Getting new life from death

New insights into cell death could open the door for more effective and comprehensive cancer therapies in the future

AN IMPORTANT NEW discovery by a Science Foundation Ireland funded Trinity College research group has the potential to lead to new cancer therapies in the future.

The group, led by Smurfit professor of medical genetics, Seamus Martin, has discovered how a process called “autophagy”, literally meaning “self-eating”, plays an important role in safeguarding against the development of cancer and has just published the findings in the internationally renowned journal, Molecular Cell.

The work was carried out in the Molecular Cell Biology Laboratory at TCD’s School of Genetics and Microbiology. The research team is internationally recognised for its work on cell death control in cancer and immunity.

The primary focus of the lab is the dissection of the molecular components of the machinery that orchestrates the natural cell death process known as apoptosis or programmed cell death. Apoptosis is a mode of cell death that is under molecular control and can be triggered by a multitude of stimuli.

Cells die by apoptosis during development, tissue homeostasis, fine-tuning of the immune system, and due to the normal wear and tear that multi-cellular organisms experience in everyday life. Apoptosis is also observed as a part of the damage limitation response seen during infectious disease and is seen during many other pathological conditions, such as cancer and neuro-degeneration.

Understanding apoptosis at a molecular level will therefore provide new insights into many fundamental biological processes and will likely result in new ways of treating conditions where either too few cells die as in the case of cancer or auto-immune diseases or too many die as with AIDS or neuro-degeneration.

In the case of autophagy, this process is normally switched on when cells experience periods of starvation and in this context is beneficial by helping to keep the “wolf from the door” until food reappears on the menu. However, Prof Martin’s team has discovered that mutations in a gene called Ras, which is involved in approximately 30 per cent of human cancers, trigger excessive autophagy leading to auto-destruction of fledgling tumour cells.

“The lab has been working on cell death and how it is regulated for the past 12 years,” says Prof Martin. “I have been working on it personally for the past 20 years. Most cell death is planned and programmed. We are making new cells in a predictable way all the time. The body is used to cells aging and dying. If we didn’t have regulated cell death, we would continue growing throughout our lives. For example, we make half a billion blood cells every hour and we need to kill off an equal number of blood cells to make room for them. Some cells have a life-span of just a couple of days and some live for far longer.”

Cell death, or rather too much or too little of it, is involved in many illnesses including cancer and neuro-degenerative disease. “With cancer, cells don’t die at the appropriate time,” he explains. “Existing treatments involve trying to kill cells with radio treatment or chemotherapy. These are poisons and the idea is to try to kill more cancer cells than healthy ones. However, cancer cells tend to be quite robust and tough and are harder to kill. We are constantly looking for a chink in their armour.”

The other side of the equation in cancer is the fact that cells are dividing at an accelerated rate. Martin describes it as like a car with “too much gas and not enough brake; there are defects on both sides”.

The group’s research focused on a mutated form of a gene known as Ras which is found in about 30 per cent of cancers. “The gene is known to promote additional cell division and we were also interested in how it would affect cell death and we found that the mutant form actually promotes autophagy, where cells eat themselves. This happens normally if the body is starved of food and cells start consuming themselves. The mutant form of Ras massively ramps up this process to a point where a cell eats itself to death.”

Mutant Ras was found to switch cells into the self-eating mode by ramping up the production of Noxa – what might be called a “killer protein”. The study suggests that autophagy represents an important natural safeguard against cancer development.

The question then arises, if mutant Ras triggers autophagy, why then do the cancerous tumours grow instead of eating themselves to death? The answer lies in another gene, this time members of the Bcl-2 gene family. These genes can override the self-eating process, effectively switching it off and allowing for the survival of cancerous cells.

The next step for Prof Martin’s team was to look at ways of using this knowledge to treat cancer. He believes there may be a “Goldilocks principle” at work in this case. “It might be a case that if there is too much or too little mutant Ras present, the cancer will continue growing and only a certain level will cause it to self-destruct,” he explains. “Tumours are under a certain amount of nutritional stress in any case, so they may need to be able to engage in the self eating process to a certain degree. What we are trying to do is unravel where the set point is for different cancers.”

And this is where the Bcl-2 family comes in. “If we can inhibit these proteins through the use of small molecule drugs this might allow the self-eating process to continue,” says Martin. “This might not normally be enough to actually kill a cell but if it is already under stress in the way many tumour cells are then it might be enough to push it over the edge.”

This is effectively depriving the tumour of the antidote to the killer protein that is trying to harm it.

“We believe that tumours become dependent on certain proteins to survive. For example, tumours with mutant Ras present will only exist if they also contain the antidote. The tumours are effectively addicted to these proteins which act as the antidote and we are trying to find what they are addicted to.”

According to Prof Martin, the research has also helped explain why the emergence of fully cancerous cells was relatively rare given the average human produces hundreds of billions of cells over a lifetime.

He believes the research has the potential to lead to new cancer treatments. “This discovery is an important step in our understanding of how cells in the early stages of cancer hit the auto-destruct button and suggests new ways in which we may be able to re-activate this process in cancers that do manage to establish. This breakthrough has led directly from investment in research made by the Irish state over the past 10 years through important initiatives such as the establishment of Science Foundation Ireland.”

But new treatments may be some way off. “As with all of these things we are at a very early stage of research,” says Prof Martin. “We find the targets for others to develop the drugs to attack.”