Abnormal Number of Chromosomes is One Step in Cancer Development

Researchers have produced the first laboratory evidence to show that a cell’s possession of an abnormal numbers of chromosomes contributes to the development of cancers. Their report on the role of this chromosomal instability, known as aneuploidy, appears in today’s online edition of the Feb. 3 Journal of Cell Biology. Because 85 percent of human cancer cells possess an abnormal number of chromosomes, researchers have long been curious about the role of aneuploidy in the multistep cancer process. From the Mayo Clinic:
Mayo Clinic Research Shows Abnormal Number of Chromosomes is One Step in Cancer Development

ROCHESTER, Minn. — Mayo Clinic researchers have produced the first laboratory evidence to show that a cell’s possession of an abnormal numbers of chromosomes contributes to the development of cancers. Their report on the role of this chromosomal instability, known as aneuploidy, appears in today’s online edition of the Feb. 3 Journal of Cell Biology.

Because 85 percent of human cancer cells possess an abnormal number of chromosomes, researchers have long been curious about the role of aneuploidy in the multistep cancer process. Questions centering on the role of aneuploidy have been regarded as classics in cancer biology — questions such as: Does chromosomal instability play a functional role that is necessary for cancers to grow? Or, is it merely a feature of cancerous growth?

The Significance of the Mayo Team’s Research

The achievement of the Mayo Clinic study is that it provides laboratory proof from animal studies supporting a theory that researchers around the world have held for several years. As such, the Mayo team found a clear correlation between the development of cancer and defects in the “mitotic checkpoint” — a cellular mechanism that, when working properly, works like a security system to guard against abnormal numbers of chromosomes being distributed to cells.

Editorial comments in the Journal of Cell Biology introducing the Mayo paper note that “the results show that the mammalian mitotic checkpoint system is extremely sensitive to under-expression of its components.” The editors conclude that the significance of the Mayo research is that it describes “new mouse models that should be useful in studying cancer progression.”

“We actually find clear correlations now between the susceptibility to cancer and the rate at which chromosomal instability occurs in the cell,” says Jan Van Deursen, Ph.D., a Mayo Clinic research scientist and principal investigator of the study. “It really confirms what everybody always suspected, but was unable to show experimentally.”

First described just five years ago, the mitotic checkpoint is still being elaborated ? and one part of the Mayo study discovers a new component of it. The mitotic checkpoint is thought to consist of at least 10-15 components that function like a molecular security system for the orderly progression through the cell growth cycle. In humans, that means every healthy cell must have 46 chromosomes.

“If you don’t have this checkpoint on the highest alert at all times, you start to make mistakes,” says Dr. Van Deursen. In some cancer cells, there may be 60 or even 80 chromosomes instead of 46.

Mayo Clinic’s Findings
Mayo researchers found the following:
*A new component of the mitotic checkpoint, called Rae1.

*That if a mouse does not possess two gene copies for Rae1, it cannot produce enough cellular protein to properly activate the mitotic checkpoint. As a result of this “lax” security system for proper cell division, the Rae1-defective cell will then be predisposed to developing an abnormal number of chromosomes, a condition called “aneuploidy.”

*Mice with aneuploidy who were exposed to a known cancer-causing substance at birth developed a significant increase in tumors, compared to mice that have normal numbers of chromosomes.

*Another component of the mitotic checkpoint — called Bub3 — behaves exactly as Rae1 does. This means that now two components of the mitotic checkpoint are known. And when either one is missing one gene copy, it can cause abnormal numbers of chromosomes.

*If one copy is missing in both Rae1 and in Bub3, then the chromosomal instability becomes more pronounced. For example, when just one component — either Rae1 or Bub3 — is defective, 10 percent of an animal’s cells at age five months will have aneuploidy. But if both Rae1 and Bub3 are defective, then 40 percent of the animal’s cells will have aneuploidy — and to a more severe degree. Not just one or two extra chromosomes per cell, but 13 or 15 extra chromosomes per cell.

*In animals with both defective Rae1 and Bub3, exposure to cancer-causing chemicals caused significantly more tumors.

How Instability Might Lead to Cancers

Think of aneuploidy as causing chromosomal instability. This state of being out of balance leads to a cascading effect in which low-level expression of one protein inside a cell produces an abnormal number of chromosomes and more instability. This instability, in turn, leads to low-level expression of other proteins and further chromosomal abnormality, and thus, more instability that perpetuates the wrong expression of proteins — which creates the vulnerability to cancers. Protein-expression level is important because proteins do the work inside of cells; genes direct which proteins are to be made.

Dr. Van Deursen describes this cascading effect of repeated instabilities as an “elegant system” — from the evolutionary point of view of a cancer cell — because the repeated instabilities through successive cell divisions favor the strongest, most aggressive cancer cells’ survival.

“It is an elegant way for a cancer cell to acquire the best set of genes so that it can grow faster” says Dr. Van Deursen.
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Contact:
Sara Lee
507-284-5005 (days)
507-284-2511(evenings)
e-mail:newsbureau@mayo.edu

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