scholarly journals Senescent Cells in Cancer: Wanted or Unwanted Citizens

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3315
Author(s):  
Sven E. Niklander ◽  
Daniel W. Lambert ◽  
Keith D. Hunter
Keyword(s):  
Cell Cycle ◽  
Cancer Treatment ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Cancer Development ◽  
Paracrine Effects ◽  
Age Related ◽  
Secretory Phenotype

Over recent decades, the field of cellular senescence has attracted considerable attention due to its association with aging, the development of age-related diseases and cancer. Senescent cells are unable to proliferate, as the pathways responsible for initiating the cell cycle are irreversibly inhibited. Nevertheless, senescent cells accumulate in tissues and develop a pro-inflammatory secretome, known as the senescence-associated secretory phenotype (SASP), which can have serious deleterious effects if not properly regulated. There is increasing evidence suggesting senescent cells contribute to different stages of carcinogenesis in different anatomical sites, mainly due to the paracrine effects of the SASP. Thus, a new therapeutic field, known as senotherapeutics, has developed. In this review, we aim to discuss the molecular mechanisms underlying the senescence response and its relationship with cancer development, focusing on the link between senescence-related inflammation and cancer. We will also discuss different approaches to target senescent cells that might be of use for cancer treatment.

scholarly journals Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype

2021 ◽  
Vol 9 ◽  
Author(s):  
Ruchi Kumari ◽  
Parmjit Jat
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Growth Arrest ◽  
Dependent Manner ◽  
Tissue Repair And Regeneration ◽  
Cycle Arrest ◽  
Age Related ◽  
Secretory Phenotype

Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.

scholarly journals Senescence and Cancer: Role of Nitric Oxide (NO) in SASP

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1145
Author(s):  
Nesrine Mabrouk ◽  
Silvia Ghione ◽  
Véronique Laurens ◽  
Stéphanie Plenchette ◽  
Ali Bettaieb ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cancer Treatment ◽  
Cellular Senescence ◽  
Negative Effects ◽  
No Donors ◽  
Cell State ◽  
Age Related ◽  
A Cell ◽  
Secretory Phenotype

Cellular senescence is a cell state involved in both physiological and pathological processes such as age-related diseases and cancer. While the mechanism of senescence is now well known, its role in tumorigenesis still remains very controversial. The positive and negative effects of senescence on tumorigenesis depend largely on the diversity of the senescent phenotypes and, more precisely, on the senescence-associated secretory phenotype (SASP). In this review, we discuss the modulatory effect of nitric oxide (NO) in SASP and the possible benefits of the use of NO donors or iNOS inducers in combination with senotherapy in cancer treatment.

scholarly journals The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 485
Author(s):  
Lorenzo Cuollo ◽  
Fabrizio Antonangeli ◽  
Angela Santoni ◽  
Alessandra Soriani
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Senescent Cell ◽  
Pharmacological Intervention ◽  
Tissue Microenvironment ◽  
Age Related ◽  
Secretory Phenotype ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

scholarly journals Cellular Senescence and Mammalian Healthspan

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 742-742
Author(s):  
Judith Campisi
Keyword(s):  
Growth Factors ◽  
Cell Fate ◽  
Cellular Senescence ◽  
Complex Cell ◽  
Transgenic Mouse Models ◽  
Bioactive Lipids ◽  
Age Related ◽  
Mammalian Tissues ◽  
Secretory Phenotype ◽  
Near Future

Abstract Cellular senescence is a complex cell fate, often induced by stress or damage, that can be beneficial or deleterious, depending on the physiological context and age of the organism. A prominent feature of senescent cells is a multi-faceted senescence-associated secretory phenotype (SASP), which includes growth factors, cytokine and chemokines, growth factors, proteases, bioactive lipids and metabolites. Senescent cells increase with age in most, if not all, mammalian tissues. Through the use of transgenic mouse models, senescent cells are now known to causally drive numerous age-related pathologies, largely through the SASP. Eliminating senescent cells, genetically or through the use of senolytic/senomorphic agents, can improve the health span, at least in mice, and hold promise for extension to humans in the near future.

scholarly journals Obstructive Sleep Apnea as an Acceleration Trigger of Cellular Senescence Processes through Telomere Shortening

