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Switch of a gene turns cancer cells healthy in mice

11.10.2004


Conventional wisdom holds that cancer cells contain so many mutations that there’s no way to return them to the straight and narrow path of their normal neighbors. This has led to cancer treatments that focus on destroying or removing the cancerous cells.



But new research by Dean Felsher, MD, PhD, assistant professor of medicine (oncology) and of pathology at the Stanford University School of Medicine, suggests that cancer cells can be reformed. His work, published in the Oct. 10 advance online issue of Nature, could lead to new ways of treating the most common forms of cancer. Felsher found that turning off just one cancer-causing gene is enough to eliminate aggressive, incurable liver tumors in mice in just four weeks. These cells still had the mutations that made them cancerous in the first place, except that one. He had documented a similar phenomenon in bone cancer two years ago, but liver cancer is more common and difficult to cure. "This is a terrible cancer," said Felsher. "Anything that is encouraging in liver cancer may be important."

Liver cancer is formed in a type of cells called epithelial cells - the same ones that form cancers in the breast, colon and prostate. Felsher’s findings about liver cancer could also apply to these types of cancer. Felsher hopes his work pushes people to find drugs that specifically hamstring the protein in question: Myc (pronounced "mick"), which is one of the most commonly mutated oncogenes in cancer cells.


Myc protein acts as a cellular conductor, orchestrating messages that tell a cell to divide. Normal cells only make the protein when it’s time to multiply. Cancer cells produce too much of this protein all the time, constantly prodding themselves to divide.

In his work, Felsher studied mice whose liver cells he had altered to carry a modified Myc gene. Unlike the normal gene, this one is constantly on. This means that it churned out the Myc protein - until Felsher turned it off. And turning it off is as simple as feeding mice the antibiotic doxycycline.

The mice remained cancer-free as long as they maintained their diet of the antibiotic. But as soon as Felsher withheld the doxycycline, the gene was back on; Myc protein accumulated in the liver cells, and the animals developed aggressive liver cancer within an average of 12 weeks.

Returning these cancer-laden mice to the doxycycline diet again turned off the production of Myc protein and eliminated the cancer. After doing that, Felsher saw normal-appearing liver cells - a finding that was confirmed by his collaborators, Boris Ruebner, Alexanxer Borowski and Robert Cardiff at University of California-Davis.

Together, the researchers found that turning the Myc gene on and off acted like a tap, releasing the cancerous cells to divide uncontrollably then shutting off their cancerous progression. "The exciting thing is that you can turn cancer cells into something that appears to be normal," Felsher said.

Still, some of these those normal-looking cells were simply dormant and retained the ability to become cancerous. This finding could explain why cancers recur after chemotherapy. If the treatment only turns the cancer cells dormant, they can easily become cancerous again at a later time.

One concern Felsher and his colleagues had is whether the liver cells were truly going in and out of a cancerous state, or if new cancers formed each time they reactivated the Myc gene. To settle this question they needed a way to watch the cancerous cells to see whether they regressed to a normal state or died when Myc was turned off.

The solution came through a collaboration with Christopher Contag, PhD, assistant professor of pediatrics, radiology and microbiology and immunology at the Stanford medical school. Felsher and his group created liver tumor cells containing a green cellular beacon that can be detected by a super-sensitive camera developed by Contag and his colleagues. When these marked cells were injected into mice, they quickly formed liver cancers. Feeding the mice doxycyclin again turned off Myc and eliminated the cancer.

But this time around, the researchers could easily detect the cells because of their green label. Aside from their color, they looked like normal liver cells and produced liver proteins. These cells were proof that turning off the Myc gene alters the cell’s fate rather than killing it outright.

The hurdle now is finding drugs that deactivate the Myc gene in humans. Felsher’s experiments worked because the group could create a modified Myc gene that responds to doxycycline. To work that same trick in human cancers, researchers need a drug that binds to the Myc protein and renders it useless.

Amy Adams | EurekAlert!
Further information:
http://www.stanford.edu

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