Xia Qi-Dong, Sun Jian-Xuan, Liu Chen-Qian, Xu Jin-Zhou, An Ye, Xu Meng-Yao, Liu Zheng, Hu Jia, Wang Shao-Gang
Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Cell Dev Biol. 2022 Mar 21;10:832892. doi: 10.3389/fcell.2022.832892. eCollection 2022.
Ferroptosis is a unique iron-dependent form of cell death and bladder cancer (BCa) is one of the top ten most common cancer types in the world. However, the role of ferroptosis in shaping the tumor microenvironment and influencing tumor clinicopathological features remains unknown. Using the data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we comprehensively evaluated the ferroptosis patterns of 570 BCa samples based on 234 validated ferroptosis genes reported in the FerrDb database and systematically correlated these ferroptosis patterns with tumor microenvironment (TME) cell-infiltrating characteristics. The ferroptosis score was constructed to quantify ferroptosis patterns of individuals using principal component analysis (PCA) algorithms. Four distinct ferroptosis patterns and two gene clusters were finally determined. Significant differences in clinical characteristics and the prognosis of patients were found among different ferroptosis patterns and gene clusters, so were in the mRNA transcriptome and the landscape of TME immune cell infiltration. We also established a set of scoring system to quantify the ferroptosis pattern of individual patients with BCa named the ferroptosis score, which was discovered to tightly interact with clinical signatures such as the TNM category and tumor grade and could predict the prognosis of patients with BCa. Moreover, tumor mutation burden (TMB) was positively correlated to the ferroptosis score, and the low ferroptosis score was related to a better response to immunotherapy using PD-1 blockade. Finally, we also found there existed a positive correlation between the sensitivity to cisplatin chemotherapy and ferroptosis score. Our work demonstrated and interpreted the complicated regulation mechanisms of ferroptosis on the tumor microenvironment and that better understanding and evaluating ferroptosis patterns could be helpful in guiding the clinical therapeutic strategy and improving the prognosis of patients with BCa.
铁死亡是一种独特的铁依赖性细胞死亡形式，而膀胱癌（BCa）是全球十大最常见的癌症类型之一。然而，铁死亡在塑造肿瘤微环境和影响肿瘤临床病理特征方面的作用仍不清楚。利用从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）下载的数据，我们基于FerrDb数据库中报告的234个经过验证的铁死亡基因，全面评估了570个BCa样本的铁死亡模式，并系统地将这些铁死亡模式与肿瘤微环境（TME）细胞浸润特征相关联。使用主成分分析（PCA）算法构建铁死亡评分，以量化个体的铁死亡模式。最终确定了四种不同的铁死亡模式和两个基因簇。在不同的铁死亡模式和基因簇之间，患者的临床特征和预后存在显著差异，mRNA转录组和TME免疫细胞浸润格局也存在显著差异。我们还建立了一套评分系统来量化BCa个体患者的铁死亡模式，称为铁死亡评分，发现它与TNM分类和肿瘤分级等临床特征紧密相关，并可以预测BCa患者的预后。此外，肿瘤突变负荷（TMB）与铁死亡评分呈正相关，低铁死亡评分与使用PD-1阻断的免疫治疗更好的反应相关。最后，我们还发现顺铂化疗敏感性与铁死亡评分之间存在正相关。我们的工作展示并解释了铁死亡对肿瘤微环境的复杂调控机制，更好地理解和评估铁死亡模式有助于指导临床治疗策略并改善BCa患者的预后。
