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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 

Studying the transition of liver cirrhosis to liver cancer

Dr Raul Mendez is studying how and why liver damage can lead to cancer.

Hepatocellular carcinoma is the most common type of liver cancer and a leading cause of death worldwide. Most people who develop hepatocarcinoma have underlying cirrhosis (scarring of the liver caused by continuous, long-term liver damage). The management of these patients continues to be a critical clinical problem, for which few therapeutic options are available. In fact, liver cancer is expected to increase in incidence due to the current “obesity epidemic”.

Dr Mendez explains “Current treatments are mostly limited to liver resection (removal of part or all of the liver) and transplants. But these options are severely restricted by tumour size and localization, and by liver availability for transplantation. Therefore, there is still a clear need for new treatment strategies to improve the therapeutic outcome of patients suffering from liver cancer. Understanding more precisely the molecular alterations underlying the transition from cirrhosis to hepatocarcinoma will contribute to this aim.”

He continued “We hypothesize that transition from liver cirrhosis to hepatocarcinoma could be regulated by CPEB proteins. Indeed we have shown that CPEBs shorten a highly specific region of RNAs (a copy of the information contained in the DNA) that holds most signals determining whether an RNA molecule is made into protein or not. Thus, CPEBs “take off the brakes" for RNAs involved in tumor growth. This allows the RNAs to be made into proteins and promotes tumour development.

We have also found that CPEB expression (which switches on the making of new proteins that favours tumour growth and new blood vessel formation) is increased in several human tumours and cirrhotic livers. It plays a major role regulating processes like angiogenesis (the formation of new blood vessels) which is crucial for tumour growth.”

He added “With this funding we aim to determine the role and therapeutic potential of CPEBs in the transition from cirrhosis to hepatocarcinoma. Targeting CPEBs may have a great potential for clinical application in liver cancer.”

He concluded “The support from the Worldwide Cancer Research has allowed us to assemble a multidisciplinary team with an expert in Liver physiology (Mercedes Fernandez, IDIBAPS), a leading Hepato-oncologist (Jordi Bruix, Clinic Hospital) and an expert in Gene expression regulation (Raúl Méndez, IRB). With this broad perspective we will approach the transition from cirrhosis to liver cancer from a new and previously unexplored angle. We aim to translate the molecular mechanism(s) responsible of the tumour initiation to diagnostic, and in the longer-term therapeutic, tools with clinical application. We are very grateful for the confidence deposited by the public in our project and very aware on the responsibility to deliver results that go beyond our respective academic fields into discoveries with social impact.”

New year, new research

We support research into all cancer types and this latest grant round was no exception. The projects contain a good mix of cancer types from mouth and lip to breast, lung, pancreatic, lymphoma and liver cancer to name but a few. And of course a large amount is being spent on understanding the very fundamental principles behind how our cells behave and what goes wrong in cancer. Keeping with our ethos of supporting the best research around the globe, the projects are taking place all over the world including England, Portugal, Greece, Spain, Australia, The Netherlands, France, Germany, USA and Canada.

Opening up about mouth cancer

Some of the projects that most excite us are Dr Guy Lyons from the University of Sydney, Australia. He is identifying genetic changes that occur when mouth cancer starts so that it can be diagnosed early, when treatment is more likely to be successful. You can read more about mouth cancer in our recent blog. Dr Lyons told us “The support of organisations such as Worldwide Cancer Research for research into the fundamental biology of cancer is essential for the discovery of new paradigms that enable new approaches in the clinic down the track.”

Developing new ‘super cameras’

Professor Carolyn Moores at Birkbeck University of London in England is developing state of the art electron microscopy to actually visualise where drugs bind (stick) to their target molecules inside the cancer cells. This is VERY cool.  She said “Revolutionary new imaging technology means that our pictures will provide unprecedented detail, from which we will calculate the three-dimensional shape of our samples. This technique could potentially revolutionise the way drug discovery is carried out and our findings could be used to design specific drugs that can be further developed to improve treatments for cancers in the future. It is an exciting time to be an electron microscopist and we are thrilled that Worldwide Cancer Research is supporting our research in this area.”

Studying ‘bubbles’ to beating childhood brain cancer

We are also funding Dr Kasper Rouschop at Maastricht University in The Netherlands (pictured above) who is studying how ‘bubbles’ released by glioblastoma tumours encourage blood vessels to grow into the tumour. Glioblastoma’s are a type of brain tumour that commonly effects.  He told us “We anticipate that the results of this research will enable us to evaluate whether targeting these particular bubbles could be a potential new way to reduce the growth of brain tumours.  Our approach is highly innovative and is based on our previous identification of “bubbles” that are specifically released by hypoxic tumour cells. Without the support of Worldwide Cancer Research, evaluation of this promising approach would not be possible.”

