BioWorld International Correspondent

LONDON - Proteins that help cells move are present at much higher levels in pancreatic cancer cells, and might explain why that type of cancer spreads so quickly and so aggressively.

Researchers in the UK who carried out the study believe that their findings might one day make it possible to design new therapies for pancreatic cancer that target the proteins, inhibiting the cells' ability to move.

Eithne Costello, senior lecturer at the University of Liverpool, told BioWorld International: "This is the first time that these proteins have been implicated in the ability of pancreatic cancer cells to spread, so it is going to be important to find out what role they play in metastasis. Pancreatic cancer spreads with particular ferocity. This finding may help us to understand better the mechanisms underlying its rapid spread."

Costello and her colleagues reported their findings in the July 18, 2006, issue of Gut in a paper titled "Pancreatic cancer cells overexpress gelsolin family capping proteins, which contribute to their cell motility." The study was partly funded by Cancer Research UK.

Worldwide, an estimated 213,000 people die from pancreatic ductal adenocarcinoma each year. In the UK, it is the 11th most common cancer, with 7,000 people diagnosed each year, most of them older than 70. The disease spreads rapidly and is difficult to treat.

In a search for proteins that were differentially expressed by benign pancreatic epithelial cells and pancreatic cancer cells, Costello and her colleagues compared levels of up to 1,000 of the most abundant cellular proteins in the two types of cell.

They found that two proteins, called CapG and gelsolin, were present at significantly higher levels in cancer cells (p<0.0001).

"We thought this was an important finding," Costello said, "because it was already known that CapG is highly expressed in macrophages - cells whose job it is to invade tissues to fight infection."

Earlier studies also had shown that CapG was involved in controlling the movement of macrophages. Furthermore, mice that lacked functional genes for CapG or gelsolin - although viable and apparently normal - had abnormal macrophage movement and other defects in cell motility.

Their further experiments involved lowering expression of CapG in pancreatic cancer cells. "We found that the motility of cells in which we had depleted CapG was impaired," Costello said. "Similarly, if we reduced levels of gelsolin, we also saw diminished motility in pancreatic cancer cells."

CapG belongs to the gelsolin superfamily of proteins, which help to control the actin cytoskeleton of the cell.

Gelsolin was the first member of that family to be identified. It binds to actin filaments and severs them, then remains as a cap on the growing end of the cut filament.

Gelsolin has six repeating domains, while CapG has only three. CapG also binds and caps actin filaments, but does not sever them.

Various other studies have looked at the expression of gelsolin in other cancers, with results that sometimes were contradictory: In some cancers, gelsolin expression was lower than in normal tissue, while in others its levels were higher than normal. This is the first time, however, that CapG has been studied in a particular cancer type.

In another part of the study, the researchers found that patients with pancreatic cancer had better prospects when the level of gelsolin is low or undetectable.

Unexpectedly, they also found that the amount of CapG in the nucleus of the pancreatic cancer cells was proportional to the size of the tumor. That could mean that this protein is closely linked to aggressive tumor growth, as well as spread.

Costello said, "We now need to find out the precise contribution of GapG and gelsolin to tumor spread, in order to provide ourselves with important leads for new approaches to treatment."

Future work will include designing ways to regulate the expression of CapG in cancer cells, in order to study the effects of different protein levels on the cells' ability to move.

"We want to understand at the molecular level how these proteins contribute to movement," Costello said.