Credit: Khoon Lay Gan / Alamy Stock Vector

Picture this: an unattended stew is boiling over and splatters everywhere. What could we do? We could put on a lid, remove the pot from the heat, and leave it to cool. Similarly, primary mammalian cells appear to have found ways to handle their own undesirable spread. Cellular senescence can serve as a break in excessive proliferation, providing an initial barrier, and eventually protection, against tumorigenesis.

Cellular senescence is provoked by either an intrinsic mitotic counter (replicative senescence) or extrinsic factors, such as oxidative stress or DNA damage at any point in the cell’s replicative history (premature senescence). The latter can also be driven by activated oncogenes, such as those in the RAS family, and is better known as oncogene-induced senescence (OIS). In the late 1990s, findings from cultured cells linked OIS to two major cell-signalling pathways that are often disrupted in cancer: INK4A–RB and ARF–p53. However, at that point, whether OIS was an authentic anticancer process or an artefact of imposed oncogene expression in cells experiencing ‘culture shock’ was unclear.

In 2005, four groups reported remarkable in vivo evidence of the existence of OIS in several mouse and human premalignant tissues. They presented a novel set of senescence markers and provided a sneak peek into the molecular groundwork. Although unified in their finding that OIS is tumour suppressive, these studies demonstrated that pathways underlying OIS are dependent on the tumour tissue and oncogenic insult.

Until 2005, senescence-associated β-galactosidase was the ‘gold standard’ in vivo marker for senescence. Collado et al. identified a small set of genes with expression profiles correlating with the KRAS-V12-induced senescence phenotype and used these to show that senescent cells exist among premalignant adenomas but not malignant adenocarcinomas in lung, skin and pancreatic tissues. Confirming the discoveries in preneoplasia, Michaloglou et al. characterized the telomere- and p53-independent BRAF-V600E-induced senescence observed in skin moles (nevi) but not melanoma cells. In contrast, Chen et al. showed that p53 is crucial for OIS in premalignant prostate tissue in vitro and in vivo when the tumour suppressor PTEN is lost. Loss of p53 and PTEN inhibits any protection from prostate cancer development, but this type of induced senescence is reversed by deletion of p53 regulators.

Senescent cells often show unusual chromatin foci of tightly packed DNA. Braig et al. researched the epigenetic contributions and found that NRAS-induced lymphocyte senescence is dependent on the histone methyltransferase SUV39H1 and the tumour suppressor RB, which jointly promote DNA compaction mediated by methylation of histone H3 Lys 9 (H3K9me); this process is crucial for triggering H3K9me-mediated senescent growth arrest and thus providing an initial barrier to lymphoma development.

Do senescence triggers interact? Two subsequent studies in 2006 provided robust evidence that OIS (induced via the oncoproteins HRAS-V12, MOS, CDC6 or cyclin E) is associated with signs of DNA-replication stress, thereby establishing that OIS is a direct consequence of a vigorous DNA-damage-checkpoint response, after DNA hyper-replication and the formation of double-strand breaks. In addition, inflammatory mediators appear to be a crucial aspect in the barrier network. Cells undergoing OIS exhibit a senescence-associated secretory phenotype (SASP). In 2008, the secretion of multiple chemokines and interleukins (including IL-6 and IL-8) was found to maintain growth arrest, thereby stabilizing the system, whereas SASP factors may act as growth promoters in other settings.

Is the induction of senescence the long-awaited tool for cancer therapy? Sadly, life is rarely that simple, and research in the past decade has exposed the multifaceted and highly dynamic nature of senescence and its star players. Although therapy-induced senescence can improve long-term outcomes, it has also been found to cause relapse, enhanced self-renewal and adverse reactions to cancer treatment. Consequently, the elimination of senescent cells has recently emerged as a sensible therapeutic strategy. Current investigations are underway to explore the clinical potential and benefits for cancer patients.

Further reading

Sherr, C. J. & DePinho, R. A. Cellular senescence: mitotic clock or cultural shock. Cell 102, 407–410 (2000).

Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

Dorr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013).

Baker, D. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).