2021 ◽  
Vol 22 (22) ◽  
pp. 12536
Author(s):  
Szymon Turkiewicz ◽  
Marta Ditmer ◽  
Marcin Sochal ◽  
Piotr Białasiewicz ◽  
Dominik Strzelecki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Circadian Clock ◽  
Chronic Inflammation ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Telomere Shortening ◽  
Age Related ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) is chronic disorder which is characterized by recurrent pauses of breathing during sleep which leads to hypoxia and its two main pathological sequelae: oxidative stress and chronic inflammation. Both are also associated with cellular senescence. As OSA patients present with higher prevalence of age-related disorders, such as atrial hypertension or diabetes mellitus type 2, a relationship between OSA and accelerated aging is observable. Furthermore, it has been established that these OSA are associated with telomere shortening. This process in OSA is likely caused by increased oxidative DNA damage due to increased reactive oxygen species levels, DNA repair disruptions, hypoxia, chronic inflammation, and circadian clock disturbances. The aim of the review is to summarize study outcomes on changes in leukocyte telomere length (LTL) in OSA patients and describe possible molecular mechanisms which connect cellular senescence and the pathophysiology of OSA. The majority of OSA patients are characterized by LTL attrition due to oxidative stress, hypoxia and inflammation, which make a kind of positive feedback loop, and circadian clock disturbance.

scholarly journals Cellular Senescence in Renal and Urinary Tract Disorders

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2420
Author(s):  
Yohan Santin ◽  
Philippe Lluel ◽  
Pascal Rischmann ◽  
Xavier Gamé ◽  
Jeanne Mialet-Perez ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Senescent Cell ◽  
Post Injury ◽  
Urinary Tract Disorders ◽  
Age Related ◽  
Adverse Remodeling ◽  
Bladder Disorders

Cellular senescence is a state of cell cycle arrest induced by repetitive cell mitoses or different stresses, which is implicated in various physiological or pathological processes. The beneficial or adverse effects of senescent cells depend on their transitory or persistent state. Transient senescence has major beneficial roles promoting successful post-injury repair and inhibiting malignant transformation. On the other hand, persistent accumulation of senescent cells has been associated with chronic diseases and age-related illnesses like renal/urinary tract disorders. The deleterious effects of persistent senescent cells have been related, in part, to their senescence-associated secretory phenotype (SASP) characterized by the release of a variety of factors responsible for chronic inflammation, extracellular matrix adverse remodeling, and fibrosis. Recently, an increase in senescent cell burden has been reported in renal, prostate, and bladder disorders. In this review, we will summarize the molecular mechanisms of senescence and their implication in renal and urinary tract diseases. We will also discuss the differential impacts of transient versus persistent status of cellular senescence, as well as the therapeutic potential of senescent cell targeting in these diseases.

scholarly journals KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype

2020 ◽  
Author(s):  
Boyi Zhang ◽  
Qilai Long ◽  
Shanshan Wu ◽  
Shuling Song ◽  
Qixia Xu ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Stromal Cells ◽  
Dynamic Change ◽  
Chromatin Accessibility ◽  
Rna Seq ◽  
H3k36 Methylation ◽  
Age Related ◽  
Secretory Phenotype ◽  
Human Stromal Cells ◽  
Therapeutic Avenue

AbstractCellular senescence restrains the expansion of neoplastic cells through several layers of regulation, including epigenetic decoration of chromatin structure and functional modulation of bioactive components. Here we report that expression of the histone H3-specific demethylase KDM4 is upregulated in human stromal cells upon cellular senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation are correlated with adverse survival of cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq and expression profiling through RNA-seq reveal extensive reorganization of chromosomes and spatiotemporal reprogramming of the transcriptomic landscape, events responsible for development of the senescence-associated secretory phenotype (SASP). Selectively targeting KDM4 dampens the SASP of senescent stromal cells and enhances the apoptotic index of cancer cells in the treatment-damaged tumor microenvironment (TME), together prolonging overall survival of experimental animals. Our study supports the dynamic change of H3K9/H3K36 methylation marks during cellular senescence, identifies an unusually permissive chromatin state, unmasks KDM4 as a key modulator of the SASP, and presents a novel therapeutic avenue to manipulate cellular senescence and curtail age-related pathologies.

scholarly journals Similarities and interplay between senescent cells and macrophages

2020 ◽  
Vol 220 (2) ◽  
Author(s):  
Jacques Behmoaras ◽  
Jesús Gil
Keyword(s):  
Tumor Microenvironment ◽  
Cellular Senescence ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Senescent Cell ◽  
Phenotypic Characteristics ◽  
Effector Functions ◽  
Inflammatory Conditions ◽  
Secretory Phenotype ◽  
Cancerous Cells

