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March 4, 2010

Worms may hold key to better cancer treatment, SickKids study finds

Researchers discover gene that influences cellular response to radiation

Researchers at The Hospital for Sick Children (SickKids) have made a surprising discovery about how cells respond to radiation. New research on the kri-1 gene in worms indicates that radiation-induced cell death is not solely controlled within the affected cell, as previously thought. It appears that signals sent from neighbouring cells are required to instruct damaged cells to destroy themselves. The discovery is published in a recent issue of Current Biology.

“We already knew that radiation activates a “suicide program” within the cell, called apoptosis,” explains Dr. Brent Derry, Scientist in Developmental & Stem Cell Biology at SickKids Research Institute and an Assistant Professor in Molecular Genetics at the University of Toronto. “This discovery, however, challenges our assumptions about how apoptosis works, and demonstrates that cell-to-cell communication is involved. This could potentially provide new insight into making radiation therapy more effective for treating cancer in humans.”

The discovery was completely unexpected, Derry noted. “We were actually investigating the role of a different gene (cep-1/p53), but were surprised by our observations in worms that lacked the kri-1 gene. As a result, we began to look at kri-1 more closely.”  Their research showed kri-1 is involved in controlling the pathway of communication between neighbouring cells in response to DNA damage.  Specifically, kri-1 is required in non-dying cells to promote the death of damaged cells.

This research was conducted on a common species of roundworm, called C. elegans. The worm provides an ideal model for genetic research because it is transparent, easy to manipulate genetically, and has a three-day life cycle that allows experiments to progress very rapidly. Genetic similarities between the worm and humans mean that discoveries made in the worm may be applicable to humans.

According to Shu Ito, lead author of the study and a graduate student in Derry's lab, humans carry a gene similar to kri-1, called CCM1/Krit1. "This gene is one of the most frequently-mutated genes in a neurovascular disease called cerebral cavernous malformations, or CCM,” says Ito, “so understanding how this gene functions in worms may also provide a better understanding of this disease."

Ito and Derry plan to continue their study of kri-1, to determine other components of this novel cell death-signalling pathway, and whether this signalling occurs in larger organisms, including humans. In the immediate future Ito will continue to conduct in depth studies to determine exactly how kri-1 functions.

This study was supported by the Canadian Institutes of Health Research, Wellcome Trust, Cancer Research UK, the American Institute for Cancer Research and SickKids Foundation. Ito was supported by a SickKids Restracomp Award.