Study finds link between blood-clotting protein and cancer

Groundbreaking research from Germany shows how stressed cells increase the production of thrombin, an important clot performer. Presented in the journal Molecular Cell, the study provides new insight into how cancer cells may be profiting from this process. Researchers could use this information to develop novel ways to treat various disorders.

In the past, stress was a sign of imminent danger, which in turn could result in loss of blood. Our body learnt to deal with stress by accumulating blood-clotting factors, experts say. Researchers from the Molecular Medicine Partnership Unit (MMPU), a partnership launched in 2002 between the European Molecular Biology Laboratory (EMBL) and the University of Heidelberg Medical Centre in Germany, say their findings will not only help physicians fight cancer but also septicaemia, a condition that refers to the presence of pathogenic organisms in the bloodstream (blood poisoning). The result is increased blood clotting, which experts say is one of the biggest causes of death.

Patients suffering from cancer are at a higher risk of blood clot formation. This was first described by French physician Armand Trousseau in the 19th century. Doctors have recently determined that people with activated blood coagulation have a higher chance of developing cancer than those who don't. Also, recent studies revealed that anti-coagulants could fight and prevent cancer. But no one had found the connection between cancer progression and blood clots. This is where the German researchers entered the picture.

"For the first time, we have something in hand that might explain this enigmatic relationship between enhanced pro-coagulatory activities and the outcome of cancer," explained MMPU's Sven Danckwardt.

The amount of thrombin produced by the body's cells is determined by two types of protein: proteins that accelerate production and proteins that slow it down. The researchers say both protein types act by binding to the cellular machinery that synthesises thrombin. In normal cases, thrombin levels are kept low by production-slowing proteins.

This study found that another protein, p38 MAPK (Mitogen-activated protein kinase), kicks into action when cells are under stress from inflammation. P38 MAPK adds a chemical tag to the slow-producing proteins. The result? Production-slowing proteins have a hard time to bind to the thrombin-synthesising machinery. This enables the proteins that speed up production to take control.

The team said inflammation triggered by cancer could result in increased thrombin levels and, as thrombin is a blood-clotting agent, this could explain why cancer patients have a higher risk of suffering from blood clots. This novel mechanism of gene regulation may apply to other genes as well, according to them.

"Knowing the exact molecules involved, and how they act, has implications for treatment, especially as drugs that inhibit p38 MAPK are already being tested in clinical studies for other conditions," said Matthias Hentze, Associate Director of EMBL and co-Director of MMPU. "Those drugs could be good candidates for potential cancer or septicaemia therapies."

Studying liver samples from septicaemic mice, the Heidelberg team found that p38 MAPK affects thrombin production during septicaemia. Besides its influence as a blood-clotting agent, thrombin helps the development of new blood vessels and can degrade the extracellular matrix that keeps cells together.

The team said there's a chance that the cancer cells are boosting thrombin production to help the tumour spread, by making it easier to invade healthy tissue and creating blood vessels to supply the new tumour cells. This could be the reason people with blood-clotting problems are more likely to develop cancer.

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