The development of cells from their normal state to that of a malignant tumour is known as ‘neoplastic transformation’, a process driven by DNA lesions. During neoplastic transformation cells acquire the ability to evade apoptosis, a process of programmed cell death, and the ability to divide uncontrollably.
Cancer cells ignore the body’s tumour suppressive signals to stop dividing and to kill off unneeded cells.
A team of Institute researchers including Dr Alex Delbridge, Dr Milon Pang and Dr Cassandra Vandenberg, led by Professor Andreas Strasser, is looking at the mechanisms that facilitate neoplastic transformation of white blood cells (i.e. leukaemia/lymphoma development). They have found that loss of the BH3-only protein BIM, a potent initiator of programmed cell death (apoptosis) accelerated tumour development is driven by loss of the tumour suppressor p53.
“The tumour suppressor p53, that is defective in about 50 per cent of human cancers, activates processes that negatively regulate cell division – processes that initiate apoptotic cell death and ones that coordinate the repair of DNA lesions,” Professor Strasser said.
He said there was evidence that loss of the ability to repair DNA lesions was particularly important for the development of tumours driven by loss or mutation of p53.
Dr Delbridge and his colleagues hypothesised that therefore processes by which potentially tumour-causing DNA lesions initiate apoptosis may constitute a safeguard against tumour development, even when p53 is absent. They found that additional loss of the apoptosis-inducing protein, BIM, substantially accelerated lymphoma/leukaemia development in mice deficient for p53. This demonstrates that BIM, which has been recognised as a tumour suppressor in several human cancers, such as mantle cell lymphoma, prevents neoplastic transformation by initiating the death of nascent neoplastic cells that have sustained potentially cancer causing DNA lesions.
By identifying the processes responsible for the development or suppression of DNA-damage induced tumour development, Professor Strasser hopes his team will move a step closer to developing novel cancer therapies.
The research was published in The Journal of Experimental Medicine and was supported by the National Health and Medical Research Council and the Victorian State Government Operational Infrastructure Support.
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