The impact of the CXC chemokine CXCL13 mediated B lymphocyte recruitment on the development and progression of hepatocellular carcinoma

肝细胞癌（HCC）是全球第五大常见癌症，预后极差，总生存率为3-5%。大多数HCC是在已有慢性肝病的背景下发生的，如慢性乙型或丙型肝炎病毒感染和非酒精性脂肪性肝炎，其组织病理学特征是慢性肝内炎症。在这种炎症过程中，炎症细胞向肝脏的募集主要是由称为趋化因子的可溶性小分子组织的。与它们的特异性受体一起，它们在肝脏内形成了一个非常复杂的系统，不仅介导肝内白细胞的浸润和归巢，而且对肝驻留细胞表现出直接的调节作用。最近，研究表明，与正常或癌前肝脏样本相比，CXC趋化因子CXCL13在肝细胞癌组织中的表达显著上调。CXCL13结合其特异性受体CXCR5，已知对B淋巴细胞是一种选择性和高效的化学引诱剂，B淋巴细胞是HCC病变中增强的细胞群，并已被证明对各种癌细胞发挥直接刺激作用。然而，对其在慢性肝病，特别是在肝癌发生中的作用知之甚少。因此，本项目的目的是确定和表征CXCL13表达增强和B淋巴细胞连续募集到肝脏对肝细胞癌发生和进展的影响。这些结果将为肝癌发生的分子机制提供新的认识，有助于早期诊断和发现新的治疗靶点，从而改善HCC患者的预后。

The hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide associated with a very poor prognosis with an overall survival rate of 3-5%. Most of the HCC develop on the background of pre-existing chronic liver diseases, e.g. chronic hepatitis B or C virus infections and non-alcoholic steatohepatitis, which are histopathologically characterized by a chronic intrahepatic inflammation. During this inflammation, the recruitment of inflammatory cells to the liver is mainly orchestrated by small, soluble molecules which are termed chemokines. Together with their specific receptors they form a very complex system within the liver mediating not only the infiltration and homing of intrahepatic leucocytes but also exhibiting direct modulatory effects on liver resident cells. Recently, it could be demonstrated that the expression of the CXC chemokine CXCL13 is significantly upregulated in the tissue of hepatocellular carcinoma compared to normal or preneoplastic liver samples. CXCL13, which binds to its specific receptor CXCR5, is known to be a selective and highly efficacious chemoattractant for B lymphocytes, a cell population which is enhanced in HCC lesions, and has been shown to exert direct stimulatory effects on various carcinoma cells. However, little is known about its role during chronic liver disease and especially during hepatic carcinogenesis. Therefore, the aim of this project is to identify and characterize the impact of an enhanced CXCL13 expression and the consecutive recruitment of B lymphocytes to the liver on the development and progression of hepatocellular carcinoma. These results should provide a new insight in the molecular mechanisms of hepatic carcinogenesis which could help to facilitate early diagnosis and identify new therapeutic targets in order to improve the prognosis of patients with HCC.