Research highlights

Tumour suppression: The power of arrest

Nature Reviews Molecular Cell Biology 8, 7 (01 July 2007) | doi:10.1038/nrm2200

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Cellular senescence is an irreversible cell-cycle arrest that can be triggered in response to several stimuli, including the shortening of telomeres. It has long been thought to represent a tumour suppression mechanism, but in vivo evidence has been lacking. Two studies that made use of sophisticated mouse cancer models now reveal the power of cellular senescence as a p53-mediated mechanism of tumour suppression.

Feldser and Greider crossed mice that lacked the RNA component of telomerase (mTR^-/-) with a transgenic mouse model of Burkitt's lymphoma that expressed the Myc oncogene in B cells. Tumour formation was suppressed in Myc mTR^-/- mice with short telomeres. To investigate whether this effect was due to induction of the apoptotic pathway (as has been demonstrated in other tumour models), the authors disabled the apoptotic pathway by selectively expressing the anti-apoptotic Bcl2 gene in Myc mTR^-/- bone marrow cells. Surprisingly, Bcl2-expressing Myc mTR^-/- mice with short telomeres were still resistant to tumour formation.

...cellular senescence as a p53-mediated mechanism of tumour suppression.

The authors also created Myc mTR^-/-p53^+/- mice, which also had short telomeres but lacked one p53 allele and formed tumours with the same rapid onset as telomerase-positive mice. Together, this requirement for p53 — but not apoptosis — suggests that p53-mediated cellular senescence is responsible for tumour suppression. Indeed, pre-tumour microlymphoma cells from Bcl2-expressing Myc mTR^-/- mice with short telomeres stained positive for markers of cellular senescence.

In a second study, Cosme-Blanco et al. used p53 mutant (p53^R172P) mice; p53^R172P cells are unable to undergo apoptosis but retain intact cell-cycle arrest and cellular senescence pathways. The authors generated telomerase-deficient mTR^-/-p53^R172P mice and found that the presence of shortened telomeres was associated with the suppression of tumour formation, indicating that cellular senescence, and not apoptosis, is important to prevent spontaneous tumorigenesis. However, the overall lifespan of these mutants did not differ significantly from wild-type p53 mice. A possible reason is that cellular senescence could negatively affect the survival of healthy, proliferative tissues. Indeed, mTR^-/-p53^R172P mice showed some hallmarks of premature ageing. However, mTR^-/-p53^R172P mice were unable to suppress carcinogen-induced skin cancer, which indicates that tumour suppression in this context might require both apoptosis and cellular senescence.

Altogether, these studies provide the long-awaited in vivo evidence for the hypothesis that senescence induced by telomere dysfunction is a powerful tumour suppression mechanism. The findings also imply that the requirements for an apoptotic response or senescence, or both, might be context dependent.

Author: Arianne Heinrichs