In health, most cells undergo a carefully orchestrated cell-division process in order to replicate. At the heart of this process is mitosis, in which a cell's nucleus duplicates its genetic material and divides. Precisely controlled mitosis is vital to survival, and rigorous checkpoint mechanisms are in place to ensure that each step in the process is properly executed before the cell moves on to the next step. Although not well proven, it is generally believed that many human cancers stem from checkpoint defects in mitosis.
In the July 27 issue of Nature, scientists at The Wistar Institute report identification of a new gene called chfr that establishes a previously unknown checkpoint in mitosis. Further, a laboratory survey of eight human cancer cell lines found chfr to be inactivated, through lack of expression or mutation, in four of the eight -- fully half of the cell lines studied. Mitotic checkpoint genes identified in earlier studies had been linked to cancers, too, but mutant versions had been found in only 1 or 2 percent of cancers.
"The frequency of mutations in previously identified mitotic checkpoint genes is too low to explain the incidence rates of cancers in which troubled cell division is thought to play a role," says Thanos D. Halazonetis, D.D.S., Ph.D., senior author on the study and an associate professor at Wistar. "So, the question was whether there were checkpoint genes we didn't know about and whether those were the genes suffering mutations in these cancers. What we found was a new gene and a wholly new mechanism that monitors progress through mitosis. Further, this gene was disrupted in 50 percent of the cancer cell lines we studied, much higher than the rates for other known checkpoint genes."
Halazonetis emphasizes that studies of tumors from patients will be needed to confirm that mutant chfr is as common in primary cancer cells as it is in laboratory cancer cell lines. If the findings are confirmed, however, clinical applications immediately suggest themselves, according to Halazonetis, as do new avenues for drug development.
"Patients whose cancers exhibit chfr defects would be likely to respond well to Taxol® or other drugs that act by interfering with mitosis," he says. "Those cancers would be unusually sensitive to drugs in this class. So, a diagnostic test for inactivated chfr might be used to predict the responsiveness of a patient's cancer to Taxol® or a related drug, allowing doctors to give their best drug at the start of therapy. Our findings could also be useful in developing new drugs that might be more effective than Taxol® or more specific in targeting only cancer cells, which would lead to reduced toxicity."
Broadly put, mitosis has four phases -- prophase, metaphase, anaphase, and telophase -- in which the chromosomes replicate and condense, align, separate, and then regroup in an orderly way prior to the division of a parental cell into two daughter cells. The process is largely guided by physical structures known as microtubules. Taxol® and drugs in its class act by interfering with the formation of microtubules.
For the current study, Halazonetis used several compounds, including Taxol®, to induce defects in mitosis and then observed the outcomes in cells with or without functional chfr. Normal cells and cancer cells with a working chfr checkpoint stopped mitosis during prophase, preventing entry into metaphase until such time as prophase could be properly executed. Cancer cells without a functional chfr checkpoint, however, continued to complete the entire process of mitosis despite serious defects and died.
Prior to the current study, the known mitotic checkpoints monitored the proper completion of metaphase before allowing the process to proceed to anaphase. The newly identified chfr gene is the first identified that monitors prophase.
Taxol® is the brand name for the drug paclitaxel; Taxotere® is the brand name for another well-known drug in this class, docetaxel. A fact sheet on these drugs is available at: http://oncolink.upenn.edu/pdq_html/6/engl/600715.html.
With senior author Halazonetis, the lead author on the two-author study is Daniel M. Scolnick, Ph.D. Support for the Halazonetis laboratory is provided by the American Cancer Society, the Department of Defense, and the National Cancer Institute, one of the National Institutes of Health.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the basic mechanisms underlying major diseases, including cancer and AIDS, and to developing fundamentally new strategies to prevent or treat them. The Institute is a National Cancer Institute-designated Cancer Center -- one of the nation's first, funded continuously since 1968, and one of only ten focused on basic research. Founded in 1892, Wistar was the first institution of its kind devoted to medical research and training in the nation. News releases from The Wistar Institute are available to reporters by direct e-mail or fax upon request. They are also posted electronically to Wistar's home page (http://www.wistar.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the public interest newswire AScribe (http://www.ascribe.org).
Journal
Nature