Cancer research springs a surprise. Researchers at Walter and Eliza Hall Institute in Melbourne have found that programmed cell death (apoptosis) or cell suicide plays a role in tumor development. This process is an important phenomenon in our body as it helps remove damaged cells. Now apoptosis has been found to be protective against cancer formation and autoimmune diseases.
The study was led by Professor Andreas Strasser from the institute's Molecular Genetics of Cancer Division who feels that this would offer 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. The research, done in collaboration with Dr Ewa Michalak, Dr Cassandra Vandenberg, Mr Alex Delbridge, Dr Li Wu, Dr Clare Scott and Professor Jerry Adams, appears in the journal Genes and Development. Prof Strasser said, “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.”
He and his team in their experiments found that repeated steps of cellular depletion and tissue regeneration, through activation of stem cells, could stimulate tumor formation. They exposed cells to repeated low doses of radiation. This damages the DNA in many cells and there are repeated steps of cell death in the body's tissues. Prof Strasser explained, “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.”
The experiments also tested 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 explained, “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…That 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 leukemias, if the stem cells doing the repopulating have cancer-causing mutations.” Thus mice that lacked the Puma gene were protected from tumor development.
Citing clinical implications of this experiment Prof Strasser says, risk of cancer was increased in people who experienced cycles of tissue destruction, followed by tissue re-population via stem cells for example “liver cancers frequently associated with viral hepatitis C infection or alcohol-related liver damage.” He also said that these experiments explain why people get secondary cancers when they are cured of their primary cancer through the use of chemotherapeutic drugs that triggered DNA damage.
He also explained that new ongoing development of drugs to kill cancer cells - the BH3 mimetics saying, “Chronic exposure to such drugs could lead to the death of large numbers of normal cells that would then need to be replaced. In certain circumstances this could promote the development of secondary cancers, particularly if patients are receiving treatments such as chemotherapy or gamma-radiation that can lead to cancer-causing mutations in stem cells.” Strasser's lab has been working with scientists from the biotechnology firm Genentech, located in South San Francisco, California, and the drugmaker Abbott, based in Abbott Park, Illinois, to develop drugs that mimic PUMA. One of these compounds, called ABT-263, has recently completed initial safety studies and is about to move into larger-scale clinical testing, says Strasser.
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