会破坏正常组织的动态平衡，因为许多 CSC 分子也由正常干细胞（NSC）表达。在这里，我们证明 Hes1 作为一种干细胞转录因子在肠道中具有 NSC 特异性和 CSC 特异性作用，使特定的癌症治疗成为可能。Hes1 在 NSCs 和肠道肿瘤中的表达上调。成年小鼠肠道中的谱系追踪实验表明，Lgr5 或 Bmi1 NSCs 中 Hes1 的缺失导致自我更新丧失，但不会破坏体内平衡。此外，在 Lgr5 NSC 中，Hes1 和 β-连环蛋白稳定的缺失限制了肿瘤的形成并延长了宿主的存活期。值得注意的是，在源自已建立的肠道肿瘤的 Lgr5 或 Dclk1 肿瘤干细胞中，Hes1 的缺失触发了即刻凋亡，从而减少了肿瘤负担。我们的研究结果表明 Hes1 如何在 NSCs 和 CSCs 中发挥不同的作用，其中 Hes1 的缺失导致肿瘤消退而不会破坏正常干细胞的体内平衡，在临床前验证了 Hes1 作为癌症治疗靶点的可行性。
