Zhang Ruoyu, Tan Yunfei, Jiang Dedi, Kong Dewei, Liu Mei, Liang Jianwei, Wu Aiwen, Wang Liming
Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli Area, Chaoyang District, Beijing 100021, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Unit III & Ostomy Service, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Biochim Biophys Acta Rev Cancer. 2025 Oct;1880(5):189401. doi: 10.1016/j.bbcan.2025.189401. Epub 2025 Jul 29.
Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with metastatic spread being the primary reason for fatalities. Anoikis, a form of programmed cell death triggered by cell detachment from the extracellular matrix (ECM), and NETosis, a neutrophil cell death mode releasing extracellular traps (NETs), play critical roles in CRC liver metastasis (CRCLM). This review explores the mechanisms of anoikis and NETosis, their interplay, and genetic underpinnings in CRCLM. Anoikis resistance in CRC cells allows survival during metastasis in the initial stage, while NETs promote tumor progression by facilitating immune evasion, ECM remodeling, and angiogenesis. Meanwhile, through bioinformatics analysis and summary, we elaborated on the relationship between anoikis and NETosis as well as the potential interaction mechanisms, exploring the connecting links between them. The crosstalk between these processes is analyzed, highlighting shared signaling pathways (e.g., PI3K/AKT, MAPK, EMT) and potential biomarkers (e.g., MUC13, GLI2, SIRT6, FASN). Therapeutic strategies targeting anoikis and NETosis, including inhibitors of integrins, EGFR, and NET components (e.g., DNase I, CXCR2 antagonists), inhibitors of autophagy (e.g., CQ, HCQ, azithromycin) are discussed. This comprehensive analysis advances understanding of CRCLM pathogenesis and provides novel perspectives for targeted interventions.
结直肠癌（CRC）是癌症相关死亡的主要原因，转移扩散是致死的主要原因。失巢凋亡是一种由细胞与细胞外基质（ECM）脱离引发的程序性细胞死亡形式，而中性粒细胞胞外陷阱形成（NETosis）是一种释放细胞外陷阱（NETs）的中性粒细胞死亡模式，它们在结直肠癌肝转移（CRCLM）中起关键作用。本综述探讨了失巢凋亡和NETosis的机制、它们之间的相互作用以及CRCLM中的遗传基础。CRC细胞中的失巢凋亡抗性使其在转移初期得以存活，而NETs则通过促进免疫逃逸、ECM重塑和血管生成来促进肿瘤进展。同时，通过生物信息学分析和总结，我们阐述了失巢凋亡与NETosis之间的关系以及潜在的相互作用机制，探索它们之间的联系。分析了这些过程之间的相互作用，突出了共享的信号通路（如PI3K/AKT、MAPK、EMT）和潜在的生物标志物（如MUC13、GLI2、SIRT6、FASN）。讨论了针对失巢凋亡和NETosis的治疗策略，包括整合素抑制剂、EGFR抑制剂和NET成分抑制剂（如DNase I、CXCR2拮抗剂）、自噬抑制剂（如氯喹、羟氯喹、阿奇霉素）。这一全面分析增进了对CRCLM发病机制的理解，并为靶向干预提供了新的视角。
