The Cancer Research UK researchers based at the University of Glasgow's Beatson Institute for Cancer Research have found out how the excessive build-up of a simple metabolic molecule in mitochondria can trigger a sequence of events that leads to tumor growth. Their findings are published in Cancer Cell 2005 7: 77-85.

How Genetic Mutations Can Lead to Cancer

The discovery sheds light on the molecular basis of several types of cancer, which is crucial for the development of new ways to prevent, diagnose and treat the disease, say the researchers.

Scientists know that a number of genes that code for the mitochondria's energy-generating machinery are tumor 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 tumor 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-1" to rise. The HIF-1 protein normally is activated only in response to certain types of crises 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.

Missing Puzzle Pieces Found

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 then can build up, resulting in inappropriate growth of blood vessels, which can feed a tumor.

"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," says Dr. Eyal Gottlieb of the University of Glasgow's Beatson Institute. "HIF-1 is then free to increase the expression of genes that facilitate blood vessel growth, tumor development and cancer spread," Dr. Gottlieb explains.

"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," notes Dr. Lesley Walker, Director of Cancer Information at Cancer Research UK.

"This study is exciting because it is the first to find a molecular mechanism that links mitochondrial mutations to tumor formation," Dr. Walker observes. "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."