Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.

By T. Kuilman, C. Michaloglou, Liesbeth C. W. Vredeveld, Sirith Douma, R. van Doorn, C. Desmet, L. Aarden, W. Mooi, D. Peeper. Cell, 2008

2,003 citations recorded by the source corpus.

Oncogene-induced cellular senescence (OIS) is emerging as a potent cancer-protective response to oncogenic events, serving to eliminate early neoplastic cells from the proliferative pool. Using combined genetic and bioinformatic analysis, we find that OIS is linked specifically to the activation of an inflammatory transcriptome. Induced genes included the pleiotropic cytokine interleukin-6 (IL-6), which upon secretion by senescent cells acted mitogenically in a paracrine fashion. Unexpectedly, IL-6 was also required for the execution of OIS, but in a cell-autonomous mode. Its depletion caused the inflammatory network to collapse and abolished senescence entry and maintenance. Furthermore, we demonstrate that the transcription factor C/EBPbeta cooperates with IL-6 to amplify the activation of the inflammatory network, including IL-8. In human colon adenomas, IL-8 specifically colocalized with arrested, p16(INK4A)-positive epithelium. We propose a model in which the context-dependent cytostatic and promitogenic functions of specific interleukins contribute to connect senescence with an inflammatory phenotype and cancer.

Subfields: Immunology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/4610dda859e30591124ee8100d69fad1bc434368

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. J. Campisi
2. J. Kirkland
3. M. Demaria
4. T. Tchkonia
5. Adam Freund
6. Tuo Li
7. C. Patil
8. Jesús Gil

In Oncology

1. J. Campisi
2. Jesús Gil
3. J. Kirkland
4. Zhijian J. Chen
5. D. Peeper
6. T. Kuilman
7. M. Demaria
8. Adam Freund

In Physiology

1. J. Campisi
2. J. Kirkland
3. Jesús Gil
4. M. Demaria
5. T. Tchkonia
6. Adam Freund
7. P. Desprez
8. C. Patil

Citations in the corpus

• The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression (2010, background): “IL-6 has been shown to be associated with DNA damage– and oncogenic stress–induced senescence of mouse and human keratinocytes, melanocytes, monocytes, fibroblasts, and epithelial cells (16, 18, 57, 58).”
• CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma (2016, neutral): “For example, inflammatory signaling can promote oncogene-induced senescence (Acosta et al., 2008; Kuilman et al., 2008).”
• Senescence is a developmental mechanism that contributes to embryonic growth and patterning. (2013, background): “Additionally, mediators of senescent reinforcement such as interleukin-6 (IL-6) and IL-8 were also not Cell 155, 1119–1130, No increased in our array (Acosta et al., 2008; Kuilman et al., 2008).”
• Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence (2017, neutral): “On a molecular level, several transcription factors have been implicated in the up-regulation of SASP-genes including NF-κ B, C/EBP-β , p38 MAPK and GATA4 12, 13, 14, 15, 16.”
• Programmed cell senescence during mammalian embryonic development. (2013, neutral): “…induced by the infliction of DNA damage (Lafferty-Whyte et al., 2010), replicative senescence (Kim et al., 2013; Shelton et al., 1999), oncogene-induced senescence (Collado et al., 2005; Kuilman et al., 2008), or activation of tumor suppressors (Abad et al., 2007; Rovillain et al., 2011).”
• The essence of senescence. (2010, background): “…interference with expression of other genes—including those encoding p53, C/EBPb, or 2466 GENES & DEVELOPMENT interleukin-6 (IL-6) (see below)—also reduces SAHF-positivity, which is associated with abrogation of senescence (Chan et al. 2005; Ye et al. 2007; Zhang et al. 2007; Kuilman et al. 2008).”