Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan.
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Massey Cancer Center, Richmond, VA, USA.
Semin Cancer Biol. 2022 Jun;81:37-47. doi: 10.1016/j.semcancer.2020.12.010. Epub 2020 Dec 20.
Senescence is a unique state of growth arrest that develops in response to a plethora of cellular stresses, including replicative exhaustion, oxidative injury, and genotoxic insults. Senescence has been implicated in the pathogenesis of multiple aging-related pathologies, including cancer. In cancer, senescence plays a dual role, initially acting as a barrier against tumor progression by enforcing a durable growth arrest in premalignant cells, but potentially promoting malignant transformation in neighboring cells through the secretion of pro-tumorigenic drivers. Moreover, senescence is induced in tumor cells upon exposure to a wide variety of conventional and targeted anticancer drugs (termed Therapy-Induced Senescence-TIS), representing a critical contributing factor to therapeutic outcomes. As with replicative or oxidative senescence, TIS manifests as a complex phenotype of macromolecular damage, energetic dysregulation, and altered gene expression. Senescent cells are also frequently polyploid. In vitro studies have suggested that polyploidy may confer upon senescent tumor cells the ability to escape from growth arrest, thereby providing an additional avenue whereby tumor cells escape the lethality of anticancer treatment. Polyploidy in tumor cells is also associated with persistent energy production, chromatin remodeling, self-renewal, stemness and drug resistance - features that are also associated with escape from senescence and conversion to a more malignant phenotype. However, senescent cells are highly heterogenous and can present with variable phenotypes, where polyploidy is one component of a complex reversion process. Lastly, emerging efforts to pharmacologically target polyploid tumor cells might pave the way towards the identification of novel targets for the elimination of senescent tumor cells by the incorporation of senolytic agents into cancer therapeutic strategies.
衰老（Senescence）是一种独特的生长停滞状态，是对多种细胞应激（包括复制性衰竭、氧化损伤和遗传毒性损伤）的反应。衰老与多种与衰老相关的病理学发病机制有关，包括癌症。在癌症中，衰老具有双重作用，最初通过在癌前细胞中强制持久的生长停滞来阻止肿瘤进展，从而发挥作用，但通过分泌促肿瘤驱动因素，可能会促进邻近细胞的恶性转化。此外，肿瘤细胞暴露于多种常规和靶向抗癌药物（称为治疗诱导衰老-TIS）时会诱导衰老，这是治疗结果的一个关键促成因素。与复制性或氧化性衰老一样，TIS 表现为大分子损伤、能量失调和基因表达改变的复杂表型。衰老细胞通常也是多倍体。体外研究表明，多倍体可能使衰老的肿瘤细胞能够逃避生长停滞，从而为肿瘤细胞逃避抗癌治疗的致命性提供了另一种途径。肿瘤细胞中的多倍体也与持续的能量产生、染色质重塑、自我更新、干性和耐药性有关-这些特征也与逃避衰老和转化为更恶性的表型有关。然而，衰老细胞高度异质，并且可以表现出不同的表型，其中多倍体是复杂回复过程的一个组成部分。最后，通过将衰老细胞溶解剂纳入癌症治疗策略中，来靶向多倍体肿瘤细胞的药理学方法的出现，可能为鉴定消除衰老肿瘤细胞的新靶标铺平道路。
