Cells with extra chromosomes (blue), and extra copies of a gene (green), are common in the intestine of mice with an APC mutation.

Aneuploidy is a hallmark of cancer, but the path from mutation to extra chromosomes is unclear. Now, Caldwell et al. help fill this gap, showing that a cancer-causing mutation promotes chromosome doubling by unfastening the mitotic spindle and hindering cell division.

The genome of a cancer cell is a mess, with breaks, rearrangements, and superfluous chromosomes. Many researchers speculate that the genomic instability that leads to aneuploidy and other chromosome chaos starts with tetraploidy, or a duplication of the genome. If so, cancer-spurring mutations should induce tetraploidy early in tumor development. One such mutation, Caldwell et al. suspected, occurs in the mitosis-controlling gene APC. The researchers previously found that APC mutations, which are prevalent in human colorectal tumors, lead to disrupted microtubules and misaligned chromosomes.

To test whether APC mutations promote tetraploidy, the researchers engineered human kidney cells to fashion a faulty version of the protein. The number of cells with two or more nuclei shot up 5 to 10 times. The cytokinetic furrow, which marks cell separation after anaphase, didn't form, and the cells often didn't divide. Moreover, the alteration seemed to unmoor the mitotic spindle, as it often spun or slid out of position.

Intestinal cells from mice that are heterozygous for an APC mutation had similar defects, the researchers found. Their cytokinetic furrows failed to form, their spindles were askew, and they tended to be tetraploid. These defects showed up in cells with no other signs of transformation and that still carried one normal version of APC.

Overall, the study suggests that tetraploidy is an early step toward cancer. Numerous cells in the mutant mice appear to complete this step—by the team's calculations, the small intestine harbored ∼100,000 tetraploid cells. Although most of these abnormal cells probably perish, their large numbers might allow cells to try out different chromosome combinations to find one that will allow them to advance toward cancer.


Caldwell, C.M., et al.
J. Cell Biol.