Cancer Research UK (CRUK) has co-funded a complex study that involved a whole series of cruel and archaic experiments on rats and mice. Conducted at Edinburgh University, the research was designed to investigate whether disrupting a particular network of proteins could help treat bile duct cancer.  Three different types of animals were used:
1. So-called ‘nude’ mice – furless animals who are genetically modified to have a deficient immune system. This makes them less likely to reject human cancer cells that are injected into them.
2. A different group of genetically modified (GM) mice, who are prone to developing cancer and were poisoned for around six months to trigger the onset of tumour growth.
3. Rats, who were subjected to the same six-month poisoning regime as the mice.
- These animals were subcutaneously injected (i.e. under the skin) with tumour cells from people with bile duct cancer.
- They had to endure the growth of the tumour inside them for three weeks before some of them were given treatments to reduce the severity of the tumours. This series of experiments was based on the theory that disrupting a particular network of proteins could treat the tumours. The treatments given to the mice worked by depleting levels of certain white blood cells (macrophages), which inflicted further damage on their immune system.
Second group of GM mice
- Another group of genetically modified (GM) mice were chemically poisoned for around six months so that they would develop cancer. The chemical used to poison them was thioacetamide (TAA), a substance that has traditionally been used in the leather and motor fuel industries.
- The creation of GM mice generally involves several painful and invasive procedures, including castration, major surgery and ear or tail mutilation. Creating just one ‘founder’ mouse with the required genetic alteration can entail the deaths of hundreds of others. These unwanted mice are often killed by being gassed or having their necks broken.
- These animals were subjected to the same chemical poisoning regime as the mice. After about five months, some of them were given substances designed to target the tumours. One of these was the treatment that depleted levels of some white blood cells (macrophages) and therefore damaged their immune system.
- Animal ‘models’ of cancer have been strongly criticised by the scientific community. One notable example of this is a comment by Azra Raza, Professor of Medicine at Columbia University: ‘An obvious truth that is either being ignored or going unaddressed in cancer research is that mouse models do not mimic human disease well and are essentially worthless for drug development.’
- Transplanting human tumours into mice (xenografts) has long been recognised as an unreliable means of predicting how humans will respond to treatments. Unlike the mice used in this type of research, cancer patients have a functioning immune system, which has a significant impact on the course of the disease. The xenografted tumour cannot develop as it would in a patient and does not spread to other parts of the body – the factor that decreases a patient’s chances of survival.
- A study by the US National Cancer Institute found that only 45 per cent of compounds that had anti-tumour effects in the xenograft ‘model’ showed benefit in human trials. Even CRUK itself has declared in a promotional poster that ‘the time for reliance on such models to determine the response to a new therapy has passed.’ It is unclear why CRUK is helping to fund studies using a ‘model’ it appears to have little faith in.
- The researchers who conducted the CRUK-funded study admit: ‘subcutaneous xenografts do not represent CC (cholangiocarcinoma or cancer of the bile duct) in terms of natural disease progression or stromal microenvironment’. This fundamental weakness is stated as a reason for also using the poisoned rat ‘model’.
Second group of GM mice
- Genetically modifying mice to develop cancer is no more reliable than injecting them with human cancer cells. It is an over-simplistic approach, since human cancers are usually caused by multiple mutations in co-existent cells, and depend on a highly individualised cellular environment. The researchers admit that only a small proportion of bile duct cancer patients have the mutation inflicted on the GM mice they used.
- Researchers are unclear as to the exact cause of bile duct cancer but contributing factors can include a rare type of liver disease, abnormalities of the bile duct and parasitic infections. Being forced to ingest an industrial chemical for six months hardly provides an accurate ‘model’ of how the disease develops in humans.
- Xenograft and poisoning studies on rodents that appeared successful have failed to translate into treatments for bile duct cancer patients. This has resulted in the withdrawal of trial drugs for the treatment of bile duct cancer such as sorafenib.
- The ‘study’ was investigating whether blocking a particular network of proteins could treat cancer of the bile duct. Yet drugs with this same target are already being trialled in patients. If these drugs are safe in humans, there is no reason why they could not have been trialled on bile duct cancer patients too.
- The researchers justify using rats and mice by arguing that human tissue samples can only provide information on the end stage of disease. However, genetic sequencing of information from cancer patients and healthy volunteers provides far more directly relevant information for comparison. This can provide valuable insights into the genetic traits involved in the development of bile duct cancer, which can even differ between one patient and another. Such complexity cannot be reflected in animal ‘models’ of bile duct cancer, which despite extensive use, have been described as correlating ‘poorly with clinical outcome’.
- As well as the animal experiments, the researchers used sophisticated DNA slides known as microarrays that can analyse thousands of genes at once. These provide much more relevant information than the crude and unreliable experiments on rats and mice.
 Boulter L et al (2015). WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest. 2015;125(3):1269–1285.
 Stallwood A (2013). Science Corrupted: The Nightmare world of GM Mice. Animal Aid, 2013.
 Brockman J (2014). What scientific idea is ready for retirement? The Observer, 12 January 2014.
 Kelland L R (2004). Of mice and men. European Journal of Cancer. 40 (6): 827-836
 Frese K, Tuveson DA (2007). The evolution of genetically engineered mouse models of cancer [poster]. Nature. September 2007.
 El-Khoueiry et al (2012). SWOG 0514: A phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest. New Drugs. 30,1646-1651.
 Muisuk K et al (2015). Novel mutations in cholangiocarcinoma with low frequencies revealed by whole mitochondrial genome sequencing. Asian Pacific Journal of Cancer Prevention. 16(5):1737-42.
 Zabron A et al (2013). The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer. Disease Models and Mechanisms. 6(2):281-92.
 Xue T et al (2015). Differentially expressed gene profiles of intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and combined hepatocellular-cholangiocarcinoma by integrated microarray analysis. Tumour Biol. Feb 2015 (Epub ahead of print).