More than a century ago, researchers discovered cancer cells often have an abnormal number of chromosomes. Whether this aberration was a cause or effect of tumor formation was controversial. Now scientists find the way chromosomes are divvied up among dividing cancer cells can help explain whether tumor formation will be promoted or suppressed, report findings detailed in the Proceedings of the National Academy of Sciences.
When cells possess more or fewer than the regular number of chromosomes, this abnormality, known as aneuploidy, is often due to how the chromosomes segregate — that is, how each chromosome splits off from its matching partner during cell division. Confusingly, aneuploidy could either promote or suppress tumor formation. What factors determined which outcome aneuploidy would result in was unclear.
To help discover the role of aneuploidy in cancer, researchers analyzed tumor development in mice with reduced levels of CENP-E, a protein that helps sort chromosomes. Previous studies found reduced CENP-E levels increased the rate of spleen and lung tumors, but could also lead to fewer and smaller spontaneous liver tumors and suppress cancers in other situations.
The researchers bred mice with normal or reduced levels of CENP-E with mice with normal and reduced levels of Mad2, another protein involved in cell division, deficiency in which also leads to aneuploidy. This led to a spectrum of mice with different levels of improper chromosome segregation.
The scientists found the rate at which chromosomes segregated improperly determined the effect of aneuploidy on tumors. Low rates of chromosome missegregation promoted tumors, but increasing the rate of chromosome missegregation beyond a certain threshold killed cells and suppressed tumors.
“The implication is that increasing the rate of chromosome missegregation may be an effective therapy in chromosomally unstable tumors,” said researcher Beth Weaver, a cell biologist at the University of Wisconsin at Madison. “This could aid in selecting patient populations for existing and novel chemotherapy agents.”