Switching off gene turns cancer cell healthy in mice

Research suggests dramatic new approach to eliminating tumors

Amy Feldman

Switching the Myc gene on and off controls whether mice liver cells become cancerous. When switched on, the liver cells in mice form a tumor. When Myc is turned off, the cells are transformed into normal liver tissue.

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, suggests that cancer cells can be reformed. His work, published in this week’s 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.

Felsher 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,” he said. “Anything that is encouraging in liver cancer may be important.”

Felsher’s discovery has prompted widespread media coverage, with a story by the wire service Reuters running in newspapers around the world. It also has been the subject of television news reports on KCBS-TV in Los Angeles and Telemundo, among others.

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 that constantly produced Myc protein – until Felsher turned it off. Through a genetic trick, Felsher had altered the Myc gene so that it could be deactivated by feeding mice the antibiotic doxycycline.

The mice remained cancer-free as long as they maintained their Myc-disabling 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.

Felsher’s experiments worked not because doxycycline fights cancer but because his mice carried a Myc gene that had been modified to respond to the drug. To work that same healing trick in human cancers, researchers must find a drug that binds to the Myc protein and renders it useless.

Once Felsher deactivated the Myc gene and the cancer cells returned to normal, the cells still 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 the researchers 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. 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 doxycycline again turned off the modified Myc gene 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 green-colored cells were proof that turning off the Myc gene alters the cell’s fate rather than killing it outright.