Journal Article

Cellular senescence in cancer: from mechanisms to detection

Ou, Hui‐Ling, Korkola, James E., Hoffmann, Reuben, Muñoz‐Espín, Daniel, González‐López, Cristina, Doherty, Gary J.

2021

Overview

Cellular senescence is considered a crucial process for tumour suppression, which can be facilitated by immune surveillance. However, when senescent cells persist in tissues, they can also trigger a plethora of tumour‐promoting effects. Here, we discuss the main hallmarks, mechanisms and roles of senescence in cancer and provide a comprehensive revision of the available tools for its detection. Senescence refers to a cellular state featuring a stable cell‐cycle arrest triggered in response to stress. This response also involves other distinct morphological and intracellular changes including alterations in gene expression and epigenetic modifications, elevated macromolecular damage, metabolism deregulation and a complex pro‐inflammatory secretory phenotype. The initial demonstration of oncogene‐induced senescence in vitro established senescence as an important tumour‐suppressive mechanism, in addition to apoptosis. Senescence not only halts the proliferation of premalignant cells but also facilitates the clearance of affected cells through immunosurveillance. Failure to clear senescent cells owing to deficient immunosurveillance may, however, lead to a state of chronic inflammation that nurtures a pro‐tumorigenic microenvironment favouring cancer initiation, migration and metastasis. In addition, senescence is a response to post‐therapy genotoxic stress. Therefore, tracking the emergence of senescent cells becomes pivotal to detect potential pro‐tumorigenic events. Current protocols for the in vivo detection of senescence require the analysis of fixed or deep‐frozen tissues, despite a significant clinical need for real‐time bioimaging methods. Accuracy and efficiency of senescence detection are further hampered by a lack of universal and more specific senescence biomarkers. Recently, in an attempt to overcome these hurdles, an assortment of detection tools has been developed. These strategies all have significant potential for clinical utilisation and include flow cytometry combined with histo‐ or cytochemical approaches, nanoparticle‐based targeted delivery of imaging contrast agents, OFF‐ON fluorescent senoprobes, positron emission tomography senoprobes and analysis of circulating SASP factors, extracellular vesicles and cell‐free nucleic acids isolated from plasma. Here, we highlight the occurrence of senescence in neoplasia and advanced tumours, assess the impact of senescence on tumorigenesis and discuss how the ongoing development of senescence detection tools might improve early detection of multiple cancers and response to therapy in the near future.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: 1-Phosphatidylinositol 3-kinase / 5-Fluorouracil / Acetylation / Adenocarcinoma / Ataxia / BAX protein / Bcl-2 protein / Bcl-x protein / Biomarkers - metabolism / Cancer / Cancer therapies / Carcinogenesis - metabolism / CCAAT/enhancer-binding protein / Cell cycle / Cellular Senescence / Chromatin / Computed tomography / Cyclic GMP / Cyclin-dependent kinase / Cyclin-dependent kinases / Dehydrogenases / detection / Dipeptidyl-peptidase IV / DNA damage / Endoplasmic reticulum / Enzyme inhibitors / Enzymes / Fibroblasts / Genotype & phenotype / Growth factors / Humans / Hyperplasia / Kinases / Lymphocytes B / Lymphoma / Magnetic resonance imaging / Metabolism / Nanoparticles / Neoplasms - diagnosis / Neoplasms - pathology / Phase transitions / Phenotype / Phenotypes / Phosphatase / Phosphorylation / Positron emission tomography / Proteins / Radiation / Reactive oxygen species / Retina / Retinoblastoma / Review / Reviews / Senescence / senoprobes / Transforming growth factor-b / Tumor Microenvironment / Tumor suppressor genes / Tumors / tumour microenvironment / Vascular endothelial growth factor / Xenografts / β2 Microglobulin