In over 50% of bowel cancer cases, the cancer spreads to other organs, the most common of which is the liver. Although often incurable, secondary liver cancer can be treated with chemotherapy and surgery. Unfortunately, however, chemotherapy drugs have been linked with the development of fatty liver disease, for reasons that are unclear. The FAL set out to try and model the effects of cancer therapy in the liver using human cell culture models.
Treating secondary liver cancer
Colorectal (bowel) cancer is one of the most common forms of cancer diagnosed in the UK after breast, prostate and lung cancer. There are around 40,000 new cases of bowel cancer registered in the UK annually. The blood from the intestines enters the hepatic portal vein and is carried to the liver. If the cancer spreads to other parts of the body (metastasis), the most common form of secondary cancer is liver cancer, with 25-30% of colorectal cancer patients developing liver metastases during the course of their disease.
Fluorouracil (5-FU) and Irinotecan are drugs commonly used in combination for treating cases of colorectal cancer. They are also used to shrink liver tumours prior to surgical removal via liver resection.
Chemotherapy drugs come with side-effects and unfortunately 5-FU and Irinotecan have been linked with the development of ‘chemotherapy associated steatosis’ (CAS) and ‘chemotherapy associated steatohepatitis’ (CASH). Steatosis or ‘fatty liver disease’ refers to the abnormal build-up of fat (lipids) within the cells of the liver. Steatohepatitis is when this fat accumulation progresses to cause fibrosis and inflammation of the liver. If these conditions develop during pre-surgery chemotherapy treatments to reduce liver tumour size, this can have adverse effect on patient prognosis and recovery times.
Using an in vitro model to study CASH
Researchers often choose to try and study adverse effects of drugs in animal models. There have been many examples of rats being used to investigate the effect and metabolism of chemotherapy drugs including 5-FU and Irinotecan and in particular the effect on the liver.
The FRAME Alternatives Laboratory (FAL) does much of its research by using and developing in vitro human liver cell models. One project the lab has been involved in aimed to create an in vitro model of CASH which can be used to study the development and treatment of the condition.
The FAL’s model used primary derived hepatocytes derived from human tissue as its basis. Key findings showed that in order to recreate steatosis caused by chemotherapy drugs, this in vitro liver model also had to include Kupffer cells – these are the immune cells of the liver and are involved in tissue repair, response to infection and the development of inflammation.
The human liver cells were exposed to the chemotherapy drugs 5-FU and Irinotecan and then cultured to allow fat deposition to occur. The human cells were found to accumulate greater amounts of fat in response to the drugs in a dose-dependent manner and showed signs of inflammatory changes in gene expression as seen in steatohepatitis.
As part of the study, rat liver cells were cultured under the same conditions for comparison. Interestingly, the rat cells did not respond to the chemotherapy drugs in the same way as the human liver cells. No increase in fat deposition occurred in the rat cells and there was no indication of inflammation.
“This data supports one of the cornerstones of the FRAME lab’s philosophy – if you want to determine the effects of drugs or chemicals in humans, or model human disease, you need to use models built using human tissues or cells.”