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Loss of caspase-8 makes neuroblastoma more aggressive

January 06, 2006

The caspase-8 gene plays a critical role in suppressing metastasis (spread) of neuroblastoma, and the expression of this gene is frequently absent in cancer cells that are aggressively metastasizing, according to investigators at St. Jude Children's Research Hospital and the University of California at San Diego (UCSD). Neuroblastoma is a tumor of the nervous system and is the most common tumor in infants younger than 1 year of age; it accounts for 7-10 percent of childhood cancers.

In the absence of caspase-8 protein, the cell is significantly more capable of escaping from the primary tumor and spreading to other sites in the body, the researchers said. The investigators also showed in laboratory studies that restoring the expression of the caspase-8 gene suppressed neuroblastoma metastases.

The study's findings are significant because they suggest that novel treatments that restore the tumor-suppression role of the caspase-8 gene might prevent the spread of neuroblastoma and improve patient outcome, according to Jill M. Lahti, PhD, an associate member of the Department of Genetics and Tumor Cell Biology. Lahti and David Cheresh, Ph.D., (UCSD) are senior authors of a report on these findings that appears in the January 5 issue of the journal Nature.

Caspase-8 triggers apoptosis by binding to molecules called integrins that project from the surface of cells, including neuroblastoma cells. Normally, integrin molecules anchor the cell to the extracellular matrix-the material outside the cell consisting of gel and fibers that support and provide structure to tissues. When cells become dislodged from the extracellular matrix, as happens during metastasis, the unbound integrin molecules are free to bind with caspase-8, Lahti said. The binding of caspase-8 to integrin then triggers integrin-mediated death (IMD), a form of apoptosis.

"Cells aren't usually supposed to break away from their location in the body, so the IMD response disposes of wayward cells before they can cause trouble," Lahti explained. "We showed that neuroblastoma metastasis is especially potent in the absence of caspase-8."

To investigate the impact of the loss of caspase-8 and/or integrins on neuroblastoma metastasis, the team tested the ability of tumor cells removed from patients for their ability to metastasize in laboratory embryo models. When the team blocked expression of the caspase-8 gene in neuroblastoma cells implanted in these models, the cancer cells broke away more readily from the tumor and spread with higher frequencies to the lung and bone marrow.

When the team implanted human neuroblastoma cells into other adult laboratory models, they generated metastases to the ovary, adrenal glands, kidneys and liver. These metastases have lost expression and activity of caspase-8. These findings suggest that the loss of caspase-8 expression promotes metastases of neuroblastoma cells, the researchers reported.

Although the presence or absence of caspase-8 did not appear to affect the growth of the primary tumor, the researches discovered that significantly more cells outside the tumor underwent apoptosis when the gene was present; and significantly fewer underwent apoptosis went the gene was absent. The team made a similar finding in human patients whose neuroblastoma had spread from the primary tumor.

"Our findings provide a basis for designing novel treatments to prevent neuroblastoma metastases," Lahti said.

St. Jude Children's Research Hospital