Department of Physiology, National University of Singapore, Singapore, Singapore (Z.Z.); Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore (Z.Z., D.M.V.); and Department of Pediatrics, Duke University, Durham, North Carolina (D.M.V.).
Department of Physiology, National University of Singapore, Singapore, Singapore (Z.Z.); Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore (Z.Z., D.M.V.); and Department of Pediatrics, Duke University, Durham, North Carolina (D.M.V.)
Mol Pharmacol. 2020 Feb;97(2):72-89. doi: 10.1124/mol.119.117978. Epub 2019 Dec 1.
Wnts are secreted proteins that bind to cell surface receptors to activate downstream signaling cascades. Normal Wnt signaling plays key roles in embryonic development and adult tissue homeostasis. The secretion of Wnt ligands, the turnover of Wnt receptors, and the signaling transduction are tightly regulated and fine-tuned to keep the signaling output "just right." Hyperactivated Wnt signaling due to recurrent genetic alterations drives several human cancers. Elevated Wnt signaling also confers resistance to multiple conventional and targeted cancer therapies through diverse mechanisms including maintaining the cancer stem cell population, enhancing DNA damage repair, facilitating transcriptional plasticity, and promoting immune evasion. Different classes of Wnt signaling inhibitors targeting key nodes of the pathway have been developed and show efficacy in treating Wnt-driven cancers and subverting Wnt-mediated therapy resistance in preclinical studies. Several of these inhibitors have advanced to clinical trials, both singly and in combination with other existing US Food and Drug Administration-approved anti-cancer modalities. In the near future, pharmacological inhibition of Wnt signaling may be a real choice for patients with cancer. SIGNIFICANCE STATEMENT: The latest insights in Wnt signaling, ranging from basic biology to therapeutic implications in cancer, are reviewed. Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.
Wnts 是一类分泌型蛋白，它们通过与细胞表面受体结合来激活下游信号级联反应。正常的 Wnt 信号通路在胚胎发育和成人组织稳态中发挥着关键作用。Wnt 配体的分泌、Wnt 受体的周转以及信号转导都受到严格的调控和精细的调节，以保持信号输出“恰到好处”。由于反复的遗传改变导致的 Wnt 信号过度激活，驱动了多种人类癌症的发生。通过多种机制，如维持癌症干细胞群体、增强 DNA 损伤修复、促进转录可塑性以及促进免疫逃逸，升高的 Wnt 信号还会赋予癌症对多种传统和靶向癌症疗法的耐药性。已经开发出了针对该通路关键节点的不同类别的 Wnt 信号抑制剂，并在临床前研究中显示出治疗 Wnt 驱动型癌症和颠覆 Wnt 介导的治疗耐药性的疗效。其中一些抑制剂已经进入临床试验，无论是单独使用还是与其他已获得美国食品和药物管理局批准的抗癌方式联合使用。在不久的将来，Wnt 信号通路的药理学抑制可能成为癌症患者的一个切实选择。
本文综述了 Wnt 信号通路的最新研究进展，包括基础生物学和癌症治疗方面的意义。最近的研究扩展了对这一古老信号通路的理解，并描述了用于癌症的抗 Wnt 治疗方式的发展和改进。
