Pushing the self-destruct button

A team at Trinity College Dublin has discovered what may be the ‘on’ and ‘off’ switches in cancer cells. This has helped them to find an autodestruct button in cancer cells

SCIENTISTS IN Dublin are unravelling the secrets of an ancient survival mechanism that helps our cells to live through periods of starvation. The findings are important because they explain how cancer cells can be forced to self-destruct literally by eating themselves.

The process is called autophagy, which means “self-eating”, explains Prof Seamus Martin, the Smurfit professor of medical genetics at Trinity College Dublin.

He and his team have discovered how cancer cells in their early stages use the autophagy process to destroy themselves. Yet the same process in the right conditions can also support tumour growth.

“There has been a conflict, a paradox, about the process of autophagy,” says Martin, whose work is funded by Science Foundation Ireland.

Tumours can use the system to help them survive. But Martin has shown in the lab that halting the process can also encourage tumour growth. “It seems to be a double edged sword. It is a matter of getting the balance right,” he explains.

Details of his work were published at the end of last week in the journal Molecular Cell.

Autophagy is an important process that comes into play when cells experience periods of starvation. “It is a kind of fail safe, an emergency rip cord that cells pull,” Martin says.

Effectively the cells begin to consume themselves from within, breaking down some of their contents in order to recycle the cell products when there is no food to provide fresh nutrients, he says.

Yet autophagy also comes into play as a way to eliminate fledgling cancer cells. His research focused on a gene called Ras that is seen in about 30 per cent of human cancers.

He assumed that oncogenic Ras (which boosts the development of tumours) would help to prevent cancer cell death, hence its involvement in so many cancer types. But when they put it into cells they found that it caused the exact opposite.

“It cranked up that process and after a period of five days the cells killed themselves. It turned on a runaway autophagy,” Martin says. The mutant Ras was able to tip the cells into self-eating mode by increasing production of a protein called Noxa.

Their work clearly suggests that the autophagy process represents an important natural protection against the development of cancer.

If Ras and Noxa may represent an off switch for cancer, Martin’s group also has discovered that there is an “on” switch in the form of a family of genes called Bcl-2.

These seem to push in the opposite direction, blocking off Noxa’s action and self-destruction and in the process helping the young cancer cells to survive and develop into full-blown cancer. “The tumour needs to fully switch off autophagy to get aggressive and to fully develop,” he says.

These discoveries are important because they immediately open up avenues of exploration for controlling the autophagy system. On the one hand, Ras and Noxa enhancers could be used to accelerate autophagy, and on the other, the Bcl-2 interference in autophagy could be blocked or slowed.

“The discovery is an important step forward in our understanding of how cells in the early stages of cancer hit the autodestruct button and suggests new ways in which we may be able to reactivate this process in cancers that do manage to establish,” Martin says.

How to attack breast cancer from within

Scientists in Belfast are using gene therapy to deliver a killer blow to breast cancer cells in the laboratory

A Belfast research team has developed what could become a powerful new treatment for breast cancer. It involves attacking individual cancer cells from within, causing them to destroy themselves.

The approach is based on the use of gene therapy, using functioning DNA to deliver a medical treatment, explains lead researcher Dr Helen McCarthy of Queen’s University Belfast’s school of pharmacy.

The highly complex method involves breaking into the cancer cell and implanting a rogue gene into the cell’s own genetic material. Once switched on, the gene produces poisonous nitric oxide at high enough levels to kill off the cell.

McCarthy has spent 10 years studying the powerful anti-cancer effects of nitric oxide gas. A gene called iNOS is able to produce the gas if installed in a cell’s DNA, but while it was easy to demonstrate the gene’s deadly effectiveness, the challenge was finding a way to use it, she says.

“The big problem was developing a delivery system. In order to make gene therapy work you need to get the DNA into the cell,” says McCarthy who is funded by Breast Cancer Campaign.

An answer to this problem eventually came in the form of a “fusion protein”, a biological construct designed by scientists at Washington State University.

Until now most gene therapies were based on using a benign virus to deliver DNA inside a cell.Viruses -– such as the cold or flu virus – are custom built to invade cells, but they also carry risks because of uncertainty over how the recipient’s immune system might react to the invasion.

The new carrier or “designer biomimetic vector” is not a virus, it is made of amino acid building blocks the same as any protein. And like a protein, its complex shape enables it to interact with cells and chemicals in the body.

McCarthy decided to use the carrier to transport her nitric oxide gene inside the cell, describing her work this week in the International Journal of Pharmaceutics.

The carrier is negatively charged while her iNOS gene is positively charged so the two readily stick together like magnets, she says. Together they still make a minute package, 400 times smaller than the width of a human hair.

Here the shape of the carrier comes into play. One part helps wrap up the iNOS gene into a small package. Another opens a hole in the cell wall to allow the carrier and gene to enter. It also has parts that crack open the cell’s nucleus and then implant the gene so it can begin producing nitric oxide, she says.

Her cell culture tests using breast cancer cells have worked very well, the first time the carrier has been used to deliver the iNOS gene. “We are producing really high levels of nitric oxide. Unless you actually get your DNA into the nucleus you are only hoping for a chance integration,” McCarthy says.

The nitric oxide builds in the cell until it switches over to a natural form of cell death, something that cancer cells typically refuse to do. And even if some cells survive, they are weakened and become twice as susceptible to being destroyed by either radiation treatments or chemotherapy.

The “designer” aspect of the carrier means it could be used to target any cell type, and importantly, it leaves healthy cells untouched, she says.

It also looks like having particular potential in dealing with breast cancers that spread to other tissues in the body.

“We want to try to assess the immune response and then formulate it into a dry powder that is stable.” This would be reconstituted and then injected into the patient a day or two before undergoing radio or chemotherapy. “The idea is this will be delivered systemically around the body and be delivered to the other tumours.”