Genetic dissection of the gp130 signalling network; implications in the initiation of gastric cancer

胃癌是世界上一个主要的健康问题。它是第二常见的癌症，也是仅次于肺癌的第二大癌症死亡原因。事实上，全世界所有新报告的癌症病例中约有10%是胃癌。胃癌的风险随着年龄的增长而增加，风险逐渐增加，并在60岁左右达到顶峰。像所有癌症一样，胃癌是由基因的逐渐突变引起的，而这些基因通常确保细胞生长和细胞死亡之间的平衡。使个体易患胃癌的突变在为胃提供衬里的上皮细胞中积累。胃癌的发展经历了许多不同的解剖阶段，病理学家很容易识别。一些基因的突变（如Kirsten-ras， p53）通常在胃肿瘤中发现。此外，一些突变与肿瘤发展的不同阶段高度相关。然而，到目前为止，我们还没有真正了解这些突变是如何相互合作产生全面的（恶性）胃癌的。在我们的提议中，我们的目标是在小鼠身上建立胃癌。我们的方法是使用现有的易患胃癌的动物模型。我们将逐步将突变基因引入胃上皮细胞，并研究它们如何相互合作，在小鼠胃中产生良性肿瘤，并最终产生恶性肿瘤。这将有助于我们了解肿瘤发展的每个阶段需要哪些突变基因，并可能为胃癌筛查和治疗提供更合理的方法。

Stomach cancer is a major health problem in the world. It is the second most common cancer and the second leading cause of death from cancer, behind lung cancer. In fact, approximately 10% of all new reported cancer cases world-wide are stomach cancer. The risk of stomach cancer increases with age, with risk rising progressively and peaking at about 60 years of age. Men are affected twice as often as women Like all cancers, stomach cancer results from the progressive acquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations which predispose individuals to stomach cancer accumulate in the epithelial cells that provide the lining to the stomach. The progression of stomach cancer proceeds through a number of distinct anatomical stages which can be easily recognised by pathologists. Mutations in a number of genes (known as Kirsten-ras, p53) are commonly found in stomach tumours. Moreover, some of the mutations are highly associated with distinct stages of tumour development. As yet, however, we have no real insights into how these mutations cooperate with each other to produce full-blown (malignant) stomach cancer. In our proposal, we are aiming to establish stomach cancer in mice. Our approach will be to use an existing animal model which is predisposed to stomach cancer. We will progressively introduce mutant genes into stomach epithelial cells and study how they cooperate with each other to produce benign, and ultimately, malignant tumours in the stomach of mice. This will help us to understand which mutant genes are required for each stage in tumour development and may provide more rational approaches to stomac cancer screening and treatment.