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Pitt Team First to Illustrate Mechanisms of Chromosome Missegregation in Cancer Cells

PITTSBURGH, January 4, 2000 — Researchers at the University of Pittsburgh have provided the first graphic illustration of mechanisms by which chromosomes are distributed unevenly during cancer cell division. These results are published in the January 4, 2000, issue of the Proceedings of the National Academy of Sciences.

"This is really the first paper showing a mechanism by which chromosome segregation can go awry in cancer cell division, leading to genetic defects such as abnormal or missing chromosomes," said William Saunders, principal investigator on the study, assistant professor of biological sciences and an investigator in the Oral Cancer Center at the University of Pittsburgh. "By witnessing these events, we can now target for study those activities within a cancer cell that become deranged during cell division. In this way, we can focus on ways to interrupt these abnormal processes with the potential to curb cancerous growth."

During normal cell division, coils of genetic material called chromosomes align neatly in the middle of the cell into 23 pencil-shaped pairs of parallel strands called chromatids. At the same time, two centrioles form at opposite poles of the cell. Thread-like microtubules attach each of the chromatids to the centrioles, forming the spindle. When the cell divides, the chromatids separate and are pulled by the microtubules to opposite poles. Thus, two identical pools of chromatids, the inherited genetic instructions of the future daughter cells, form at the poles. The interior of the cell separates in barbell-like fashion with a narrow bridge that eventually pinches in two to form the two daughter cells.

Using fluorescent markers to label cell structures involved in the division of oral cancer cells, the Pittsburgh team is the first to capture the unusual activities that account for well-recognized genetic derangements characteristic of cancer cells. In one set of experiments, the researchers found that an oral cancer cell could produce not two but three or four spindle poles, each with its own set of microtubules, thus forming bizarre, Y- shaped or cruciform spindle structures. Specifically, the researchers found in the cancer cells that a protein within each spindle pole, called the nuclear mitotic apparatus protein (NuMA), split apart in renegade fashion, generating new poles in an apparently haphazard way. As a result, chromatids migrated to various parts of the cell. During cell division, the haphazard alignment of chromosomes will lead to daughters with different numbers and types of chromosomes.

"For years, scientists have recognized these bizarre mitotic spindle structures in pathology specimens, and we've known for some time that NuMA is involved in organizing the spindle poles. However, this study is the first to show how multiple spindles form, how NuMA may be involved and thus why cancer cells contain too few or too many chromosomes," said Susanne Gollin, Ph.D., senior author on the paper and associate professor of human genetics, otolaryngology and pathology at the University of Pittsburgh School of Medicine.

Another set of experiments by the Pittsburgh team revealed how chromosomes in cancer cells often break and reform, producing chromatids with extra sections that may contain abnormal numbers of genes, contributing to cancer cell growth.

Normally, each chromatid strand has one special segment called a centromere, and the chromosome ends remain capped by regions called telomeres that protect the ends from sticking to one another. But sometimes, harmful substances like cigarette smoke or radiation damage a chromatid, causing it to break. Without telomere caps, the new ends stick to each other and the resulting fused chromosome has two centromeres as well as a duplication of some of the genes from that chromosome. When cell division occurs, the two centromeres of this unusual chromosome may be pulled to the opposite spindle poles of the cell, forming an irregular, long chromosome bridge between the two newly forming daughter cells. Eventually, the abnormal chromatid breaks in two or may be left behind during cell division, producing a small micronucleus. If the chromosome ends are broken, they are likely to rejoin again, reforming the chromosome bridge at division.

This process, called a breakage-fusion-bridge cycle, is repeated with each cell division, yielding chromosomes with ever-increasing copies of genetic material. These amplified segments may contain multiple copies of genes that drive cancer growth.

"We know that smoking damages chromosomes somehow leading to micronuclei and chromosome damage. Our study shows how these events may occur in cancer cells. By understanding this process, we may be able to intervene and prevent additional gene amplification that contributes to cancer growth," said Saunders.

This research was supported by an oral cancer center planning grant from the National Institute of Dental and Craniofacial Research, which has since awarded the University of Pittsburgh an $11.2 million grant to establish a comprehensive oral cancer center, the only such designated comprehensive center in the country.

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