Cancer and the Ageing Process

Abstract

The ageing process is a highly complex eventual outcome of development. Cancer is a disease of multicellular organisms that results primarily due to uncontrolled cell proliferation. Although cancer is a pathological phenomenon, ageing by itself is a natural process. However, ageing can promote certain age‐related pathologies including cancer. Both cancer and the ageing process have deleterious effects on the well‐being of an organism. At the cellular level, a complex phenotype known as cellular senescence regulates both cancer and the ageing process. A cell undergoes senescence due to telomere shortening or exposure to various stress factors. Senescent cells are morphologically and functionally distinct from proliferating and apoptotic cells. These cells do not divide but are metabolically active. In the context of a tissue or an organ, senescent cells exert both cell autonomous and nonautonomous effects, which regulate cancer and the ageing process.

Key Concepts:

  • Ageing is the key risk factor for cancer and it promotes cancer.

  • All normal cells undergo cellular senescence, a permanent growth‐arrested phase.

  • Cellular senescence results due to intrinsic factors such as telomere shortening or extrinsic factors such as stress.

  • Induction of senescence by intrinsic or extrinsic factors is mediated by p53/p21 and p16INK4A/pRB tumour suppressor pathways.

  • Tumour suppressor pathways not only regulate cancer but also regulate organismic ageing.

  • Cellular senescence contributes to ageing and cancer via its cell autonomous and nonautonomous effects.

  • Cellular senescence can suppress or promote cancer via cell autonomous and nonautonomous mechanisms.

  • Model systems can be used to study the mechanism of ageing and cancer.

Keywords: cancer; ageing; senescence; telomeres; telomerase; SA‐β‐gal; SASP

Figure 1.

Molecular mechanism of cellular senescence. The senescence‐inducing signals such as telomere attrition, oncogene activation and a variety of stresses that cause genomic and epigenomic damage initiate a DDR pathway, which activates p53 and its target genes inducing growth arrest. These signals also activate cell cycle inhibitor p16INK4A, which by inhibiting CDK4/6 activity promotes pRB in un‐ or hypophosphorylated (inhibitory) form. The hypophosphorylated pRB and consistent DDR signal relayed by the p53/p21 pathway maintains senescent phenotype. Senescent cells secrete SASP factors, which regulate ageing and senescence via cell autonomous and cell nonautonomous mechanism. These cells inhibit oncogenesis via cell‐autonomous mechanism, which maintains a stable proliferation arrest. Senescent cells can also promote oncogenesis via cell nonautonomous mechanism that involves paracrine signalling by SASP factors such as cytokines and growth factors secreted by the senescent cells.

Figure 2.

SASP factors secreted by senescent cells play a major role in ageing and cancer. The SASP programme is regulated by NF‐κB, C/EBPβ, and p38MAPK pathways. At least three categories of SASP factors, cytokines and chemokines, growth factors and matrix remodelling proteases are secreted by senescent cells. These proinflammatory, growth‐promoting and matrix degrading factors contribute to various age‐related physiological and pathological traits. SASP factors also promote cancer by increasing proliferation of preneoplastic cells, and increasing migration, EMT, invasion and metastasis of neoplastic cells. SASP factors can also promote chemoresistance and self‐renewal of cancer stem cells (CSC).

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Further Reading

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Dimri, Manjari, and Dimri, Goberdhan P(Mar 2014) Cancer and the Ageing Process. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025372]