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Cancer Linked to Abnormal Number of Chromosomes


LA JOLLA, Calif. -- Aneuploidy can cause cancer or, in some circumstances, can keep it from happening, according to researchers here.

LA JOLLA, Calif., Dec. 28 -- A century ago, a German biologist named Theodor Boveri suggested that one of the causes of cancer was aneuploidy.

The suggestion made sense, because many cancer cells have too many or two few chromosomes, but in all these years no one has been able to prove it, mainly because of the difficulty of inducing aneuploidy in experimental models.

Now researchers here say they've demonstrated that Boveri was on target. Aneuploidy does cause cancer, declared Don Cleveland, Ph.D., of the University of California at San Diego.

But surprisingly, Dr. Cleveland and colleagues found, the same condition can also prevent cancer in some circumstances. That finding may open up new therapeutic avenues, Dr. Cleveland and colleagues reported in the January issue of Cancer Cell.

The researchers reported a series of experiments in vitro and in experimental animals genetically engineered to have reduced levels of CENtromere-associated Protein-E (CENP-E).

That protein, Dr. Cleveland and colleagues said, is essential to the process of mitosis, but appears to have little other function in the cell.

The researchers first showed that cells from mouse fibroblasts, modified so they contained one normal and one disrupted CENP-E allele, tended to give rise to aneuploid daughter cells more often than wild-type cells.

For that reason, the researcher created a line of nude mice with only one functioning CENP-E allele and compared them, as they aged, to wild-type counterparts.

Cells from all the animals demonstrated increased aneuploidy as they aged, but those with reduced levels of CENP-E had more aneuploid cells at every time point, Dr. Cleveland and colleagues reported.

The link with cancer was demonstrated by observing CENP-E-deficient and wild-type mice between the ages of 19 and 21 months, and comparing the incidence of spontaneous tumors.

Lymphomas of the spleen were detected in 10% of the modified mice, but in none of the wild-type mice -- a difference that was statistically significant at P=0.0402. Also, the researchers saw a statistically significant threefold increase in lung tumors in the modified mice, compared with normal littermates (P=0.0492).

The observation "validates Boveri's initial hypothesis, the researchers said: "Aneuploidy can indeed promote tumorigenesis in the absence of other observable defects."

But, surprisingly, aneuploidy appeared to confer a protective effect against liver cancer. Among the wild-type mice, 14% had one or more liver tumors, while the modified mice had half that rate and none had more than one tumor.

The difference in numbers did not reach statistical significance, but the tumors in the wild-type mice were also larger on average - a difference that was significant at P=0.0037.

In these wild-type mice, about one in five cells becomes aneuploid at every cell division, the researchers said, and increasing the rate of aneuploidy in the modified mice appeared to protect against tumors.

Dr. Cleveland and colleagues then asked what would happen if they tried to induce tumors using the carcinogen DMBA (7,12-dimethylbenz[a]anthracene). Thirty-eight animals were given a single dose of DMBA and examined at eight months for tumors.

The researchers found that 40% of the wild-type animals had a single lung tumor and an additional mouse that did not develop a lung tumor contained one ovarian and two mammary tumors.

In contrast, lung tumors were seen in 31% of the modified mice and tumors tended to be smaller. No tumors were seen in any other organs, the researchers said.

In a final surprise, the researchers found that mice with reduced levels of CENP-E as well as a complete lack of the tumor suppressor gene p19/ARF did better than mice that were also missing p19/ARF but had normal CENP-E.

The elevated aneuploidy increased tumor-free survival by 93 days, which was highly statistically significant at P=0.0079.

"When we created mice missing a tumor suppressor gene that also had a high rate of aneuploidy, tumor development was actually sharply delayed," Dr. Cleveland said.

One possible explanation suggested by the authors is a "mutational meltdown." Thus, "high levels of chromosomal instability can prevent clonal expansion," they wrote, "since cells that have acquired a rare transformative karyotype through multiple chromosome missegregations are likely to lose that karyotype in the next round of cell division."

One implication of the finding may be that deliberately creating aneuploidy in tumors might have a therapeutic effect, he added.

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