Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
Clin Cancer Res. 2014 Nov 1;20(21):5372-8. doi: 10.1158/1078-0432.CCR-13-2491. Epub 2014 Jul 8.
Aberrant regulation of the canonical Wnt signaling pathway (Wnt-β-catenin-GSK3 axis) has been a prevalent theme in cancer biology since earlier observations until recent genetic discoveries gleaned from tumor genome sequencing. During the last few decades, a large body of work demonstrated the involvement of the Wnt-β-catenin-GSK3 signaling axis in the formation and maintenance of cancer stem cells (CSC) responsible for tumor growth in several types of human malignancies. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment on how embryonic and normal tissue stem cells are dysregulated in cancer to give rise to CSCs, and how canonical Wnt signaling might be involved. Here, we review emerging concepts highlighting the critical role of epigenetics in CSC development through abnormal canonical Wnt signaling. Finally, we refer to the characterization of novel and powerful inhibitors of chromatin organization machinery that, in turn, restore the Wnt-β-catenin-GSK3 signaling axis in malignant cells, and describe attempts/relevance to bring these compounds into preclinical and clinical studies.
自从早期观察到最近的肿瘤基因组测序遗传发现以来，经典的 Wnt 信号通路（Wnt-β-连环蛋白-GSK3 轴）的异常调控一直是癌症生物学中的一个普遍主题。在过去的几十年中，大量的工作表明 Wnt-β-连环蛋白-GSK3 信号轴参与了癌症干细胞（CSC）的形成和维持，CSC 负责几种人类恶性肿瘤的肿瘤生长。最近的研究阐明了控制多能性和干性的表观遗传机制，并首次评估了胚胎和正常组织干细胞在癌症中是如何失调的，从而产生 CSCs，以及经典的 Wnt 信号可能是如何参与的。在这里，我们回顾了新兴的概念，强调了表观遗传在通过异常经典 Wnt 信号通路发展 CSC 中的关键作用。最后，我们提到了对染色质组织机制的新型有效抑制剂的表征，这些抑制剂反过来又恢复了恶性细胞中的 Wnt-β-连环蛋白-GSK3 信号轴，并描述了将这些化合物引入临床前和临床研究的尝试和相关性。
