Relationship between incorrect chromosome number and cancer is reassessed after surprising experiments

Over a century ago, a German-born scientist experimenting with impregnated sea urchin eggs had an insight that led to one of the first modern theories of cancer. Theodor Boveri linked incorrect chromosome number in urchin embryos with abnormal development. In 1902 he reasoned that having the wrong number of chromosomes could cause cells to grow uncontrollably and become the seeds of cancerous tumors.

Today in the journal Cancer Cell, Cold Spring Harbor Laboratory (CSHL) Fellow Jason Sheltzer, Ph.D., and colleagues at CSHL and MIT report surprising results of experiments intended to explore the consequences of having too many or too few chromosomes, a phenomenon that biologists call aneuploidy (AN-you-ploid-ee).

Ever since Boveris era, its been known that cells in most cancers 90% of solid tumors and 75% of blood cancers have abnormal chromosome numbers. (Most human cells normally have 46 chromosomes: two sets of 23, one set inherited from each parent.) The newly published experiments suggest the relation between aneuploidy and cancer is more complex than previously believed.

"Boveri brilliantly hypothesized that having the wrong chromosome number disrupted an equilibrium in cells between signals that promote and inhibit proliferation, leading normal cells to be transformed into cancerous ones" Sheltzer says. "We set out to test this in cell lines derived from mice and humans, and came up with a result we definitely did not expect which then led us to dig deeper for answers."

Sheltzer, who began his project in the laboratory of Dr. Angelika Amon at MIT and carried it to conclusion in his own research group at CSHL, placed two sets of otherwise identical cells in culture dishes, side by side. One set consisted of cells with normal chromosome number; the other set, cells with a single extra chromosome. They observed that cells in the aneuploid set grew much more slowly. This was all the more perplexing given that both sets of cells had been primed for cancerous transformation, via the activation of cancer-promoting genes called oncogenes. Moreover, when the pre-malignant aneuploid cells were injected into rodents, they consistently formed smaller tumors than the pre-malignant cells with normal chromosome numbers.

If having one extra chromosome caused an anti-tumorigenic effect in pre-malignant cells, then perhaps aneuploidy was not, in itself, a direct cause of cancer. This raised an obvious question, however: why are human cancer cells overwhelmingly aneuploid?