Role of extra chromosomes reconsidered

Tumor cell proliferation may not be due to aneuploidy, according to new study

By | August 16, 2007

Cells containing extra copies of chromosomes exhibit slowed proliferation regardless of what chromosome is affected, according to a new study of yeast cells published in Science this week. The results may help researchers better understand and target tumor cells, which are characterized by rapid proliferation and changed chromosome numbers - a condition known as aneuploidy. "One very interesting thing, which you wouldn't necessarily have expected to be the case, is this common set of phenotypes that has come out from all these different aneuploid strains," said Mike Tyers of the Samuel Lunenfeld Research Institute in Toronto, who was not involved in the study. Angleika Amon and her team found that aneuploid yeast cells suffer a suite of disadvantageous physiological traits, suggesting that it is the cell's physiological reaction to having extra chromosomes, rather than the extra chromosomes themselves, that the cause cancer cells' unchecked growth. Researchers have long postulated that extra chromosomes, and the oncogene copies they contain, may be to blame for cancer cells' unchecked proliferation. "Aneuploidy in itself is actually bad news for the cell. It disrupts the cellular homeostasis in a fundamental way," Amon of the Massachusetts Institute of Technology, lead researcher on the study, told The Scientist. Amon and her collaborators engineered several strains of aneuploid yeast cells by transferring one yeast chromosome at a time into normal nuclei. This resulted in separate strains that each had one extra copy of 13 of the yeast's 16 chromosomes. The aneuploid cells proliferated more slowly, used more glucose, and were more sensitive disruptions in protein synthesis and folding, such as high temperature and protein synthesis inhibitors. The researchers suggested that what caused these changes is the general over expression of proteins, and that yeast cells responded in ways similar to responses to environmental stress. "The cells get stressed out and start kicking in all these mechanisms to get a grip on all the extra proteins," Amon said. Steve Elledge of Harvard University, who was not involved in the study, predicted that studies describing cellular responses to aneuploidy will cause a "sea-change" in understanding cancer. "[Amon's] work goes toward pushing the concepts of cancer cells as being highly stressed and that there are going to be potential drug targets that are not oncogenes," Elledge told The Scientist. Tumor cells seem to be expert at dealing with aneuploidy and the resultant profusion of proteins that are expressed from extra chromosomes, Amon said. "Clearly there's an advantage to begin with by having extra oncogenes, but what our results really point to is that if you get extra oncogenes by gaining extra chromosomes, the cell has to evolve mechanisms to deal with these extra chromosomes." She and her colleagues have begun to identify aneuploid yeast strains that have developed such mechanisms and will search for the mutations within their genomes that confer the ability to cope with extra chromosomes. "The mutations, if we find them, will probably be subtle mutations," she said. "Finding that all out and dissecting out the contributions of the many mutations that we will find will be challenging." The researchers also plan to study aneuploidy in murine cell lines, an important step towards linking the findings to cancer in humans. Tyers said it is likely that the response seen in yeast cells will turn up in other species. "All these different yeast aneuploids are responding in the same manner, and it's clearly a general response to perturbation of the system," he said, "I would be very surprised if this didn't happen in mammalian cells." Bob Grant Links within this article: E. M. Torres et al., "Effects of aneuploidy on cellular physiology and cell division in haploid yeast," Science, August 2007.
Mike Tyers Lab
D. Steinberg, "Appraising aneuploidy as a cancer cause," The Scientist , March 2004.
S. Jaffe, "Migrating minds," The Scientist , April 2002.
Steve Elledge Lab

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