Senescence is a cellular program that prevents the replication of old, damaged, or cancerous cells. Senescent cells become growth arrested and undergo changes in their morphology, chromatin organization, and metabolism, and produce a bioactive secretome. This secretome, the senescence-associated secretory phenotype (SASP), mediates many of the pathophysiological effects associated with senescent cells, for example, recruiting and activating immune cells such as macrophages. The relation between senescent cells and macrophages is intriguing: senescent cells recruit macrophages, can induce them to undergo senescence, or can influence their polarization. Senescent cells and macrophages share multiple phenotypic characteristics; both have a high secretory status, increased lysosome numbers, or the ability to activate the inflammasome. Senescent cells accumulate during aging and disease, and killing them results in widespread benefits. Here we discuss similarities between senescent cells and macrophages and interpret the latest developments in macrophage biology to understand the molecular mechanisms of cellular senescence. We describe evidence and effects of senescence in macrophages and speculate on the ontogeny of the senescent-like state in macrophages. Finally, we examine the macrophage–senescent cell interplay and its impact on macrophage effector functions during inflammatory conditions and in the tumor microenvironment.

scholarly journals Insights from In Vivo Studies of Cellular Senescence

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 954
Author(s):  
Luis I. Prieto ◽  
Sara I. Graves ◽  
Darren J. Baker
Keyword(s):  
Cellular Senescence ◽  
Cell Biology ◽  
Senescent Cell ◽  
In Vivo Studies ◽  
Cycle Arrest ◽  
Mammalian Cell Lines ◽  
Age Related ◽  
Cell Accumulation ◽  
Secretory Phenotype

Cellular senescence is the dynamic process of durable cell-cycle arrest. Senescent cells remain metabolically active and often acquire a distinctive bioactive secretory phenotype. Much of our molecular understanding in senescent cell biology comes from studies using mammalian cell lines exposed to stress or extended culture periods. While less well understood mechanistically, senescence in vivo is becoming appreciated for its numerous biological implications, both in the context of beneficial processes, such as development, tumor suppression, and wound healing, and in detrimental conditions, where senescent cell accumulation has been shown to contribute to aging and age-related diseases. Importantly, clearance of senescent cells, through either genetic or pharmacological means, has been shown to not only extend the healthspan of prematurely and naturally aged mice but also attenuate pathology in mouse models of chronic disease. These observations have prompted an investigation of how and why senescent cells accumulate with aging and have renewed exploration into the characteristics of cellular senescence in vivo. Here, we highlight our molecular understanding of the dynamics that lead to a cellular arrest and how various effectors may explain the consequences of senescence in tissues. Lastly, we discuss how exploitation of strategies to eliminate senescent cells or their effects may have clinical utility.

Inflammaging of Female Reproductive System: a Molecular Landscape

2020 ◽  
Vol 13 ◽  
Author(s):  
Valeriia Rodichkina ◽  
Igor Kvetnoy ◽  
Victoria Polyakova ◽  
Alexander Arutjunyan ◽  
Ruslan Nasyrov ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Functional Decline ◽  
Reproductive Function ◽  
Reproductive Age ◽  
Loss Of Function ◽  
Negative Effects ◽  
Age Related ◽  
Complex Biological Process ◽  
Secretory Phenotype ◽  
Cellular Stresses

: Aging is a complex biological process, a major aspect of which is the accumulation of somatic changes throughout the life. Cellular senescence is a condition in which cells undergo an irreversible cell cycle arrest in response to various cellular stresses. Once the cells begin to senesce, they become more resistant to any mutagens, including oncogenic factors. Inflammaging (inflammatory aging) is an age-related, chronic and systemic inflammatory condition realized by cells with the senescence associated secretory phenotype (SASP). These recently recognized senescent phenotypes associated with aging have been reported to promote better wound healing, embryonic development, as well as stimulation and extension of the tumor process. It is assumed that cellular senescence contributes to age-related decline of reproductive function due to the association of senescent cells with aging and age-related diseases. Thus, SASPs have both positive and negative effects, depending on the biological context. SASP cell accumulation in tissues contributes to an age-related functional decline of the tissue and organ state. In this review, the term “cellular senescence” is used to refer the processes of cells irreversible growth inhibition during their viable state, while the term “aging” is used to indicate the deterioration of tissues due to loss of function. Late reproductive age is associated with infertility and possible complications of the onset and maintenance of pregnancy. Senescent cells express pro-inflammatory cytokines, growth factors, and matrix metalloproteinases and some other molecules, collectively called the senescence associated secretory phenotype (SASP).

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