Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
Comput Biol Med. 2024 Nov;182:109196. doi: 10.1016/j.compbiomed.2024.109196. Epub 2024 Oct 2.
Cellular senescence (CS) is characterized by the irreversible cell cycle arrest and plays a key role in aging and diseases, such as cancer. Recent years have witnessed the burgeoning exploration of the intricate relationship between CS and cancer, with CS recognized as either a suppressing or promoting factor and officially acknowledged as one of the 14 cancer hallmarks. However, a comprehensive characterization remains absent from elucidating the divergences of this relationship across different cancer types and its involvement in the multi-facets of tumor development. Here we systematically assessed the cellular senescence of over 10,000 tumor samples from 33 cancer types, starting by defining a set of cancer-associated CS signatures and deriving a quantitative metric representing the CS status, called CS score. We then investigated the CS heterogeneity and its intricate relationship with the prognosis, immune infiltration, and therapeutic responses across different cancers. As a result, cellular senescence demonstrated two distinct prognostic groups: the protective group with eleven cancers, such as LIHC, and the risky group with four cancers, including STAD. Subsequent in-depth investigations between these two groups unveiled the potential molecular and cellular mechanisms underlying the distinct effects of cellular senescence, involving the divergent activation of specific pathways and variances in immune cell infiltrations. These results were further supported by the disparate associations of CS status with the responses to immuno- and chemo-therapies observed between the two groups. Overall, our study offers a deeper understanding of inter-tumor heterogeneity of cellular senescence associated with the tumor microenvironment and cancer prognosis.
细胞衰老（CS）的特征是不可逆的细胞周期停滞，在衰老和疾病（如癌症）中发挥关键作用。近年来，人们对 CS 与癌症之间复杂关系的探索日益增多，CS 被认为是抑制或促进因素，并被正式确认为癌症的 14 个标志性特征之一。然而，对于不同癌症类型中这种关系的差异及其在肿瘤发展的多方面的参与，仍缺乏全面的特征描述。在这里，我们系统地评估了来自 33 种癌症类型的超过 10000 个肿瘤样本的细胞衰老情况，首先定义了一组与癌症相关的 CS 特征，并得出了一个表示 CS 状态的定量指标，称为 CS 评分。然后，我们研究了 CS 的异质性及其与不同癌症的预后、免疫浸润和治疗反应之间的复杂关系。结果表明，细胞衰老表现出两个截然不同的预后组：具有 11 种癌症（如 LIHC）的保护组和具有 4 种癌症（包括 STAD）的风险组。在这两组之间进行的深入调查揭示了细胞衰老的不同作用背后的潜在分子和细胞机制，涉及特定途径的不同激活和免疫细胞浸润的差异。这些结果还得到了两组之间观察到的 CS 状态与免疫和化学治疗反应之间的不同关联的支持。总的来说，我们的研究提供了对与肿瘤微环境和癌症预后相关的细胞衰老的肿瘤间异质性的更深入的理解。
