Aneuploidy throws up a surprise

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There is now formal confirmation that not only can aneuploidy promote tumorigenesis, but that, in certain cellular contexts, it can also inhibit tumor formation.

The so-called aneuploidy hypothesis postulates that an abnormal chromosome number can drive tumorigenesis. It is only now, some 100 years since it was first proposed, that Weaver et al. provide its formal confirmation. Unexpectedly, their results reveal that not only can aneuploidy promote tumorigenesis, but that, in certain cellular contexts, it can inhibit tumour formation.

Although it has been shown that aneuploidy-inducing carcinogens and mitotic checkpoint aberrations drive tumorigenesis, the potential effects of aneuploidy on tumorigenesis initiation could not be distinguished from other potentially tumorigenic effects in these cases. The authors turned to a system in which such complications could be avoided. They turned to Cenpe (centromere-associated protein E), which encodes a conserved motor protein with a crucial function in chromosome segregation during mitosis. Using Cenp^+/- mouse embryo fibroblasts, they show that halving CENPE levels leads to aneuploidy but has no other discernable defects.

Using a number of cell-growth and behaviour assays, the authors show that aneuploidy contributes to transformation in vitro; although aneuploidy-induced transformation is a slow and incompletely penetrant process. Aneuploidy is also tumorigenic — transformed aneuploid Cenpe^+/- cells formed tumours when injected into nude mice. Moreover, old Cenpe^+/- mice developed more spontaneous tumours, such as splenic lymphomas and lung tumours, than their wild-type counterparts.

The surprise came when Weaver et al. saw that Cenpe^+/- mice had fewer and smaller liver tumours. A similar 'protective' effect was seen in these mice after carcinogen treatment. And when the authors compared tumour development in Cenpe^+/+ and Cenpe^+/- mice that also carried a null mutation in the p19/ARF tumour suppressor gene, Cenpe^+/-; p19/ARF mice showed substantially longer tumour latency, indicating that aneuploidy can slow down tumorigenesis in vivo.

To explain the tumour suppressor effects of aneuploidy, the authors suggest that high levels of chromosomal instability can prevent clonal expansion — cells that have acquired a rare transforming karyotype are likely to lose it in the subsequent round of cell division. The effect is akin to that of chemotherapeutic drugs, which provoke cell death and tumour regression by producing high levels of DNA damage. So in the process of providing a long-awaited proof for a 100-year-old hypothesis, Weaver et al. uncovered a surprising, hitherto unknown face of aneuploidy.

Magdalena Skipper

References

Weaver, B. A. A. et al. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11, 25–36 (2007) | Article | PubMed |
Kops, G. J. P. L. et al. On the road to cancer: aneuploidy and the mitotic checkpoint. Nature Rev. Cancer 5, 773–785 (2005) | Article | PubMed |