肿瘤相关巨噬细胞调控内皮CXCR4表达促进肝癌独特血管结构形成的研究

Recently, we have revealed that endothelium-coated tumor cell cluster (ECTC), a distinct vascular pattern in hepatocellular carcinoma (HCC), facilitates the entry of the whole tumour cluster into the bloodstream in an invasion-independent manner, and that C-X-C chemokine receptor 4 (CXCR4), the levels of which are increased on endothelial cells, is essential for ECTC formation. However, the mechanisms underlying upregulation of CXCR4 expression in ECTC remains unclear. In our preliminary study, we found the density of tumor-associated macrophages (TAMs) was significantly positively correlated with high levels of CXCR4 on endothelial cells; TAMs may promote the expression of CXCR4 in ECTC by secreting TNF-α. This project intends to combine the clinical sample analysis, experimental studies and mouse model to: 1.Confirm the correlation of TAM density and CXCR4 expression in ECTC; 2. Investigate underlying molecular mechanisms whereby TAMs regulate CXCR4 expression on endothelial cells to affect the formation of ECTC; 3. Explore the influence of selective blocking potential signaling pathways on CXCR4 expression and the formation of ECTC. The results obtained from this project will not only unveil the mechanisms of TAMs affecting the formation of ECTC via regulating CXCR4 expression on endothelial cells in HCC, but also provide a novel strategy for anti-metastasis therapy by regulating vascular pattern.

我们前期研究发现肝癌中的独特血管结构——ECTC可通过“非侵袭依赖”的方式促进肿瘤血行转移，且已证实 C-X-C趋化因子受体4（CXCR4）是参与ECTC形成的关键分子，但ECTC结构中内皮CXCR4表达上调的具体机制尚不明确。预实验中，我们发现肝癌血管周围分布的肿瘤相关巨噬细胞（TAM）与ECTC结构中内皮CXCR4的表达呈显著正相关，并可能通过分泌TNF-α上调内皮CXCR4的表达影响ECTC的形成。以此为基础，本课题拟结合临床样本分析，体外模型和小鼠实验：1.进一步明确TAM与ECTC中CXCR4表达的相关性；2.阐明TAM调控内皮CXCR4上调促进ECTC形成的具体分子机制；3.探讨阻断相关通路对CXCR4表达和ECTC形成的干预作用及潜在临床应用。所得结果不仅有助于揭示TAM对肿瘤血管内皮细胞及ECTC形成的调控机制，还有望为临床上通过干预血管形态抑制肝癌转移提供理论基础。

我们前期研究发现肝癌中的独特血管结构——ECTC可通过“非侵袭依赖”的方式促进肿瘤血行转移，且已证实C-X-C趋化因子受体4（CXCR4）是参与ECTC形成的关键分子，但ECTC结构中内皮CXCR4表达上调的具体机制尚不明确。在本基金资助及课题组成员共同努力下，我们在TNF-α调控HCC中内皮细胞CXCR4表达的分子机制方面展开系列研究，主要发现如下：1. 机制研究显示Mo/Mφ分泌的炎症因子TNF-α可以通过激活EC相关的Raf-Erk信号通路来上调CXCR4在EC上的表达，而调控Tip Cell的经典通路--Notch信号通路并不参与这个过程；2. 在小鼠模型中发现，联合ZA和索拉菲尼的治疗方案可以进一步下调CXCR4的表达水平，并显著增强索拉菲尼的治疗效果。这些结果不仅揭示了肝癌血管生成的新机制，还为临床肝癌抗血管生成治疗提供了的新思路和方案。以上述结果为基础，共发表论文3篇，单篇最高影响因子5.869。共协助培养研究生8名，其中1名硕士和3名博士已毕业，目前在读博士2名，硕士2名。