Avalos-Navarro Guadalupe, Gallegos-Arreola Martha Patricia, Reyes-Uribe Emmanuel, Jave Suárez Luis Felipe, Rivera-Sánchez Gildardo, Rangel-Villalobos Héctor, Madriz-Elisondo Ana Luisa, Gutiérrez Hurtado Itzae Adonai, Varela-Hernández Juan José, Ramírez-Patiño Ramiro
Departamento de Ciencias Médicas y de la Vida, Centro Universitario de la Ciénega (CUCIÉNEGA), Universidad de Guadalajara, Av. Universidad 1115, Lindavista, Ocotlán 47820, Mexico.
División de Genética, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Independencia Oriente, Guadalajara 44340, Mexico.
Int J Mol Sci. 2025 Jul 20;26(14):6954. doi: 10.3390/ijms26146954.
Metastases are the leading cause of cancer-related deaths. The spread of neoplasms involves multiple mechanisms, with metastatic tumors exhibiting molecular behaviors distinct from their primary counterparts. The key hallmarks of metastatic lesions include chromosomal instability, copy number alterations (CNAs), and a reduced degree of subclonality. Furthermore, metabolic adaptations such as enhanced glycogen synthesis and storage, as well as increased fatty acid oxidation (FAO), play a critical role in sustaining energy supply in metastases and contributing to chemoresistance. FAO promotes the infiltration of macrophages into the tumor, where they polarize to the M2 phenotype, which is associated with immune suppression and tissue remodeling. Additionally, the tumor microbiome and the action of cytotoxic drugs trigger neutrophil extravasation through inflammatory pathways. Chemoresistant neutrophils in the tumor microenvironment can suppress effector lymphocyte activation and facilitate the formation of neutrophil extracellular traps (NETs), which are linked to drug resistance. This article examines the genomic features of metastatic tumors, along with the metabolic and immunological dynamics within the metastatic tumor microenvironment, and their contribution to drug resistance. It also discusses the molecular mechanisms underlying resistance to chemotherapeutic agents commonly used in the treatment of metastatic cancer.
转移是癌症相关死亡的主要原因。肿瘤的扩散涉及多种机制，转移性肿瘤表现出与其原发肿瘤不同的分子行为。转移性病变的关键特征包括染色体不稳定、拷贝数改变（CNA）以及亚克隆性程度降低。此外，代谢适应，如增强的糖原合成和储存，以及增加的脂肪酸氧化（FAO），在维持转移灶的能量供应和导致化疗耐药方面起着关键作用。FAO促进巨噬细胞浸润到肿瘤中，在那里它们极化为M2表型，这与免疫抑制和组织重塑有关。此外，肿瘤微生物群和细胞毒性药物的作用通过炎症途径触发中性粒细胞外渗。肿瘤微环境中具有化疗抗性的中性粒细胞可抑制效应淋巴细胞的激活，并促进中性粒细胞胞外陷阱（NETs）的形成，而NETs与耐药性有关。本文研究了转移性肿瘤的基因组特征，以及转移性肿瘤微环境中的代谢和免疫动力学，及其对耐药性的影响。它还讨论了转移性癌症治疗中常用化疗药物耐药的分子机制。
