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

胆管癌（胆管癌，简称CCA）是一种严重的，通常是致命的癌症，在西方世界很少见。然而，在泰国、老挝和越南地区，这种情况比世界上任何其他地方都要常见一百倍。这主要是因为它可能是由一种叫做Opisthorchis的肝吸虫引起的。这是一种寄生在该地区河流中鱼类体内的寄生虫。这种寄生虫引起的癌症的确切类型与其他胆管癌症不同。这意味着我们可以将CCA视为两种（或更多）不同类型的癌症——opisthorchisinduced 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NonO-CCA。在泰国，这种疾病是毁灭性的，特别是在贫困地区，在那里，患有这种疾病的男女都无法养家糊口，孩子死后就成了孤儿。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（淀粉样分子），存在于细胞间隙，包括癌细胞。这些hb - gf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已经被制造出来并用于各种癌症（例如赫赛汀治疗乳腺癌），但尚未显示对CCA有用。我们最近发现，从泰国食品中常用的海藻中分离出一种类似肝素的分子，可以在实验室中干扰HB-GFs帮助cca生长的方式。这种海藻提取物，被称为硫酸半乳聚糖（SG），可以阻止CCA细胞生长移动，并产生新的血管。然而，我们不知道它坚持哪些HB-GFs，也不知道它是如何阻止它们工作的。在这个项目中，我们打算通过使用手术从患者身上切除的部分癌症来开发一组O-CCA细胞，并将它们与英国的NonO-CCA患者进行比较，并找出它们的肝素结合生长因子的制造或工作方式是否存在显着差异。找出这些泰国特定癌症的生长是否可以用靶向HB-GFs的药物来阻止，以及泰国海藻提取物是否可以用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，我们将能够设计针对泰国CCA患者使用这些药物组合的试验。此外，我们想调查泰国海藻提取物是否可以用于帮助研究泰国和世界其他地区的胆管癌。

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.