Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells

Hwang, Han-Jeong; Lee, Ye Rim; Kang, Donghee; Lee, Hyung Chul; Seo, Haeng Ran; Yin, Guo Nan; Kim, Yong Nyun; Ko, Young Gyu; Park, Heon Joo; Lee, Jae Seon

doi:10.1016/j.canlet.2020.06.019

Cited by 90 publications

(62 citation statements)

References 51 publications

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“…The dichotomous effects of senescence on the cancer phenotype is attributed to some of the SAS factors [ 11 , 12 , 42 , 43 ]. In this regard, IL-6 [ 52 ], IL-8 [ 18 , 53 ], vascular endothelial growth factor (VEGF) [ 54 ], osteopontin [ 55 ], chemerin [ 56 ], matrix metalloproteinase [ 57 ], C-X-C motif chemokine 11 (CXCL11) [ 58 ] are associated with tumor growth, vascularization, invasion, migration as well as metastasis [ 59 ]. For instance, MCF-7 and MDA-MB-231 breast cancer cells exhibit increased proliferation index, migratory and invasive capacities when cultured in conditioned media from senescent mesenchymal stromal or fibroblast cells, effects attributed to IL-6 and/or IL-8 and signal transducer and activator of transcription 3 (STAT3) activation [ 52 , 53 ].…”

Section: Onco-suppressor and Oncogenic Facets Of Senescencementioning

confidence: 99%

The redox-senescence axis and its therapeutic targeting

et al. 2021

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Significance Cellular growth arrest, associated with ‘senescence’, helps to safeguard against the accumulation of DNA damage which is often recognized as the underlying mechanism of a wide variety of age-related pathologies including cancer. Cellular senescence has also been described as a ‘double-edged sword’. In cancer, for example, the creation of an immune-suppressive milieu by senescent tumor cells through the senescence-associated secretory phenotype contributes toward carcinogenesis and cancer progression. Recent advances The potential for cellular senescence to confer multi-faceted effects on tissue fate has led to a rejuvenated interest in its landscape and targeting. Interestingly, redox pathways have been described as both triggers and propagators of cellular senescence, leading to intricate cross-links between both pathways. Critical issues In this review, we describe the mechanisms driving cellular senescence, the interface with cellular redox metabolism as well as the role that chemotherapy-induced senescence plays in secondary carcinogenesis. Notably, the role that anti-apoptotic proteins of the Bcl-2 family play in inducing drug resistance via mechanisms that involve senescence induction. Future directions Though the therapeutic targeting of senescent cells as cancer therapy remains in its infancy, we summarize the current development of senotherapeutics, including recognized senotherapies, as well as the repurposing of drugs as senomorphic/senolytic candidates.

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Section: Onco-suppressor and Oncogenic Facets Of Senescencementioning

confidence: 99%

The redox-senescence axis and its therapeutic targeting

et al. 2021

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“…HUVECs with replicative senescence produce high levels of interleukin 8 (IL-8) ( Hampel et al, 2006 ), IL-6, PAI-1, and monocyte chemotactic protein-1 ( Lin et al, 2015 ). Senescent HUVECs induced by irradiation or doxorubicin produce high levels of C-X-C motif chemokine 11 ( Hwang et al, 2020 ). In senescent HUVECs induced by disturbed flow, cells display a strong SASP phenotype including excessive ROS, which is different from the SASP produced by HUVECs with replicative senescence ( Dominic et al, 2020 ).…”

Section: Cellular Senescence Of Endothelial Cellsmentioning

confidence: 99%

“…Moreover, senescent ECs are sufficient to impair insulin signaling in mice consuming normal chow diet through a SASP factor - IL-1α ( Barinda et al, 2020 ). Furthermore, the SASP of ECs induced by irradiation or doxorubicin can adversely affect the success of cancer therapy ( Hwang et al, 2020 ). Lastly, the SASP factors secreted by senescent ECs trigger platelet activation in vitro ( Venturini et al, 2020 ).…”

Section: Cellular Senescence Of Endothelial Cellsmentioning

confidence: 99%

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

Sun

Feinberg

2021

Front. Physiol.

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Cellular senescence is a stable form of cell cycle arrest in response to various stressors. While it serves as an endogenous pro-resolving mechanism, detrimental effects ensue when it is dysregulated. In this review, we introduce recent advances for cellular senescence and inflammaging, the underlying mechanisms for the reduction of nicotinamide adenine dinucleotide in tissues during aging, new knowledge learned from p16 reporter mice, and the development of machine learning algorithms in cellular senescence. We focus on pathobiological insights underlying cellular senescence of the vascular endothelium, a critical interface between blood and all tissues. Common causes and hallmarks of endothelial senescence are highlighted as well as recent advances in endothelial senescence. The regulation of cellular senescence involves multiple mechanistic layers involving chromatin, DNA, RNA, and protein levels. New targets are discussed including the roles of long noncoding RNAs in regulating endothelial cellular senescence. Emerging small molecules are highlighted that have anti-aging or anti-senescence effects in age-related diseases and impact homeostatic control of the vascular endothelium. Lastly, challenges and future directions are discussed including heterogeneity of endothelial cells and endothelial senescence, senescent markers and detection of senescent endothelial cells, evolutionary differences for immune surveillance in mice and humans, and long noncoding RNAs as therapeutic targets in attenuating cellular senescence. Accumulating studies indicate that cellular senescence is reversible. A better understanding of endothelial cellular senescence through lifestyle and pharmacological interventions holds promise to foster a new frontier in the management of cardiovascular disease risk.

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“…Senescent endothelial cells secrete cytokines and chemokines that affect damaged tissues and contribute to SASP [38][39][40][41]. PAI-1, a prominent component of SASP, is an essential mediator of inflammation in response to intestinal radiation toxicity [21,24,42,43].…”

Section: Atorvastatin Inhibits Pai-1 Expression In Irradiated Huvecs mentioning

confidence: 99%

Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy

Kwak

Park

Kim

et al. 2021

IJMS

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Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.

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Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells

Cited by 90 publications

References 51 publications

The redox-senescence axis and its therapeutic targeting

The redox-senescence axis and its therapeutic targeting

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy

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