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Pitt researchers find errors in replication in cancerous cells
Tuesday, January 04, 2000 By Anita Srikameswaran, Post-Gazette Staff Writer
Researchers from the University of Pittsburgh have uncovered for the first time some of the missteps that lead to chromosome mix-ups characteristic of cells that have become cancerous.
The scientists identified specific errors made during the process of replication that create cells with abnormal or missing chromosomes, they report in today's issue of the Proceedings of the National Academy of Sciences.
"It's very well established that cancer is related to changes in genome structure," said principal investigator William Saunders of Pitt's Oral Cancer Center.
The new findings show the mechanics of how such changes can occur and could eventually lead to more effective interventions for treating cancer.
When a normal human cell gets ready to divide, the DNA of its 46 chromosomes doubles to provide genetic material for each daughter cell.
The two copies of each chromosome, called sister chromatids, are linked to each other at a region called the centromere. At opposite ends of the cell, structures called spindle poles form, from which spring threadlike microtubules.
The chromosomes, which are strings of genes, line up in the middle of the cell.
Microtubules grab on to the centromeres, pulling the sister chromatids apart, and dragging them to opposite spindle poles. Then the cell can pinch through its middle into two daughters, each of which will hold a set of identical chromosomes. This scientific name for this cell division process is mitosis.
Pitt researchers cultured oral cancer cells in the lab and took a close look at how they divided.
They found that unlike healthy cells, cancer cells can form three or four spindle poles, each with its own microtubules to pull on the chromatids. Because of that, the chromosome copies are not evenly distributed at opposite ends of the cell. When the body of the cell divides, "extra" chromosomes can end up in one daughter while the other finds itself a few genetic bricks shy of a load.
Thus, cells might gain genes that lead to cancer growth or lose genes that can suppress tumor development. Also, subsequent generations of cells will contain the errors and perhaps produce a variety of new ones.
Saunders will be conducting studies to see if overproduction of a key component of spindle poles, called nuclear mitotic apparatus protein, or NuMA, leads to formation of multiple poles. If this is so, cancer treatment in the future could include measures to prevent excess NuMA from being made.
Further experiments revealed other abnormalities during cancer cell division.
The scientists saw chromosomes that contained more than one centromere, an aberration that can be caused by cigarette smoke and radiation damage. The microtubules attach to both centromeres, resulting in a tug-of-war that can break the chromosome and lead to a cycle in which multiple copies are made of genes located near the breakpoint, potentially spurring tumor growth.
Sometimes the cell divided despite a fought-over chromosome's inability to migrate to one pole.
That leaves such a chromosome floating in a daughter cell to form a micronucleus, separated from the nucleus where the rest of the chromosomes reside.
Scientists had seen micronuclei in cancer cells, but did not know where they came from until now, Saunders explained.
The mechanisms identified by the researchers are probably not the first steps in the development of a cancerous cell, but they explain the variety of abnormal cells that are found in some cancers and why it would be impossible to "fix" them.
"Something bad happens in the cancer cell that leads to this aberrant cell division," said investigator Susanne Gollin of the Graduate School of Public Health. "The cells are doomed to a kind of chromosomal instability."
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