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Milestones in cell division

Cell senescence and cancer

Key Points

  • Recently, it has been demonstrated that cell senescence in culture is not only induced by an intrinsic cell division counter mechanism (replicative senescence), but can also be induced by extrinsic factors such as culture conditions (premature senescence). The only known cell division counter is telomere shortening.

  • It has been proposed that replicative senescence suppresses tumorigenesis in vivo, as >90% tumours express telomerase at high levels and maintain telomere lengths. This is essential for their continued proliferation.

  • The increased cancer phenotype of the telomerase knockout mouse has shown that the role of telomere shortening in human cancer is difficult to predict. Depending on genetic context, telomere shortening can either promote or protect against tumorigenesis in mice. It is difficult to extrapolate these results to humans due to differing telomerase expression patterns and different telomere lengths.

  • Telomerase expression in human cells appears to correlate with proliferative requirements. These expression patterns may reflect a balance between different aspects of telomerase function: maintenance of telomere length and thus proliferative capacity; maintenance of genetic integrity; and a possible direct proliferative role.

  • Premature senescence, for example induced by oncogenic RAS or by suboptimal conditions equivalent to 'culture shock', may also operate as a tumour-suppressive mechanism.

  • Telomere shortening and thus increased genetic instability may account for the increased incidence of cancer as we age. An accumulation of senescent cells may also create environments that are more sustainable for tumour growth.

  • Both premature and replicative senescence could contribute to the progressive decline in bodily function associated with ageing. An accumulation of senescent cells may hinder normal function, decrease regenerative capacity and increase genetic damage.

  • The elevated expression of telomerase in almost all tumours may provide a diagnostic and prognostic tool for cancer. Moreover, as tumour cells require telomerase expression for continued proliferation, inhibitors of telomerase activity may provide effective cancer therapies.

Abstract

Historically, the senescent state has been associated with, and was named after, the cell-cycle arrest that occurs after cells have undergone an intrinsically defined number of divisions in vitro. More recently, however, it has been shown that extrinsic factors, including those encountered in normal tissue-culture environments, can prematurely induce an indistinguishable senescent phenotype. In this review, we discuss the pathways of cell senescence, the mechanisms involved and the role that these pathways have in regulating the initiation and progression of cancer.

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Figure 1: Telomere shortening determines the proliferative lifespan of human diploid fibroblasts.
Figure 2: Pathways to senescence.
Figure 3: Telomerase regulation during tumorigenesis.

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Acknowledgements

We thank M. Raff and A. Hall for critical reading of the manuscript. A.C.L. is a Cancer Research Campaign Senior Cancer Research Fellow. N. F. M. is funded by the Medical Research Council graduate programme.

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Correspondence to Alison C. Lloyd.

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DATABASES

LocusLink:

Apc

β-galactosidase

Cdkn2a

CDKN2A

MYC

p53

RAS

RB

TERT

Tert

TRF1

TRF2

Glossary

SCHWANN CELL

Glial cell of the peripheral nervous system.

OLIGODENDROCYTE PRECURSOR CELL

Glial cell precursor of the central nervous system.

ALT

(Alternative lengthening of telomeres). A recombination-based mechansim that allows telomere length maintenance in the absence of telomerase activity.

DOMINANT NEGATIVE

A defective protein that inhibits wild-type function by retaining interaction capabilities that result in distortion or competition with normal proteins.

SV40 LARGE T ANTIGEN

A large multifunctional protein that is encoded by the Simian virus 40 (SV40). SV40 large T can bind and inhibit functions of p53- and RB-family members.

MULTICENTRIC CHROMOSOMES

Chromosomes with more than one centromere.

CDKN2A

This locus, which is commonly mutated in cancer, encodes two transcripts with overlapping reading frames — Ink4a and Arf. Both protein products are involved in negative regulation of the cell cycle.

INK4A

A 16-kDa cyclin-dependent kinase inhibitor that is expressed from the Cdkn4a locus. It acts on cyclinD–CDK4/6 activity to inhibit cell-cycle progression.

ARF

A 19-kDa protein (14 kDa in humans) that is expressed from the Cdkn2a locus in response to oncogenic stimuli. It functions by stabilizing p53.

FAMILIAL ADENOMATOUS POLYPOSIS

Genetic disorder that is characterized by an increased predisposition to colorectal cancer, associated with germ-line mutations of the APC gene.

CYCLIN-DEPENDENT KINASE INHIBITORS

(CDKIs). Proteins that inhibit cell-cycle progression by binding to and inhibiting cyclin-dependent kinases.

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Mathon, N., Lloyd, A. Cell senescence and cancer. Nat Rev Cancer 1, 203–213 (2001). https://doi.org/10.1038/35106045

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