Using genetically manipulated mice to study the pathophysiologic consequences of castration-induced prostatic cell death

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Prostate cancer is the second leading cause of cancer death among Australian men. The disease is incurable once it spreads beyond the confines of the prostate gland. Hormonal treatments can keep the cancer at bay for a number of years until they are no longer effective. Hormonal treatments cause shrinkage of prostate cancer because they interfere the function of the male hormone, testosterone, which encourages growth of prostate cancer. Hence, there is a need for other treatments that may improve the quality of life and survival of prostate cancer patients. It appears that a cancer patient can make immune cells known as T cells, which can recognise his own tumour but which are prevented from destroying the tumour. Using a mouse model of prostate cancer, we wish to understand how prostate tumours act to prevent immune destruction in circumstances that are common to the treatment of human prostate cancer. For example, hormonal treatments produce dead prostate cancer cells that will be cleared by the body's professional scavenger cells in a way that suppresses an active immune response against the tumour. To learn how the removal of dead cells suppresses the immune response, we propose to perturb the normal clearance of dead prostate cells by at least two means. First, we will study mice that have an inherited deficiency in the removal of dead cells. Second, these mice will be given a growth factor to produce an excess of immune stimulating cells known as dendritic cells in the prostate gland. The dendritic cell is the main type of cell that initiates immune responses. We will investigate whether the greater number of dendritic cells, which were put into the prostate gland by the growth factor, can remove the dead prostate cells in a way that excites rather than suppresses the anti-tumour immune response. Positive results obtained from these studies may lead to the design of new treatments for advanced prostate cancer.