文章：

肿瘤缺氧驱动基因组不稳定性和肿瘤进化

Tumour hypoxia in driving genomic instability and tumour evolution

原文发布日期：2025-01-28

DOI: 10.1038/s41568-024-00781-9

类型: Review Article

开放获取: 否

英文摘要：

Intratumour hypoxia is a feature of all heterogenous solid tumours. Increased levels or subregions of tumour hypoxia are associated with an adverse clinical prognosis, particularly when this co-occurs with genomic instability. Experimental evidence points to the acquisition of DNA and chromosomal alterations in proliferating hypoxic cells secondary to inhibition of DNA repair pathways such as homologous recombination, base excision repair and mismatch repair. Cell adaptation and selection in repair-deficient cells give rise to a model whereby novel single-nucleotide mutations, structural variants and copy number alterations coexist with altered mitotic control to drive chromosomal instability and aneuploidy. Whole-genome sequencing studies support the concept that hypoxia is a critical microenvironmental cofactor alongside the driver mutations in MYC, BCL2, TP53 and PTEN in determining clonal and subclonal evolution in multiple tumour types. We propose that the hypoxic tumour microenvironment selects for unstable tumour clones which survive, propagate and metastasize under reduced immune surveillance. These aggressive features of hypoxic tumour cells underpin resistance to local and systemic therapies and unfavourable outcomes for patients with cancer. Possible ways to counter the effects of hypoxia to block tumour evolution and improve treatment outcomes are described.

摘要翻译： 

肿瘤内缺氧是所有异质性实体瘤的一个特征。肿瘤缺氧水平增加或亚区域的存在与不良的临床预后相关，尤其当这种情况与基因组不稳定性同时发生时更为明显。实验证据表明，增殖中的缺氧细胞会因同源重组、碱基切除修复和错配修复等DNA修复途径受到抑制而获得DNA和染色体改变。在修复缺陷的细胞中，细胞适应和选择形成了一种模型，即新的单核苷酸突变、结构变异和拷贝数改变与有丝分裂控制改变共存，共同驱动染色体不稳定性和非整倍体。全基因组测序研究支持这样一个概念：在多种肿瘤类型中，缺氧是关键的微环境协同因素，与MYC、BCL2、TP53和PTEN等驱动突变一起决定克隆和亚克隆的进化。我们认为，缺氧的肿瘤微环境选择那些不稳定的肿瘤克隆，这些克隆在免疫监视减弱的情况下存活、增殖并转移。缺氧肿瘤细胞的这些侵袭性特征是导致其对局部和全身治疗产生抵抗以及癌症患者预后不良的基础。文中还描述了可能对抗缺氧效应以阻止肿瘤进化并改善治疗结果的途径。

原文链接：

Tumour hypoxia in driving genomic instability and tumour evolution