Scientists Reveal Cells' 'Energy Factories' Linked To Cancer

Mitochondria are complex structures that exist in cells to generate energy for growth and activity.

The Cancer Research UK researchers based at the University of Glasgow's Beatson Institute for Cancer Research in Glasgow have found out how the excessive build-up of a simple metabolic molecule in mitochondria can trigger a sequence of events that leads to tumour growth.

The discovery increases our understanding of the molecular basis of several types of cancer, which is crucial for the development of new ways to prevent, diagnose and treat the disease.

Scientists know that a number of genes that code for the mitochondria's energy generating machinery are tumour suppressors and that defects in these genes can lead to cancer. But, until now, it was unclear as to how mutations in these genes resulted in the disease.

The team looked at one of the known tumour suppressor genes called SDH, which codes for a molecule called succinate dehydrogenase. When the SDH gene is damaged, a metabolic product called succinic acid accumulates in cells. This then causes the levels of a protein called HIF-1to rise. The HIF-1 protein is normally only activated in response to certain types of crisis in the cell, such as a lack of oxygen. Under these conditions it encourages the growth of blood vessels to help cells get more oxygen.

The researchers have found the missing pieces in this puzzle. They show how the high levels of succinic acid in the cell that result from SDH mutations block the cell's usual method of ridding the cell of HIF-1. HIF-1 levels can then build up, resulting in inappropriate growth of blood vessels, which can feed a tumour.

Dr. Eyal Gottlieb, from the University of Glasgow's Beatson Institute, said: "We found that damage to the SDH gene boosts the levels of succinic acid in a cell and this, in turn, prevents the degradation of HIF-1. HIF-1 is then free to increase the expression of genes that facilitate blood vessel growth, tumour development and cancer spread.

Dr. Lesley Walker, Director of Cancer Information at Cancer Research UK, says: "Mutations in SDH can predispose a person to cancer of the kidney, adrenal gland and thyroid gland. Changes in SDH activity may also be associated with stomach and bowel cancer.

"This study is exciting because it is the first to find a molecular mechanism that links mitochondrial mutations to tumour formation. Increasing our understanding of the molecular basis of cancer is crucial if we are to find new ways of preventing, diagnosing and treating the disease in the future."

"Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-a prolyl hydroxylase", is published in Cancer Cell 2005 7: 77-85.