Inside and out: the activities of senescence in cancer

Pérez–Mancera, Pedro A.; Young, Andrew; Narita, Masashi

doi:10.1038/nrc3773

Cited by 405 publications

(402 citation statements)

References 160 publications

(166 reference statements)

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“…Senescence was first described in vitro , but its relevance as a physiological process in vivo is increasingly clear. Senescence induced in response to oncogenes has been recognized as a tumour suppressor mechanism (Kuilman et al ., 2010; Perez‐Mancera et al ., 2014). In addition, senescence also has roles in early embryogenesis and aging amongst other physiological processes (Munoz‐Espin & Serrano, 2014).…”

Section: Introductionmentioning

confidence: 99%

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

et al. 2015

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SummaryPolycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR‐9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR‐9‐1 and miR‐9‐2 as part of a regulatory negative feedback loop. The miR‐9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin‐dependent kinase inhibitor (CDKI) p16INK 4a during senescence. The ability of the miR‐9 family to regulate senescence could have implications for understanding the role of miR‐9 in cancer and aging.

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Section: Introductionmentioning

confidence: 99%

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

et al. 2015

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“…IL‐6, IL‐8, and some other ZEB1‐regulated secretory proteins are related to the senescence‐associated secretory phenotype (Perez‐Mancera et al ., 2014). However, the induction of cellular senescence in MDA‐231‐D cells by irradiation or doxorubicin treatment, followed by SA‐βGal staining, failed to show a significant correlation between ZEB1 expression and cellular senescence (Fig.…”

Section: Resultsmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

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“…117 The senescent-associated secretory phenotype provokes further immune-mediated deleterious effects on the local tissue microenvironment. Senescence also evokes an anti-Warburg effect.…”

Section: Macrophage Conditioning Angiogenesis and Tissue Viabilitymentioning

confidence: 99%

Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

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Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses.

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Inside and out: the activities of senescence in cancer

Cited by 405 publications

References 160 publications

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

ZEB1‐regulated inflammatory phenotype in breast cancer cells

Doyne lecture 2016: intraocular health and the many faces of inflammation

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Inside and out: the activities of senescence in cancer

Cited by 405 publications

References 160 publications

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

ZEB1‐regulated inflammatory phenotype in breast cancer cells

Doyne lecture 2016: intraocular health and the many faces of inflammation

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Resources

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CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a