Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA.
Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA.
Semin Cancer Biol. 2022 Nov;86(Pt 3):566-582. doi: 10.1016/j.semcancer.2021.12.004. Epub 2021 Dec 18.
Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.
胃癌是全球癌症死亡的主要原因之一，治疗选择有限，患者生存率低。随着我们对胃癌分子认识的提高，我们现在开始认识到，这些癌症是一组具有独特发病机制和活跃致癌途径的异质性疾病。正是这种分子多样性，以及常常缺乏常见的致癌驱动突变，导致肿瘤学家在治疗胃癌时经常面临治疗反应不佳的情况。在这篇综述中，我们将探讨胃癌的治疗方法，包括最新的分子靶向治疗和免疫疗法。然后，我们将回顾胃癌的分子亚型，以突出该疾病的多样性。然后，我们将把讨论转移到基础科学和胃癌小鼠模型，作为研究胃癌分子异质性的工具。此外，我们将详细阐述一个称为返祖现象的分子过程和周期性打击模型，作为胃癌起始过程中的关键事件，赋予非分裂成熟分化细胞重新进入细胞周期的能力，并在多年的慢性炎症和损伤过程中积累不同的基因组突变。随着我们对胃癌基础科学认识的提高，我们的转化和临床努力也必须如此。我们将以单细胞分子分析和癌症类器官技术作为未来转化的途径，以深入了解胃癌的异质性，并设计基于精准医学的胃癌治疗方法结束讨论。阐明患者间和肿瘤内异质性是推进未来癌症预防、诊断和治疗的唯一途径。
