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Gene Plays Key Role in Stopping Spread of Some Cancers

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Certain tumors silence its ability to make metastatic cells commit suicide, study finds

By Ed Edelson

HealthDay Reporter

WEDNESDAY, Jan. 4 (HealthDay News) -- Researchers have found a genetic reason for the aggressiveness of some cancers, and perhaps a pathway toward taming their spread.

A gene that tells a cell to commit suicide if it wanders into the wrong part of the body gets silenced in some cancer cells, claims a report in the Jan. 5 issue of Nature. Those cells can grow in any tissue, however foreign, in a process called metastasis.

"It's not the growth of the primary tumor that kills," explained David Cheresh, associate director for translational research at the University of California at San Diego Moores Cancer Center. "Growth of metastatic tumors does kill."

The gene involved is called caspase 8. Cheresh and his colleagues previously have shown that it acts as a police officer, making sure that skin cells stay in the skin, liver cells in the liver, and so on. When a cell migrates to the wrong location, caspase 8 activates molecules called integrins that, in effect, tell the cell to commit suicide.

But experiments show that caspase 8 doesn't do its job in some cancer cells. The researchers found limited or no caspase 8 activity in metastases of a childhood cancer called neuroblastoma, and they have evidence that the same thing happens in other kinds of cancer.

Loss or suppression of caspase 8 is seen in about 70 percent of small cell lung cancers, 10 percent of colon cancers and 35 percent of medulloblastomas, the researchers said. It is seen in 70 percent of aggressive neuroblastomas in children.

The finding has some important medical implications, Cheresh said. Tests for caspase 8 function could be used to help guide treatment, he noted: "If it is missing, those are the most aggressive tumors, and [they] need to be treated early and aggressively."

Another clinical possibility is that caspase 8 activity could be manipulated to make cancer cells initiate apoptosis, the process of cellular suicide. "What we hope we can do is determine ways of initiating apoptosis in these invasive cells," Cheresh said.

The discovery casts light on a different way the body can attack cancer, said Marcus E. Peter, a professor of cancer biology at the University of Chicago Ben May Institute for Cancer Research. In 1995, his group first described the role of caspase 8 in programmed cell death.

"This has been viewed entirely as an immune system process," Peter said. "Tumor cells are recognized by the immune system, immune system cells move in, dock on the tumor and kill it. Here, integrins mediate death through caspase 8, with no role for the immune system."

The good news in the discovery is that "for the most part, tumors don't get rid of this gene entirely," Peter said. "They silence it through a process called methylation. There are a number of drugs that can block this methylation."

Whatever the ultimate impact of the finding on medical practice, "it gives us a molecular insight into the difference between cells that are metastatic and those that are not," Cheresh said.

More information

A constantly updated list of cancer-related genes is kept by the Sanger Institute (www.sanger.ac.uk ).

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