Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan.
Department of Pathology, Microbiology, and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan.
Biosci Rep. 2021 May 28;41(5). doi: 10.1042/BSR20210079.
Senescence is a cell stress response induced by replicative, oxidative, oncogenic, and genotoxic stresses. Tumor cells undergo senescence in response to several cancer therapeutics in vitro (Therapy-Induced Senescence, TIS), including agents utilized as neoadjuvant chemotherapy (NAC) in the treatment of invasive breast cancer. TIS has been proposed to contribute to adverse therapy outcomes including relapse. However, there is limited evidence on the induction of senescence in response to NAC in clinical cancer and its contribution to disease outcomes. In this work, the expression of three senescence-associated markers (p21CIP1, H3K9Me3 (histone H3 lysine 9 trimethylation), and Lamin B1) was investigated in breast cancer samples that developed partial or incomplete pathological response to NAC (n=37). Accordingly, 40.54% of all samples showed marker expression consistent with a senescence-like phenotype, while the remainders were either negative or inconclusive for senescence (2.70 and 56.8%, respectively). Moreover, analysis of core-needle biopsies revealed minimal changes in p21CIP1 and H3K9Me3, but significant changes in Lamin B1 expression levels following NAC, highlighting a more predictive role of Lamin B1 in senescence detection. However, our analysis did not establish an association between TIS and cancer relapse as only three patients (8.1%) with a senescence-like profile developed short-term recurrent disease. Our analysis indicates that identification of TIS in tumor samples requires large-scale transcriptomic and protein marker analyses and extended clinical follow-up. Better understanding of in vivo senescence should elucidate its contribution to therapy outcomes and pave the way for the utilization of senolytic approaches as potential adjuvant cancer therapy.
衰老（senescence）是一种由复制、氧化、致癌和遗传毒性应激引起的细胞应激反应。肿瘤细胞在体外对几种癌症治疗药物（治疗诱导的衰老，TIS）会发生衰老，包括在浸润性乳腺癌治疗中用作新辅助化疗（NAC）的药物。TIS 被认为会导致不良的治疗结果，包括复发。然而，关于 NAC 治疗后临床癌症中衰老的诱导及其对疾病结果的贡献，证据有限。在这项工作中，研究了在对 NAC 部分或不完全病理反应的乳腺癌样本中三种衰老相关标志物（p21CIP1、H3K9Me3（组蛋白 H3 赖氨酸 9 三甲基化）和 Lamin B1）的表达。相应地，所有样本中有 40.54%显示出与衰老样表型一致的标志物表达，而其余的则为阴性或衰老结果不确定（分别为 2.70%和 56.8%）。此外，对核心针活检的分析显示，p21CIP1 和 H3K9Me3 的变化最小，但 Lamin B1 的表达水平在 NAC 后有显著变化，突出了 Lamin B1 在衰老检测中的更具预测性作用。然而，我们的分析并没有建立 TIS 与癌症复发之间的联系，因为只有 3 名（8.1%）具有衰老样特征的患者发生了短期复发性疾病。我们的分析表明，在肿瘤样本中识别 TIS 需要大规模的转录组和蛋白质标志物分析以及延长的临床随访。更好地了解体内衰老应该阐明其对治疗结果的贡献，并为使用衰老溶解剂作为潜在的辅助癌症治疗铺平道路。
