COX2 regulates senescence secretome composition and senescence surveillance through PGE2

Goncalves, S.; Yin, Kai; Itō, Yoko; Chan, Adelyne; Olan, Ioana; Gough, Sarah; Cassidy, Liam; Serrao, Eva M.; Smith, Stephen; Young, Andrew; Narita, Masashi; Hoare, Matthew

doi:10.1016/j.celrep.2021.108860

Cited by 53 publications

(40 citation statements)

References 47 publications

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“…Whether the observed COX-2-mediated inflammatory effects of CTX-treated dying cancer cells promote or hinder CTX efficacy cannot be easily inferred. PGE 2 can have pleiotropic and often contrasting effects on the immune system 52 , 53 , recently implicated both in subverting anti-tumor immunity 27 – 30 as well as promoting immunosurveillance of senescent cells and suppression of early tumorigenesis 54 . Additionally the contribution of myeloid cells, such as neutrophils, to the efficacy of cytotoxic therapy is also conflicted 55 .…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

et al. 2022

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Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations.

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Section: Discussionmentioning

confidence: 99%

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

et al. 2022

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“…Thus, in addition to its population-scale pro-tumor effects, the SASP is also involved in anti-tumorigenesis at early stages by targeting individual senescent cells that could potentially become tumorigenic [ 107 , 118 , 120 ]. Many studies report divergent conclusions as to the anti- or pro-tumor role of the SASP [ 121 ].…”

Section: Sasp: a Major Determinant Of Tumorigenesismentioning

confidence: 99%

“…Particularly in the non-pathological context of wound healing, senescent cells present at a wound site secrete chemokines like CCL2 as part of the inflammatory secretome, which can attract immature monocytes expressing the chemokine receptor CCR2. These monocytes then become activated into polarized M1 (inflammatory) macrophages that produce interleukins such as IL-1alpha, IL-1beta and IL-6 and allow the recruitment of NK cells to the wound site [ 120 , 124 , 125 , 126 ]. NK cells will subsequently recognize and eliminate senescent cells [ 126 , 127 , 128 , 129 ].…”

Section: Acquisition Of Plasticity Allows Immunoevasion By Senescent Cellsmentioning

confidence: 99%

Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis

Blander

Morel

Senaratne

et al. 2021

Cancers

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Senescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the proliferation of damaged cells. Cells undergoing senescence sustain important morphological changes, chromatin remodeling and metabolic reprogramming, and secrete pro-inflammatory factors termed senescence-associated secretory phenotype (SASP). SASP activation is required for the clearance of senescent cells by innate immunity. Therefore, escape from senescence and the associated immune editing would be a prerequisite for tumor initiation and progression as well as therapeutic resistance. One of the possible mechanisms for overcoming senescence could be the acquisition of cellular plasticity resulting from the accumulation of genomic alterations and genetic and epigenetic reprogramming. The modified composition of the SASP produced by these reprogrammed cancer cells would create a permissive environment, allowing their immune evasion. Additionally, the SASP produced by cancer cells could enhance the cellular plasticity of neighboring cells, thus hindering their recognition by the immune system. Here, we propose a comprehensive review of the literature, highlighting the role of cellular plasticity in the pro-tumoral activity of senescence in normal cells and in the cancer context.

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“…For instance, fibroblasts that enter senescence initially predominantly secrete anti-inflammatory chemokines and TGF-β in a pathway driven by Notch-1 ( Hoare and Narita, 2017 ), while later ROS- and p38MAPK-induced activation of NF-kB and C/EBPbeta results in a pro-inflammatory SASP ( Acosta et al, 2008 , Coppé et al, 2008 ). Recently, COX-2 emerged as another critical regulator of SASP composition ( Gonçalves et al, 2021 ). The SASP attracts phagocytic immune cells and thus contributes to senescence resolution.…”

Section: Cellular Senescencementioning

confidence: 99%

How good is the evidence that cellular senescence causes skin ageing?

Low

Alimohammadiha

Smith

et al. 2021

Ageing Research Reviews

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Skin is the largest organ of the body with important protective functions, which become compromised with time due to both intrinsic and extrinsic ageing processes. Cellular senescence is the primary ageing process at cell level, associated with loss of proliferative capacity, mitochondrial dysfunction and significantly altered patterns of expression and secretion of bioactive molecules. Intervention experiments have proven cell senescence as a relevant cause of ageing in many organs. In case of skin, accumulation of senescence in all major compartments with ageing is well documented and might be responsible for most, if not all, the molecular changes observed during ageing. Incorporation of senescent cells into in-vitro skin models (specifically 3D full thickness models) recapitulates changes typically associated with skin ageing. However, crucial evidence is still missing. A beneficial effect of senescent cell ablation on skin ageing has so far only been shown following rather unspecific interventions or in transgenic mouse models. We conclude that evidence for cellular senescence as a relevant cause of intrinsic skin ageing is highly suggestive but not yet completely conclusive.

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COX2 regulates senescence secretome composition and senescence surveillance through PGE2

Cited by 53 publications

References 47 publications

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis

How good is the evidence that cellular senescence causes skin ageing?

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