Double Trouble: Cells With Duplicate Genomes Can Trigger Tumors

The so-called "double-value" cells are produced by random errors incell division that occur with unknown frequency. The generation ofthese genetically unstable cells appears to be a "pathway forgenerating a tumor," says David Pellman, MD, a pediatric oncologist atDana-Farber and at Children's Hospital Boston. He is the senior authoron a report in the Oct. 13 issue of Nature. Takeshi Fujiwara, PhD, andMadhavi 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 andin a precancerous condition called Barrett's esophagus. In addition tothe extra chromosomes, the "double value" or "tetraploid" cells alsoduplicate a cell structure called the centrosome that plays a role inmaintaining a stable genome. The extra centrosomes may be at the rootof 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 neartriploid chromosome number (one and a half times the normal chromosomecontent). Because the cells with extra chromosomes and centrosomes arebiologically different from normal cells, cancer drugs designed to killthem while sparing normal cells are "an interesting possibility," saysPellman, who is also an associate professor of Pediatrics at HarvardMedical School.

The researchers treated normal breast cells with a compound thatinterfered with the final step of cell division, causing many of themto have the extra chromosome set. To make the cells more likely tobecome malignant, the researchers used cells that lacked a protectivegene, p53 that is inactivated in many forms of cancer. Compared withnormal breast cells, the double-value cells tended to be genomicallyunstable.

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

The new findings confirm a far-sighted notion of TheodorBoveri, a German scientist of the 19th Century who was one of thediscoverers that the chromosomes in the nucleus of the cell carry thematerial of heredity, or genes. In 1914, he published what Pellmancalls an "amazingly accurate and prescient" treatise suggesting, amongother 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 thedouble-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 cellscontain 44 pairs plus the sex chromosomes.

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

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

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

In addition to Pellman and Fujiwara, the other authors are fromDana-Farber, Children's Hospital Boston, Harvard Medical School, andTufts University Veterinary School.

The work was supported by the National Institutes of Health and the Mathers Foundation.

Dana-Farber Cancer Institute (www.dana-farber.org)is a principal teaching affiliate of the Harvard Medical School and isamong the leading cancer research and care centers in the UnitedStates. It is a founding member of the Dana-Farber/Harvard CancerCenter (DF/HCC), designated a comprehensive cancer center by theNational Cancer Institute.