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.