• 1/8/2005
  • Pittsburgh
  • Jennifer Bails
  • Science Magazine as reported by Pittsburgh Tribune-Review

A team of University of Pittsburgh researchers has discovered that too much of a single protein can cause a cascade of calamitous changes in a cell leading to the formation of cancerous tumors.
The findings published in today’s issue of Science, a prestigious peer-review journal, could help scientists develop cancer treatments that are safer and more effective than chemotherapy, said Susanne Gollin, one of the paper’s authors.

“The more we understand about tumor cells and how they misbehave compared to normal cells, the more we can target our research to developing potential cancer therapies,” said Gollin, a human geneticist at Pitt’s Graduate School of Public Health.

Gollin collaborated with Pitt biologists Nicholas Quintyne and William Saunders. They found that too much of a protein called nuclear mitotic assembly protein — or NuMA — disrupts cell division by interfering with a second protein called dyenin.

Large amounts of dyenin help make up the mitotic spindle, an assembly of fibers and proteins used to ensure that new cells are allotted the proper number of chromosomes. Before a healthy cell divides, it duplicates its chromosomes. These chromosomes are then evenly separated by the spindle so the two new cells have equal amounts of genetic material.

Normal cells have mitotic spindles with two ends, or poles, with structures at either end called centrosomes that help direct cell division. But cancer cells often have extra centrosomes, which can lead to defective spindles with too many poles, Quintyne said.

“Cells with multipolar spindles sometimes divide unevenly so the (new) cells have too many genes or not enough genes,” said Quintyne, a post-doctoral research fellow at Pitt and the study’s lead author. “This is just asking for the cell cycle to be disrupted and for the cells to divide like mad, which is essentially cancer.”

Scientists didn’t know why some cells with extra centrosomes formed tumors and others didn’t — until now.

Several models have been proposed to explain this phenomenon in the past three years, but Quintyne said his team has found the answer.

In cells that don’t form tumors, the extra centrosomes cluster together into two active spindle poles. But this clustering, which protects the cells, is stymied when there is too much of the NuMA protein, Quintyne said.

The researchers studied tumor cells taken from patients with head and neck cancer and found that 45 percent of those cells had excessive NuMA.

“NuMA was amplified in some of the tumors we looked at in my lab so it looked important to me — I just had a gut feeling about it,” Gollin said.

Quintyne and his colleagues found that cells with excess amounts of NuMA and extra centrosomes lacked dyenin around their spindles. This prevented the centrosomes from clustering together, leading to cancer, Quintyne said.

If the researchers can figure out how to encourage the clustering of centrosomes by restoring dyenin, they might develop therapies that stop the growth of some tumors without chemotherapy, he said.

Next, the researchers plan to study how NuMA interferes with dyenin and investigate how the problematic spindles form.

“We have known for quite a few years that something was going on to cause spindle multipolarity beyond having extra centrosomes,” Quintyne said. “Now we have a foundation to examine why this is happening.”

The study was financed by the National Institutes of Dental and Craniofacial Research and the American Cancer Society.