A key protein to treat cirrhosis

A group of experts, led by Raul Mendez, the Institute of Biomedical Research, and Mercedes Fernandez of the IDIBAPS of Barcelona, indicate the CPEB4 protein as the molecule to disable and prevent the generation of new abnormal blood vessels associated with cirrhosis. The study results are published in the latest issue of "Gastroenterology".

Pathological angiogenesis is one of the most important complications in patients with cirrhosis and a key factor in the development and aggravation of the disease. In Western countries, liver cirrhosis is among the top ten causes of death in adults.

It is a very common disease and the leading cause of liver transplantation in the world. It represents a high rate of hospital admissions and use of health resources due to complications that occur in advanced stages of the disease.

Cirrhosis is a chronic liver injury characterized by the accumulation of scar (fibrous nodules) on the tissue structure interfering with the normal functioning of the organ. The main causes of chronic liver lesions are alcoholism, hepatitis C and, in increasing numbers, obesity.

The cluster of scars complicates blood circulation through the liver, causing portal hypertension (portal vein). To release pressure in the vein, collateral blood vessels are generated outside the liver. The problem then is twofold, first because they still get less blood to the liver, leading to liver damage and also more vessels are of poor quality (pathological angiogenesis).

The liver cells try to repair injuries but the way they do it ends fatally to the body. It is a circle that is amplifying and that ends up being very critical to the lives of patients. In addition, collateral vessels are varicose veins in the esophagus and stomach of patients with cirrhosis; these veins are very fragile and are prone to rupture, causing intense and very difficult to stop bleeding. Therefore, a therapy aimed to reversing the pathological vessels, which does not exist today, would be efficient.

The main effector protein in the generation of blood vessels is VEGF (vascular endothelial growth factor). All current drugs that seek to prevent neovascularization are based on inhibiting VEGF or its receptors, but the problem is that this protein attacking indiscriminately disabling normal generation of vessels, so that adverse effects are intolerable.

Following a previous study published in "Nature Medicine", the researchers had already discovered that CPEB is involved in the generation of blood vessels in pancreatic and brain cancer. Given the urgency of finding new targets for pathological angiogenesis, they began studying the role of CPEB4 in pathological angiogenesis in the context of cirrhosis, where neovascularization is abundant.

The nicest thing about the work is that we show that interfering proteins CPEB4 only eliminate the formation of pathological vessels, while positive vascularization remains intact. Experiments with cells in vitro, in animal models and samples from patients with cirrhosis have revealed the molecular mechanisms by which increased CPEB4 VEGF overexpression and promotes cirrhosis.

Liver cancer

The repairing cycle including liver worsens the situation, causing appearance of the regenerative nodules with high levels of CPEB4 end forming hepatocarcinomas.

In this context, the Spanish Association Against Cancer has awarded more than one million euros in researches to unravel the role of this molecule and propose a treatment for hepatocellular carcinoma, the primary liver cancer and the third leading cause of cancer death worldwide, with a survival rate at 5 years less than 10%.

In parallel, the researchers have launched CPEB4 inhibitors study. Last year they managed to reveal the atomic structures of these proteins, after passing the computational design.