Distant metastases and drug resistance account for poor survival of patients with gastrointestinal (GI) malignancies such as gastric cancer, pancreatic cancer, and colorectal cancer. GI cancers most commonly metastasize to the liver, which provides a unique immunosuppressive tumour microenvironment to support the development of a premetastatic niche for tumor cell colonization and metastatic outgrowth. Metastatic tumors often exhibit greater resistance to drugs than primary tumors, posing extra challenges in treatment. The liver metastases and drug resistance of GI cancers are regulated by complex, intertwined, and tumor-dependent cellular and molecular mechanisms that influence tumor cell behavior (e.g. epithelial-to-mesenchymal transition, or EMT), tumor microenvironment (TME) (e.g. the extracellular matrix, cancer-associated fibroblasts, and tumor-infiltrating immune cells), tumor cell-TME interactions (e.g. through cytokines and exosomes), liver microenvironment (e.g. hepatic stellate cells and macrophages), and the route and mechanism of tumor cell dissemination (e.g. circulating tumor cells). This review provides an overview of recent advances in the research on cellular and molecular mechanisms that regulate liver metastases and drug resistance of GI cancers. We also discuss recent advances in the development of mechanism-based therapy for these GI cancers. Targeting these cellular and molecular mechanisms, either alone or in combination, may potentially provide novel approaches to treat metastatic GI malignancies.

中文翻译：

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胃肠道癌、肝转移和耐药的细胞和分子机制


远处转移和耐药性是胃肠道 （GI） 恶性肿瘤（如胃癌、胰腺癌和结直肠癌）患者生存率低的原因。胃肠道癌症最常转移到肝脏，肝脏提供了独特的免疫抑制性肿瘤微环境，以支持肿瘤细胞定植和转移性生长的转移前生态位的发育。转移性肿瘤通常比原发性肿瘤表现出更大的药物耐药性，这给治疗带来了额外的挑战。胃肠道癌症的肝转移和耐药性受复杂、交织和肿瘤依赖性细胞和分子机制的调节，这些机制影响肿瘤细胞行为（例如 上皮-间充质转化，或 EMT）、肿瘤微环境 （TME）（例如 细胞外基质、癌症相关成纤维细胞和肿瘤浸润免疫细胞）、肿瘤细胞-TME 相互作用（例如 通过细胞因子和外泌体）、肝脏微环境（例如 肝星状细胞和巨噬细胞）以及肿瘤细胞播散的途径和机制（例如 循环肿瘤细胞）。本文综述了调控胃肠道癌症肝转移和耐药性的细胞和分子机制研究的最新进展。我们还讨论了这些胃肠道癌症的基于机制的疗法开发的最新进展。单独或联合靶向这些细胞和分子机制，可能会为治疗转移性胃肠道恶性肿瘤提供新的方法。