And last, but by no means marking the end of my list of fab new projects, is Dr Ruben van Boxtel at the Hubrecht Institute in the Netherlands. He is trying to figure out why cancer arises in some parts of the body more than others. Great question to try to answer!

Our next grant round is already underway and our Scientific Committee will meet in March to decide who gets funded.  But this relies on donations, no money means no research.  If you would like to join team Worldwide Cancer Research and make a donation today just text WORLDWIDE to 70004 to donate £10. Thank you.

Image kindly provided by Dr Kasper Rouchop.

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.

 

Studying the link between obesity and liver cancer

Primary liver cancer is the sixth most common cancer in the world. Most liver cancers start after cancer cells have spread from a different part of the body, this is called secondary cancer. Primary liver cancer, where the liver is the first place that the tumour grows, is one the third most common cause of death from cancers worldwide, and survival rates are very low. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, accounting for 90% of cases. HCC is more common in developing countries, where it is associated with long term Hepatitis B infection. HCC has almost doubled in the US & nearly tripled in Australia in the last 20 years, and the obesity epidemic is believed to play a large part in this drastic increase.

Professor Tiganis will be using his Worldwide Cancer Research grant to study the molecular changes that happen within the liver as a result of obesity, and how these molecular changes can lead to HCC.

Liver cancer and the role of the URI protein

Cells have a complex internal system of proteins controlling everything they do. These proteins are organized into pathways in which the first activates the second and that activates the third, and so on, passing the activation signal down the pathway. These pathways are often very complex, with many crosstalks and branches. Several of these signalling circuits are involved in controlling how cells grow and divide and can become significantly altered in cancer cells. One such pathway is the mTOR pathway which has been linked to low survival rates for patients with liver cancer. However the final 'targets' of this pathway are not yet fully understood. Dr Djouder has recently identified one of these "targets" called URI which allows cells to survive when turned on and promotes cell death when turned off. In several human cancer cells however, including liver cancer, URI is present at high levels. This prevents the cells from dying, resulting in aggressive cancer and is therefore associated with lower patient's survival rates. This indicates that URI may help cancer cells avoid being killed and it may also have cancer-causing abilities. With a grant from Worldwide Cancer Research Dr Djouder is examining exactly how URI is involved in liver cancer.

Obesity and liver cancer

Liver cancer is one of the most common causes of cancer death worldwide, partly due to the lack of effective treatment options.

Chronic liver damage and inflammation caused by viral infection, toxins or alcohol abuse is known to cause liver cancer. Obesity is also an important risk factor, but scientists still don’t fully know why.

Professor Manolis Pasparakis and his team are interested in how obesity can lead to liver cancer. “Considering the obesity epidemic in western countries, obesity associated liver cancer is likely to become a major health hazard in the near future,” explains Professor Pasparakis. “We need a better understanding of the mechanisms controlling liver cancer, and especially the role obesity has in triggering these mechanisms.”

During this project Professor Pasparakis will study one particular cell molecule, called RIPK1, which he believes could be a ‘missing link’ in the understanding of how obesity can lead to liver cancer.

“We hope our studies will not only provide new insights into the mechanisms driving liver cancer, but will also be able to validate the potential importance of RIPK1 as a much needed therapeutic target,” says Professor Pasparakis.

Investigating liver cancer

Primary liver cancer is quite rare. In total, about 3,600 cases are diagnosed in the UK each year and it is more common in men than in women. However, for those that do get it the outlook is poor because by the time someone has symptoms and goes to their doctor, the disease is very often in the advanced stages. Only about 1 out of 10 people (10%) are diagnosed in the early stages of this disease when surgery can help. Worldwide Cancer Research have recently awarded a grant to Professor Wilhelm Krek to study how liver cancer begins. Cells have a complex internal system of genes and proteins which control everything they do. These genes and proteins are organised into pathways in which the first activates the second and that activates the third, and so on, passing the activation signal down the pathway. Several signalling pathways are involved in controlling how cells grow and divide and can become significantly altered in cancer cells. One of these, known as the mTOR pathway, is known to be turned on in liver cancer and has been linked to poor survival for patients. One of the molecules at the end of the mTOR signalling pathway is URI. URI is often found at high levels in liver cancer and correlates with increased cell growth and poor patient survival. It is thought that it is involved in switching off cell suicide messages and promoting cell survival in cancer cells. With his Worldwide Cancer Research grant Professor Krek therefore intends to investigate how it does this.