"Min" mouse saved from cancer
Scientists have genetically engineered a mouse with extraordinary resistance to bowel cancer, delegates at the Cancer Research UK senior researchers' conference in Harrogate will hear today.
Researchers studied 'Min' mice1, which are highly susceptible to tumours in the bowel, often developing dozens of tumours before they die.
But by removing a single gene called Mbd2, Cancer Research UK scientists created healthy Min mice that almost never developed these tumours.
This work suggests a vital role for Mbd2 in the development of new ways to prevent and treat human bowel cancer.
Loss of the gene had almost no effect on the mice: they remained healthy and fertile. Results showed a dramatic reduction in the number of bowel tumours compared to ordinary Min mice, and any tumours that did occur were significantly smaller.
The only problem for the scientists is that knocking out the gene is working too well. To fully understand why the risk of cancer falls so dramatically, they need to compare tumours in Min mice with and without Mbd2. But the mice without the gene are developing so few tumours that making the comparison is proving difficult.
Today's speaker Professor Alan Clarke, who led the work at Cardiff University, says: "It's extremely exciting to knock out an entire gene and have the mice lose their predisposition to cancer - and with virtually no adverse effects.
"If it is as safe to dispense with Mbd2 activity in humans, then blocking it could become a powerful way to treat bowel cancer, and to protect high-risk groups from developing the disease."
The researchers now want to find a drug that will inactivate the molecule produced by Mbd2 without the need for removing the gene. They are working to develop a test that will rate the ability of chemicals to block Mbd2.
Professor Clarke adds: "Mbd2 is part of a complicated interaction where there are few molecular features for a drug to latch on to. With the test we hope to be able to try lots of potential drugs and find out which one works best."
To generate the cancer-resistant mice, scientists first removed the Mbd2 gene from ordinary mice. They then crossbred these mice with the cancer-prone Min mice. The resulting offspring all inherited the susceptibility to intestinal cancer, but some still had Mbd2 while others did not.
Those without the gene lived twice as long as those with it, and there was a ten-fold reduction in the number of tumours.
The team is now investigating the role of Mbd2 in normal cells, and the extent of its involvement in other cancers, including lymphoma and breast cancer.
Similar genes have been found to promote tumours. However, when these genes are removed, other cancer causing genes become activated with lethal consequences.
More work is needed to fully understand the effects of blocking the function of Mbd2 in humans, but the signs so far are promising. Studies have shown the only effect of removing Mbd2 from mice to be a decrease in the average number of offspring in their litters.
Professor Robert Souhami, Director of Clinical and External Affairs at Cancer Research UK, says: "Most genes involved in cancer also have vital roles in healthy tissue, making it difficult or harmful to target them. Deleting Mbd2 from these mice stops them developing a cancer to which they are highly predisposed, without apparently causing any other damage.
"This research is tremendously exciting because, if a similar gene is implicated to the same degree in human cancer, it raises the possibility of developing a safe, effective alternative in the prevention and treatment of bowel cancer."
- Multiple Intestinal Neoplasia
Note to editors:
See also: Sansom, O.J. et al. Nature Genetics34 (2) pp.145-147