c-Met调控肝癌微环境中单核巨噬细胞表型与功能的机制研究

Macrophages (Mφ) constitute one of the most important immune infiltrates in most solid tumors and display great functional plasticity and diversity. Exploring novel Mφ subset/funcional marker under specific tumor microenvironments is essential for the better understanding of their pro-tumoral regulatory mechanisms. Our recent study found that c-Met - a membrane receptor essential for embryonic development and wound healing - was significantly up-regulated on Mφ isolated from tumor tissues of patients with hepatocarcinoma (HCC). In vitro experiments showed that c-Met was involved in the regulation of migration and MMP9 secretion by tumor associated Mφ, and therefore might represent a novel functional marker for Mφ in specific tumor microenvironments. To confirm this hypothesis, we will combine experimental studies and clinical sample analysis to: 1) Analyze the phenotypes and evaluate the clinical significance of c-Met+Mφ isolated from human HCC samples; 2) Define key molecules and signaling pathways regulating the expression of c-Met on Mφ in specific tumor microenvironments; 3) Examine the possible regulation of phenotype and function of Mφ (such as cytokine secretion, migration, phagocytosis, as well as interaction with other immune cells) by c-Met; 4) Confirm the relative mechanisms obtained through the above experiments in mouse model and clinical samples. The prospective results would not only help to unveil a novel subset/functional marker of Mφ in tumor environment, but would also contribute to the rational design of Mφ function-dependent, immune-based therapies.

单核巨噬细胞（Mφ）具有强大的可塑性与异质性，探索特定肿瘤微环境中新型的Mφ亚群/功能性标记对理解Mφ的促肿瘤调控机制具有重要意义。我们新近发现并证实：肝癌病人肿瘤组织中的Mφ显著上调了肝细胞生长因子受体c-Met分子的表达水平，该分子能够有效调控Mφ的迁移及分泌基质金属蛋白酶MMP9等功能。我们推测：c-Met可能代表了一个新型的肿瘤相关Mφ亚群/功能性标记。以此为基础，本课题拟：鉴定从肝癌临床样本中分选出来c-Met+Mφ的表型，分析它们与病人临床分期和预后的相关性；通过建立体外模型，研究肿瘤微环境中Mφ表达c-Met分子的相关调控网络；进一步探索c-Met分子对Mφ分泌细胞因子，迁移吞噬，及调控其它免疫细胞亚群功能的可能影响及机制；最后在小鼠模型及多种实体瘤样本中验证相关机制。所得结果将有助于揭示新型的Mφ亚群/功能性标记，并为重建/恢复特定组织微环境中Mφ的抗肿瘤功能提供理论依据

单核巨噬细胞具有强大的可塑性与异质性，探索特定肿瘤微环境中新型单核巨噬细胞亚群/功能性标记对理解其促肿瘤作用机制具有重要意义。在本项目的支持下，我们鉴定了从肝癌临床样本中分选出来的新型单核巨噬细胞亚群，并探讨其调控肿瘤进展的具体机制与临床意义。研究结果包括：1）鉴定了肝癌组织中一群具有促肿瘤活性的c-Met+单核细胞亚群：肿瘤来源的可溶性因子诱导单核细胞活化并分泌大量细胞因子，其中TNF-α能够诱导单核细胞上调表达c-Met分子，该分子与其他间质细胞来源的肝细胞生长因子HGF相互作用后，能够刺激单核细胞分泌基质金属蛋白酶MMP9等，促进肿瘤转移（2015 J Pathol；共一；IF 6.25）；2）鉴定了肝癌组织中一群具有抗肿瘤活性的CD169+巨噬细胞亚群：正常肝组织中CD169+巨噬细胞能够以CD169依赖的方式激活CD8+T淋巴细胞的杀伤活性，但肿瘤诱导巨噬细胞自分泌的TGF-β能够下调CD169的表达水平，从而使肿瘤实现免疫逃逸（2016 J Pathol；共通；IF 6.25）；3）揭示了肿瘤活化单核细胞通过诱导肿瘤自噬、促进肿瘤转移的新机制：肿瘤诱导单核巨噬细胞自分泌的各种细胞因子，包括TNF-α 和IL-1β，不仅能够调控自身的分化与功能，还能够通过诱导侵袭前沿区域癌细胞自噬水平的上调，促进肿瘤的转移（2018 Autophagy；共通；IF 11.1）。这些结果不仅有助于我们更好地理解肿瘤的免疫逃逸与编辑机制，更为肝癌的临床诊断与治疗提供了潜在的新型靶标分子。