063: Mitochondrial physiology in tumourigenesis Date: Tue Mar 28 14:24:01 BST 2006 Mitochondria are energy-producing organelles within cells. Mitochondria consume oxygen (respire) to generate chemical energy. Cells rely on energy to survive, but mitochondria also play a critical role in regulating programmed cell death. This is an active process of cellular self destruction which aims to avoid damage to the organism. Inability of cells to undergo programmed cell death when required is a major contributory factor to cancer. Interestingly, during the 1930s, Otto Warburg described a direct link between mitochondrial physiological functions and cancer development. The 'Warburg effect' or 'aerobic glycolysis' is the observation that many cancer cells consume glucose (a form of sugar) at a much higher rate than expected. This means that although oxygen is abundant and there is no apparent reason for not producing energy by respiration, cancer cells "prefer" to generate energy by a less efficient pathway of accelerated glucose consumption. Warburg actually suggested that defects in respiration may be the sole cause for cancer formation. What may be the advantage of glucose consumption over respiration in cancer cells is not clear. One answer may be a prior adaptation to survival under low oxygen (hypoxia), a condition that most tumours reach as they grow. We I now know that this low oxygen condition facilitates blood vessel growth into the tumour and the spreading of cancer cells to other parts of the body (metastasis). It is possible that accelerated glucose consumption may confer resistance to mitochondria-mediated programmed cell death. The causes for the accelerated glucose production in cancer cells are largely unknown. Along with many other explanations, it is possible that oncogenes (cancer-generating genes) may activate this process. Also, conditions that lead to a state called pseudo-hypoxia activate abnormal glucose consumption. Pseudo-hypoxia is a state in which cells behave as if they are under low oxygen despite the presence of normal oxygen levels and is controlled by a protein complex called hypoxia inducible factor. This complex induces the expression of many genes, some of which increase the activity of glucose consumption. Moreover, several genetic studies have recently shown that some mitochondrial proteins that are important for energy production by the mitochondria are 'tumour suppressors'. This means that certain types of cancer can occur when these proteins are inactivated (due to mutations). Due to the nature of these mutations, energy production in mitochondria is disrupted in these cancer cells and accelerated glucose consumption is observed. Recently, a link between mutations in these tumour suppressor genes and pseudo-hypoxia has been made. Overall, whether glucose consumption is induced by low oxygen (hypoxia) or by pseudo-hypoxia, it is clear that blocking the switch for accelerated glucose consumption by cancer cells could render these cells energy-deprived and cause cell death, a desired outcome of cancer treatment. As mentioned above, the switch to accelerated glucose consumption is largely controlled by hypoxia inducible factor. Our research aims to understand the mitochondrial signals that mediate the activation of hypoxia inducible factor and to block or reverse this process. By doing so, we hope to make cancer cells use less glucose and therefore become more susceptible to programmed cell death as well as incapable of activating blood vessel growth or of spreading to distant parts of the body (metastasis). We have extensively studied the process of hypoxia inducible factor activation due to mitochondrial dysfunction in cell culture. Based on our studies, we have synthesised several new compounds that are capable of preventing and reversing the induction of hypoxia inducible factor. Obviously, we hope that these compounds have the potential to be used in the clinic in the future. The next step towards clinical use must be to analyse the effectiveness of these drugs in tumour models in mice. This study will examine the potential of the new compounds, to further change them, if required, in order to make them more efficient, and to understand the exact mechanism of tumour regression in order to optimize their use with other potential treatments. Two general types of models will be used. The first is based on mice that are defective in their immune system and therefore human cancer cells can be transplanted to these mice. The transplantation is done under the skin, a site that causes minimal discomfort to the animals. Another advantage of this system is that human cancer cells are used and the response to the treatment is more relevant to human cancers. A limitation of the system is that the cells are not genetically defined and therefore which genes lead to cancer development in these cells are unknown. For this reason a second model will be used based on mice that are genetically altered in specific genes that are known to cause cancer in humans. Therefore, mice that develop similar tumours are a good model for studying these human cancers. In both models, we will use the minimal number of animals required to achieve statistically significant results. Moreover, a small pilot experiment will be performed to study the optimal delivery procedure of the drugs in healthy animals and therefore will limit the treatment of tumour-bearing animals only to the most effective method. Furthermore, initial studies of effective doses have been performed in cell culture systems, so a significant amount of valuable information has already been accumulated prior to the experiments with mice. It is also important to mention that in this type of study, animals with tumours are treated early in the process of cancer development to minimise suffering. When the cancer burden is increased, animals are killed in a humane manner to prevent any unnecessary suffering.