Molecular Oncology Laboratory, University of Melbourne, Melbourne, VIC, Australia.
Victorian Infectious Diseases Reference Laboratory, Doherty Institute of Infection and Immunity, Melbourne, VIC, Australia.
Br J Pharmacol. 2017 Dec;174(24):4666-4683. doi: 10.1111/bph.13890. Epub 2017 Jul 5.
Gastric cancer persists as a frequent and deadly disease that claims over 700 000 lives annually. Gastric cancer is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal cancers, making it therapeutically challenging. As such, and largely attributed to late-stage diagnosis, gastric cancer patients show only partial response to standard chemo and targeted molecular therapies, highlighting an urgent need to develop new targeted therapies for this disease. Wnt signalling has a well-documented history in the genesis of many cancers and is, therefore, an attractive therapeutic target. As such, drug discovery has focused on developing inhibitors that target multiple nodes of the Wnt signalling cascade, some of which have progressed to clinical trials. The collective efforts of patient genomic profiling has uncovered genetic lesions to multiple components of the Wnt pathway in gastric cancer patients, which strongly suggest that Wnt-targeted therapies could offer therapeutic benefits for gastric cancer patients. These data have been supported by studies in mouse models of gastric cancer, which identify Wnt signalling as a driver of gastric tumourigenesis. Here, we review the current literature regarding Wnt signalling in gastric cancer and highlight the suitability of each class of Wnt inhibitor as a potential treatment for gastric cancer patients, in relation to the type of Wnt deregulation observed.
This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
胃癌仍然是一种常见且致命的疾病，每年导致超过 70 万人死亡。胃癌是一种多因素疾病，在遗传、细胞学和结构上比其他胃肠道癌症更为异质，因此治疗具有挑战性。由于诊断较晚，胃癌患者对标准化疗和靶向分子治疗仅表现出部分反应，这突出表明迫切需要为这种疾病开发新的靶向治疗方法。Wnt 信号在许多癌症的发生中有着有据可查的历史，因此是一个有吸引力的治疗靶点。因此，药物发现的重点是开发针对 Wnt 信号级联多个节点的抑制剂，其中一些已进入临床试验。对胃癌患者的基因组进行的集体分析揭示了胃癌患者 Wnt 通路的多个组成部分的遗传病变，这强烈表明 Wnt 靶向治疗可能为胃癌患者带来治疗益处。这些数据得到了胃癌小鼠模型研究的支持，这些研究确定了 Wnt 信号是胃肿瘤发生的驱动因素。在这里，我们回顾了有关胃癌中 Wnt 信号的现有文献，并根据观察到的 Wnt 失调的类型，强调了每种 Wnt 抑制剂类别作为潜在胃癌治疗方法的适用性。
本文是关于 Wnt 信号：机制和治疗机会的专题部分的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
