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Hope for patients at risk of developing liver cancer

Worldwide Cancer Research funded scientists have identified a key molecule in non-alcoholic steatohepatitis (NASH), a condition that can lead to hepatocellular carcinoma, the most common type of liver cancer.  Blocking the molecule could prevent this condition in high risk patients, particularly those with diabetes or viral hepatitis infection.

The study, conducted at the Spanish National Cancer Research Centre (CNIO), was published on Monday in Cancer Cell, and shows that a molecule called IL-17A, that helps cause inflammation, is a key factor in the development of NASH.  NASH is currently untreatable, and can go on to cause a type of liver cancer called hepatocellular carcinoma (HCC).

HCC is the most aggressive type of liver cancer and a major cause of liver cancer-related death. Scientists are still trying to understand the changes that occur to allow liver cancer to develop, although several risk factors have been associated with it, including infection with hepatitis B or C. Another important risk factor is non-alcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation, and is common among obese individuals, virus-infected patients and diabetics.

“Accumulation of fat by itself cannot explain the appearance of NASH as only ten to twenty per cent of obese patients with fatty liver disease will develop NASH. Instead, inflammation determines the progression and outcome of the disease”, explains Dr Nabil Djouder, leader of the study.

Dr Djouder and his colleagues observed that NASH is the result of several “hits” and that the first ‘hit’ is DNA damage promoting inflammation, caused by excess nutrients (too much food).

Working with different mouse models, the scientists showed how an excess of nutrients switches on a cancer-causing gene (known as an oncogene) called URI in the liver. URI - which is also switched on in viral hepatitis - leads to DNA damage in the liver cells (hepatocytes).  This DNA damage causes immune system cells to go to the liver, especially Th17 cells, which make the proinflammatory cytokine molecule IL-17A. This molecule causes neutrophils (other immune system cells) to penetrate the adipose fat tissue. This leads to insulin resistance and fatty acid release, resulting in NASH.

The researchers treated healthy mice with IL-17A injections and observed how the first signs of NASH appeared after four weeks, confirming its crucial role in the disease development.

Finally, Dr Djouder and his team blocked IL-17A using various methods - antibodies and the drug digoxin among others - and this prevented the development of NASH and HCC. These findings could pave the way for a new prevention strategy for NASH and HCC in high risk patients, in particular those with diabetes or hepatitis viral infection.

This research project has been funded by Worldwide Cancer Research, the Spanish Ministry of Economy and Competitiveness and the European Foundation for the Study of Diabetes (EFSD).

Press release written by the CNIO Press Office and edited by Worldwide Cancer Research.