TRR 209: Liver Cancer - New mechanistic and therapeutic concepts in a solid tumor model

肝癌是第六大最常见的癌症疾病，也是第三大最常见的与癌症相关的死亡原因，即使在工业化国家，发病率也在上升。它包括肝细胞癌、肝内胆管癌和混合分化的原发性肝脏肿瘤。LC代表了实体癌的理想模型：主要的、有充分记录的癌症危险因素与LC相关，即慢性病毒感染（乙型/丙型肝炎）、肥胖/代谢综合征（非酒精性脂肪性肝炎）、毒性损伤（酒精/黄曲霉毒素）和慢性炎症；然而，对于已知危险因素驱动LC发展的致癌机制、致死性肿瘤如何在其特定微环境中发生以及如何相应地改进治疗方法，我们知之甚少。随着LC中优秀的模型系统，特别是创新的小鼠技术和充分注释的人类LC队列，反映了其原因和分子变化，我们可以解决这些问题。SFB/TR 209整合并利用了这一强大的模范模型系统星座和国际领先的LC研究人员的专业知识，以协调和互补的方式解决相关的机制和干预问题。研究领域A集中在西方世界日益领先的LC病因——非酒精性脂肪性肝炎的致瘤机制，以及主要的效应机制——慢性炎症。研究领域B研究形成LC细胞与其环境相互作用的关键进展机制，如复杂的调节肿瘤细胞机制、肿瘤细胞可塑性和肿瘤-基质相互作用。研究领域C集中于新颖的、床边-台上驱动的治疗方法，主要针对间质室，即肿瘤免疫反应和脉管系统。模型系统评价、生物银行、数据储存和生物信息学分析问题集中在中央inf项目，为模型、生物样品和数据提供统一和可持续的方法。SFB/TR 209的研究工作与所有三个合作站点的强大LC转化和临床结构密切相关。SFB/TR 209将利用并特别补充在所有三个伙伴地点建立的关于促进初级科学家、兼顾家庭和事业以及性别问题的现有有效结构。SFB/TR 209基于其强大的研究轨迹、互补和合作研究项目，并与完善的转化结构相关联，获得了相关的新机制见解和介入策略，有望影响其他实体肿瘤疾病，甚至超越这种临床相关的模型癌症。

Liver cancer (LC) represents the sixth most frequent cancer disease and third most frequent cancer related cause of death with rising incidence even in industrialized countries. It comprises Hepatocellular Carcinoma, Intrahepatic Cholangiocarcinoma, and primary liver tumors of mixed differentiation. LC represents an ideal model for solid cancer: major, well documented cancer risk factors are relevant for LC, namely chronic viral infection (Hepatitis B/C), obesity/metabolic syndrome (Non-alcoholic steatohepatitis), toxic injury (alcohol/aflatoxin) and chronic inflammation; still, little is known in regard to the oncogenic mechanism by which the established risk factors drive LC development, how lethal tumor progression takes place in its specific microenvironment, and how to improve treatment approaches accordingly. With excellent model systems available in LC, especially innovative mouse technologies and well annotated human LC cohorts, which reflect its causes and molecular changes, we can solve these questions.The SFB/TR 209 integrates and exploits this strong and exemplary model system constellation and the expertise of internationally leading LC researchers to tackle the relevant mechanistic and interventional questions in a coordinated and complementary manner. Research area A concentrates on tumorigenic mechanisms of the increasingly leading LC etiology in the Western World, Non-alcoholic steatohepatitis, and the main effector mechanism, chronic inflammation. Research area B investigates key progression mechanisms that shape the interaction between the LC cell and its environment, such as complex regulatory tumor cell mechanisms, tumor cell plasticity, and tumor-stroma interaction. Research area C concentrates on novel, bedside-bench-driven therapeutic approaches mainly addressing the stroma compartment, i. e. tumor immune response and vasculature. Model systems evaluation, biobanking, data storage and bioinformatics analyses issues are concentrated in the central INF-project providing a harmonized and sustainable approach to models, biological samples and data. The research efforts of the SFB/TR 209 are well linked to strong LC translational and clinical structures at all three partner sites. Existing efficient structures addressing the promotion of junior scientists, the compatibility of family and career, and gender issues established at all three partner sites will be used and specifically complemented by the SFB/TR 209. Built on its strong research track, complementary and cooperative research program, and linked to well established translational structures, the SFB/TR 209 gains relevant new mechanistic insights and interventional strategies that are expected to impact on other solid tumor diseases even beyond this clinically relevant model cancer.