Role of heparin binding growth factors in O.viverrini induced Cholangiocarcinoma (O-CCA) development, progression and angiogenesis

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Cancer of the bile duct (cholangiocarcinoma, or CCA) is a severe, often fatal cancer, rare in the western world. However, it is a hundred times more common in areas of Thailand, Laos and Vietnam than anywhere else in the world. This is mainly because it may be caused by a liver fluke called Opisthorchis. This is a parasite that lives in fish found in the rivers of that area. The exact type of cancer caused by this parasite is different from other cancers of the bile duct. This means that we can think of CCA as being two (or more) different types of cancer - Opisthorchis-induced CCA (or O-CCA), and CCA cause by other causes (e.g. hepatitis, inflammatory bowel disease, smoking, etc - which we have termed NonO-CCA. In Thailand this disease is devastating, particularly in poor areas, where both men and women suffering from this disease are unable to provide for their families and leave children as orphans when they die. There is a known class of proteins that contribute to cancer growth called the heparin binding factor growth factors (HB-GF). Heparin is a carbohydrate (starch like molecule) that is found in the space between cells, including in cancer. These HB-GFs include epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF). Drugs that inhibit these growth factors have all been made and are used for various cancers (e.g. Herceptin for breast cancer), but not yet shown to be useful for CCA. We have recently found out that a molecule that mimics heparin, isolated from a seaweed commonly used in Thai food, can interfere with how HB-GFs help CCAs grow in the laboratory. This seaweed extract, called sulphated galactan (or SG) can stop CCA cells from growing moving, and making new blood vessels. However, we do not know which HB-GFs it sticks to, or how I stops them working. In this project we intend to develop a panel of O-CCA cells by using parts of the cancers surgically removed from patients with the disease, and compare them with NonO-CCA patients in the UK and find out whether there are notable differences in the way their heparin binding growth factors are made or work, find out whether growth of these Thailand specific cancers can be halted with drugs that target HB-GFs and whether the Thai seaweed extract can be used to tell us what is different about these types of cancer cell. Ultimately we would like this work to pave the way for clinical trials of specific, already approved, drugs in CCA in Thailand. We think that by understanding the biology of these cancer cells we will be able to design trials that use these drugs in combination to target Thai CCA patients. Moreover, we would like to investigate whether the Thai seaweed extract can be used to help research into cancer of the bile duct in Thailand and the rest of the world.