The liver is the largest organ inside the body. It is located on the right side of the abdomen and protected by the ribcage. The liver will function normally with only a small portion of it in working order. Its functions include:
• destroying harmful substances, such as alcohol, and getting rid of waste products
• converting food containing fats and sugars to energy that is used by the body
• producing bile to help with the digestion of food.
Liver cancer can be a primary cancer (starts in the liver) or a secondary cancer (starts in another part of the body and spreads to the liver). Primary liver cancer is the sixth most frequently diagnosed cancer globally and the second leading cause of cancer death. Cancers can form from either the liver itself or from structures within the liver, including blood vessels, or the bile duct.
Liver cancer is most often caused by:
- cirrhosis – scarring of the liver tissue from alcohol
- long-term infection with a hepatitis virus – hepatitis B, C or D
- some chemicals – (for example, arsenic) that are now rarely used
- smoking – hepatitis B or C infection increases the risk of liver cancer in people who smoke
- diabetes – people with diabetes have a risk or that is two or three times higher than people who do not have diabetes.
- Haemochromatosis – an increased absorption of iron through diet that can casue liver damage
There are very few nerves running through the liver and as such, there are often no noticeable symptoms in the early stages of liver cancer. In later stages, liver cancer can lead to an ache in the upper abdomen or back. Swelling, irritation or inflammation of the liver can result in pain in areas surrounding the liver. Other symptoms include loss of appetite, weakness and loss of weight (particularly loss of muscle in the arms and legs), nausea, fever and jaundice (yellowing of the skin and whites of the eyes). The abdomen may also be swollen.
Treatment for liver cancer will depend on whether it is a primary or secondary cancer. Treatment options may include:
- Surgery – to remove the cancer and damaged tissue. This is the main treatment for primary liver cancer. Surgery is only useful for secondary liver cancer if the cancer cells only affect one area of the liver.
- Chemotherapy – the use of tablets or injections of anti-cancer drugs. Sometimes, they are introduced into the veins via a drip, or injected directly into the artery that feeds the cancer in the liver. Chemotherapy is the main treatment for secondary liver cancer and it is also sometimes used for primary liver cancer.
- Radiotherapy – x-rays are used to target and kill cancer cells. Radiotherapy may help in treating some types of primary liver cancers, and may be used to relieve symptoms of pain and discomfort from secondary liver cancer.
Liver research at the Perkins is focussed on the biology of the liver progenitor cell (LPC) called an “oval cell” which describes its shape. Our long-term vision is to use human LPCs to treat liver cancer, especially end-stage liver cancer for which organ transplant is the only possible solution. To do this we have to understand mechanisms underlying the differentiation of LPCs as opposed to their transformation into liver cancer.
As a result, one objective of our research is to document molecular and cellular differences between tumorigenic and non-tumorigenic LPCs and to show which of these are causal and which are consequential in regards to transformation. Causal changes can form the basis of prevention strategies and unique characteristics of tumorigenic LPCs can be used to selectively target liver cancer cells which develop from LPCs.
[Image]: BMEL TAT LPCs cell lines which have been differentiated to form ducts (a), hepatocytes (b) and ducts and hepatocytes (c). X-gal staining reveals LPCs expressing the beta-gal reporter which have differentiated into mature hepatocytes.
To utilise LPCs we must identify and understand the action of growth factors and cytokines, which influence them. To accomplish this, we have determined the pattern of growth factors and cytokines in pre-clinical models with liver disease that induces the appearance of LPCs. The importance of these factors has been confirmed by showing that they affect cultured LPCs. These studies indicate that IL6, TNF alpha, Interferon alpha and gamma and lymphotoxin beta are important LPC regulatory factors. To effectively use LPCs as vehicles for cell therapy we need to define conditions which enhance their growth and differentiation. Knowledge of cytokines which enhance LPC proliferation can be used to increase their contribution to liver regeneration in humans which can lead to positive outcomes for liver disease patients.
Recent research breakthroughs in this area include:
- Establishment of LPCs from a transgenic model which expresses a liver specific reporter (see image)
- Acquisition of the Cellscreen instrument which allows for progressive, accurate, high throughput and comparative growth characteristic of multiple cell cultures
- Establishment of specific phenotypic differences in mitochondria between normal and transformed LPCs
Current research projects will further investigate these new developments and they are designed to increase our understanding of LPCs and establish their utility for treating liver disease.