Double trouble: Cells with duplicate genomes can trigger tumors

10/12/05

Study confirms century-old theory about cancer causation

BOSTON--Abnormal cell division that yields cells with an extra set of chromosomes can initiate the development of tumors in mice, researchers at Dana-Farber Cancer Institute have shown, validating a controversial theory about cancer causation put forth by a scientific visionary nearly 100 years ago.

The so-called "double-value" cells are produced by random errors in cell division that occur with unknown frequency. The generation of these genetically unstable cells appears to be a "pathway for generating a tumor," says David Pellman, MD, a pediatric oncologist at Dana-Farber and at Children's Hospital Boston. He is the senior author on a report in the Oct. 13 issue of Nature. Takeshi Fujiwara, PhD, and Madhavi Bandi of Dana-Farber, are the paper's co-first authors.

The research was performed in experimental animals, but such "double-value" cells are seen in a variety of early human cancers and in a precancerous condition called Barrett's esophagus. In addition to the extra chromosomes, the "double value" or "tetraploid" cells also duplicate a cell structure called the centrosome that plays a role in maintaining a stable genome. The extra centrosomes may be at the root of the cancer-triggering process. Once the genetic instability sets in, tumors "evolve " by losing, gaining and rearranging chromosomes.

Late-stage tumors commonly have too many centrosomes and a near triploid chromosome number (one and a half times the normal chromosome content). Because the cells with extra chromosomes and centrosomes are biologically different from normal cells, cancer drugs designed to kill them while sparing normal cells are "an interesting possibility," says Pellman, who is also an associate professor of Pediatrics at Harvard Medical School.

The researchers treated normal breast cells with a compound that interfered with the final step of cell division, causing many of them to have the extra chromosome set. To make the cells more likely to become malignant, the researchers used cells that lacked a protective gene, p53 that is inactivated in many forms of cancer. Compared with normal breast cells, the double-value cells tended to be genomically unstable.

When injected under the skin of laboratory mice, about 25 percent of the animals developed breast cell tumors, and these tumors, like the tetraploid cells that seeded them, were also marked by similar chromosomal irregularities.

The new findings confirm a far-sighted notion of Theodor Boveri, a German scientist of the 19th Century who was one of the discoverers that the chromosomes in the nucleus of the cell carry the material of heredity, or genes. In 1914, he published what Pellman calls an "amazingly accurate and prescient" treatise suggesting, among other things, that genetic instability was a cause of malignant tumors.

One way to obtain this lack of chromosomal integrity, Boveri proposed, was a result of cells failing to divide normally, generating the double-value or tetraploid cells. Normally, human cells carry a "diploid" set of chromosomes that is, 22 pairs plus an "X" and "Y" chromosome in males and two "X" chromosomes in female. Tetraploid cells contain 44 pairs plus the sex chromosomes.

"Our experiments test an idea that's been percolating along among cell biologists for many years but was never really embraced by the cancer community," says Pellman. "We set up this experiment to test it in a real cancer setting."

A companion paper being published simultaneously in Nature by Randy King and colleagues at Harvard Medical School reports that tetraploid cells may arise more frequently than had been thought. According to Pellman, the instability of tetraploid cells may have played a role in evolution, because many organisms, including humans, are thought to have undergone ancient genome doublings.

The therapeutic implications arise from biological differences between the tetraploid cells and normal cells that might make the tetraploid-derived cancerous cells vulnerable to doses of drugs that aren't harmful to the normal cells and tissues. " In other experiments, we identified genes in a model organism-- yeast-- that are essential for the survival of tetraploid cells but not for cells with a normal number of chromosomes" Pellman says. "You knock out those genes, and the tetraploid cells die. We are eager to find out if this can be extended to cancer cells and the new animal model should help us do this."

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