Scientists at the University of Wisconsin Carbone Cancer Center report the discovery of a novel type of cell division in human cells. They believe it serves as a natural back-up mechanism during faulty cell division.
"If we could promote this new form of cell division, which we call klerokinesis, we may be able to prevent some cancers from developing," says lead researcher Mark Burkard, M.D., Ph.D., an assistant professor of hematology-oncology in the department of medicine at the UW School of Medicine and Public Health. He presented the finding yesterday at the American Society for Cell Biology’s annual conference in San Francisco.
Dr. Burkhard, a physician investigator who treats breast cancer patients, also studies polyploidy. About 14% of breast cancers and 35% of pancreatic cancers have three or more sets of chromosomes, instead of the usual two sets. Many other cancers have cells containing defective chromosomes rather than too many or too few.
"Our goal in the laboratory has been to find ways to develop new treatment strategies for breast cancers with too many chromosome sets," continued Dr. Burkhard.
The original goal of the current study was to make human cells that have extra chromosomes sets. But after following the accepted recipe, the researchers unexpectedly observed the new form of cell division. Until now, Dr. Burkard and most cell biologists today accepted a century-old hypothesis developed by German biologist Theodor Boveri, who studied sea urchin eggs. Boveri surmised that faulty cell division led to cells with abnormal chromosome sets, and then to the unchecked cell growth that defines cancer. With accumulated evidence over the years, most scientists have come to accept the hypothesis.
Normal cell division is at the heart of an organism's ability to grow from a single fertilized egg into a fully developed individual. More than a million-million rounds of division must take place for this to occur. In each division, one mother cell becomes two daughter cells. Even in a fully grown adult, many kinds of cells are routinely remade through cell division.
Dr/ Burkard and his team were making cells with too many chromosomes to mimic cancer. The scientists blocked cytokinesis with a chemical and waited to see what happened. "We expected to recover a number of cells with abnormal sets of chromosomes," explained Dr. Burkard.
The researchers found that, rather than appearing abnormal, daughter cells ended up looking normal most of the time. Contrary to Boveri's hypothesis, abnormal cell division rarely had long-term negative effects in human cells. So the group decided to see how the human cells recovered normal sets of chromosomes by watching with a microscope that had the ability to take video images.
"We started with two nuclei in one cell," continued Dr. Burkard. "To our great surprise, we saw the cell pop apart into two cells without going through mitosis."
Each of the two new cells inherited an intact nucleus enveloping a complete set of chromosomes. The splitting occurred, unpredictably, during a delayed growth phase rather than at the end of mitosis. The scientists did a number of additional experiments to carefully make sure that the division they observed was different than cytokinesis.
"We had a hard time convincing ourselves because this type of division does not appear in any textbook," noted Dr. Burkard.
Over time, they found that only 90% of daughter cells had recovered a normal complement of chromosomes. Dr. Burkard would like to leverage that statistic up to 99%. "If we could push the cell toward this new type of division, we might be able to keep cells normal and lower the incidence of cancer," he said.
Dr. Burkard now thinks that among all those rounds of cell division an organism goes through, every once in a while cytokinesis can fail. And that this new division is a back-up mechanism that allows cells to recover from the breakdown and grow normally. The group has dubbed the new type of division klerokinesis to distinguish it from cytokinesis.
In addition to his work on klerokinesis, Dr. Burkhard’s lab seeks to advance cancer therapy by two approaches—candidate evaluation (“bottom-up”) and therapeutic strategy (“top-down”). In the first approach, his team interrogates the function of specific kinases such as Plk1 to determine how these control human cell division and evaluate the potential worth as a cancer drug target. Using chemical genetics, Dr. Burkhard says they dispense with the “arduous task of up-front drug discovery” and simply mutate the target kinase to prepare for chemical interrogation of function.
In contrast, the top-down approach seeks to selectively target a unique characteristic of cancer cells that sensitize them to specific drugs. For example, Dr. Burkhard’s group has identified compounds that specifically block the proliferation of cells which harbor excess number of chromosomes; such polyploid cells are commonly found in cancer. “Using the combination of these two approaches, we hope to identify new drug targets or allow improved selection of patients likely to benefit from existing treatments,” he says.