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

胆道癌是一种严重的、通常是致命的癌症，在西方世界很少见。然而，它在泰国、老挝和越南地区的发病率是世界其他地区的100倍。这主要是因为它可能是由一种名为尾棘吸虫的肝吸虫引起的。这是一种寄生在该地区河流中发现的鱼身上的寄生虫。这种寄生虫引起的癌症的确切类型与其他胆道癌不同。这意味着我们可以认为CCA是两种(或更多)不同类型的癌症--由刺五加引起的CCA(或O-CCA)，以及由其他原因(如肝炎、炎症性肠病、吸烟等)引起的CCA，我们称之为非CCA。在泰国，这种疾病是毁灭性的，特别是在贫困地区，在那里，患有这种疾病的男子和妇女都无法养活家人，并在儿童死亡时留下孤儿。有一类已知的蛋白质有助于癌症的生长，称为肝素结合因子生长因子(HB-GF)。肝素是一种碳水化合物(类淀粉分子)，存在于细胞间隙，包括癌症中。这些HB-GFs包括表皮生长因子(EGF)、血管内皮生长因子(VEGF)和肝细胞生长因子(HGF)。抑制这些生长因子的药物都已被制造出来，并用于各种癌症(例如，赫赛汀治疗乳腺癌)，但尚未被证明对CCA有效。我们最近发现，从泰国食品中常用的一种海藻中分离出的一种模拟肝素的分子，可以干扰HB-GFS如何帮助CCA在实验室中生长。这种海藻提取物被称为硫酸盐半乳糖(或SG)，可以阻止CCA细胞生长、移动和生成新的血管。然而，我们不知道它坚持哪个HB-GFS，也不知道我如何阻止它们工作。在这个项目中，我们打算通过使用手术切除的部分癌症患者的癌症来开发一组O-CCA细胞，并将他们与英国的非O-CCA患者进行比较，找出他们的肝素结合生长因子的制造或工作方式是否有显著差异，以及是否可以通过针对HB-GFS的药物来阻止这些泰国特有的癌症的生长，以及是否可以使用泰国海藻提取物来告诉我们这些类型的癌细胞有什么不同。最终，我们希望这项工作为泰国CCA已经批准的特定药物的临床试验铺平道路。我们认为，通过了解这些癌细胞的生物学特性，我们将能够设计出联合使用这些药物来针对泰国CCA患者的试验。此外，我们想调查泰国海藻提取物是否可以用于泰国和世界其他地区的胆道癌研究。

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.