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New revelations about the root causes of liver cancer

The transformation of hepatocytes (the main type of liver cells) into cancerous cells is the origin of most hepatocellular carcinomas, an aggressive type of liver cancer with high mortality rates. But these cells do not act alone. New research, partly funded by Worldwide Cancer Research, and published in Cell Reports, showed that new liver cells, known as hepatic progenitor cells, are recruited to help create a range of different cell types within the liver (known as heterogeneity).  They also lead to the formation of non-cancerous (benign) tumours, and can sometimes lead to aggressive cancers.

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Liver section with a Sox9 staining showing the expansion of the hepatic progenitor cells at the early stages of tumorigenesis and after expression of oncogenic URI specifically in hepatocytes. / CNIO

The scientists at the Spanish National Cancer Research Centre (CNIO), used genetic experiments and a special strain of mice, generated by Dr Nabil Djouder and his team, which accurately mimics the human tumour formation process seen in liver cancer development (hepatocarcinogenesis).  Together, these techniques enabled them to discover that hepatic progenitor cells participate in liver tumour heterogeneity and allowed them to follow the formation of the benign or malignant tumours and define the changes in the liver tissue.

Dr Djouder, who led the research, explains “We observed that oncogenic hepatocytes lead to hepatocellular carcinoma, but hepatic progenitor cells also grow and expand during tumour growth. At one point, the progenitor cells become transformed into cancerous cells; enabling them to participate in liver tumour development. The progenitor cells mostly lead to benign tumours, but sometimes they can lead to aggressive carcinomas like hepatocellular carcinomas.”

The cancerous hepatocytes cross-talk, recruit and instruct neighboring progenitor cells to become activated, maintaining them in an undifferentiated state (not fully formed as liver cells) while at the same time multiplying, becoming cancerous, and contributing to the tumours. The team found that this activation occurs when the hepatocytes secrete two substances (alpha-ketoglutarate and galectin-3) that act and transform progenitor cells.

Blocking galectin-3 can stop the cross-talk between these cells, thereby reducing tumourigenesis”, a finding that could have therapeutic implications, explains Djouder.

Dr Lara Bennett from Worldwide Cancer Research added “Survival rates for liver cancer are still low. An estimated 745,000 people around the world died from liver cancer in 2012 alone.  That is why discovery research like this, to understand the root cause of liver cancer, is vital.  Further work is now needed to investigate whether blocking galectin-3 or alpha-ketoglutarate could form the basis of new ways to prevent or treat liver cancer in the future and help save more lives in the future.

This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness (grant SAF2013-46089-R) and Worldwide Cancer Research.

This text was adapted from the original press release by CNIO.

Reference article:

Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells. Krishna S. Tummala, Marta Brandt, Ana Teijeiro, Osvaldo Graña, Robert F. Schwabe, Cristian Perna and Nabil Djouder (Cell Reports 2017). DOI: 10.1016/j.celrep.2017.03.059