Scientists at Walter and Eliza Hall Institute in Melbourne have furthered the understanding of programmed cell death (apoptosis) and its role in tumor development.

Apoptosis is a vital process in the human body, as it removes damaged cells from our system. The process is understood to be protective against cancer formation and autoimmune diseases.

The discovery that have shifted the understanding about cell death, based on the study led by Professor Andreas Strasser from the institute's Molecular Genetics of Cancer Division offers a broader understanding of cancer formation, the results will influence the direction of the ongoing development of a new type of anti-cancer drugs called BH3 mimetics.

Prof Strasser says, Until now everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumor development.

That's certainly still true but we discovered that, in certain settings, the opposite holds - the body's natural cell-suicide program can fuel tumor development.

Based on their experiments, they found that repeated steps of cellular depletion and tissue regeneration, through activation of stem cells, could stimulate tumor formation.

For instance, when the body is exposed repeatedly to low doses of radiation, the DNA is many cells are damaged and there are repeated steps of cell death in the body's tissues.

Prof Strasser says, Attempts by the body's stem cells to repopulate the depleted tissue can then actually drive the tumor development.

That's because the radiation, while killing many cells within a tissue, will create mutations in some of the surviving stem cells. When such abnormal (mutated) stem cells repopulate the tissue, they will divide many times and this can promote the development of tumors.

Another key element of the research is centered on what happens to mice exposed to radiation, if they lack a gene called Puma. The Puma gene is present in normal mice and it plays an important role in the destruction of cells with damaged DNA.

Prof Strasser says, If normal mice -which have the Puma gene- are given a low dose of radiation it destroys around 80 per cent of the white blood cells.

Tha does not kill the mouse but it does mean the stem cells in the bone marrow have to work extra hard to replenish the blood system. This can lead to the formation of tumors of white blood cells called leukaemias, if the stem cells doing the repopulating have cancer-causing mutations.

The results revealed that mice that lacked the Puma gene were protected from tumor development. In mice that did not have the Puma gene that received loses doses of radiation, the white blood cells were not destroyed - thus mutated stem cells were not forced to become activated and divide to replenish the blood system.

The findings on the role of Puma gene in mice, according to Prof Strasser, suggested that risk of cancer was increased in people who experienced cycles of tissue destruction, followed by tissue re-population via stem cells.

He says, Such cycles may account for liver cancers frequently associated with viral hepatitis C infection or alcohol-related liver damage.

The study provided insight into the development of secondary cancers in patients who were cured of their primary cancer through the use of chemotherapeutic drugs that triggered DNA damage.

As for the new ongoing development of drugs to kill cancer cells - the BH3 mimetics, Prof Strasser said that chronic exposure to them could lead to the destruction of high numbers of normal cells that would then require replacement.

He believes that in certain circumstances, there is a chance of secondary tumor development, specifically in patients that are receiving chemotherapy or gamma-radiation which can cause cancer-causing mutations in stem cells.

Medicine Cancer