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

肝癌(LC)是第六大常见癌症和第三大与癌症相关的死亡原因，即使在工业化国家，其发病率也在上升。它包括肝细胞癌、肝内胆管细胞癌和混合分化的原发性肝肿瘤。LC是一个理想的实体癌模型：主要的、有充分证据的癌症危险因素与LC相关，即慢性病毒感染(乙肝/C)、肥胖/代谢综合征(非酒精性脂肪性肝炎)、中毒损伤(酒精/黄曲霉毒素)和慢性炎症；然而，关于已建立的风险因素驱动LC发展的致癌机制、其特定微环境如何发生致命性肿瘤进展以及如何相应地改进治疗方法，人们知之甚少。凭借LC提供的优秀模型系统，特别是创新的鼠标技术和反映其原因和分子变化的良好注释的人类LC队列，我们可以解决这些问题。SFB/TR209集成并利用了这一强大的模范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械性和干预性问题。研究领域A集中在非酒精性脂肪性肝炎这一西方世界日益重要的LC病因学的致瘤机制，以及其主要作用机制慢性炎症。研究领域B研究塑造LC细胞与其环境之间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-间质相互作用。研究领域C集中于新颖的、床边驱动的治疗方法，主要涉及间质隔间，即肿瘤免疫反应和血管系统。模型系统评价、生物库、数据存储和生物信息学分析问题集中在中央INF项目--对模型、生物样本和数据采取统一和可持续的办法。SFB/TR209的研究努力与所有三个合作伙伴站点的强大LC翻译和临床结构很好地联系在一起。在所有三个伙伴地点建立的解决初级科学家晋升、家庭和职业兼容以及性别问题的现有有效结构将得到SFB/TR209的使用和具体补充。SFB/TR209建立在其强大的研究轨道、互补和合作研究计划的基础上，并与成熟的翻译结构相联系，获得了相关的新机制见解和干预策略，预计将对其他实体肿瘤疾病产生影响，甚至超出这一临床相关的癌症模型。

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.