巨噬细胞亚群及其趋化对肝癌组织新生血管形态的影响与机制

Our resent study has demostrated the presence of endothelium-coated tumor cell cluster (ECTC) in hepatocellular carcinoma (HCC) might represent a novel alternative metastatic pathway. The density and location of macrophage (Mφ) in HCC tumor was significantly correlated with the presence of ECTC, and a number of Mφ-related chemokine were highly up-regulated in ECTC samples. Therefore, we speculate that Mφ might constitute a novel mechanism to regulate the formation of ECTC through certain chemokine axis. To further confirm this hypothesis, we will combine experimental studies, mouse model and clinical sample analysis to: 1) Select the chemokines that were significant associated the ECTC structure; 2) Examine the chemokine axis in directing Mφ subset to vessel front, and define the key molecules and signaling pathways by which this Mφ subset regulates ECTC formation; 3) Explore the potential of clinic application by selective blocking ECTC formation. The prospective results would not only help to unveil the novel mechanisms of Mφ regulating tumor angiogenesis, but would also contribute to the alternative rationale for selecting potential patients who may benefit from proper molecular-targeted drugs by regulating vascular structure.

我们新近发现在肝癌组织中存在着由血管内皮细胞包裹肿瘤细胞团的新生血管结构（ECTC），该结构很可能是引起肝癌血行转移的重要因素。肝癌组织中浸润巨噬细胞（Mφ）的数量和分布与ECTC结构密切相关，芯片筛查的结果也发现多个与Mφ相关的趋化因子在ECTC样本中高表达，提示某特定Mφ亚群在组织中的趋化与聚集参与调节了ECTC结构的形成。以此为基础，本课题拟以Mφ及其趋化对ECTC这一新生血管形态的调控机制为目标，结合体外实验、小鼠模型和临床样本研究：1）通过肝癌组织芯片明确与ECTC形成相关的Mφ趋化因子；2）研究相关趋化因子引导Mφ亚群趋化至ECTC形成部位的机制，以及该Mφ亚群对ECTC形成的调控机制；3）探讨通过选择性抑制相关通路阻断ECTC形成的潜在临床意义。所得的结果不仅有助于揭示Mφ影响肝癌血管生成的新机制，还可有助于为通过选择性调控肿瘤血管形态作为临床干预的潜在新靶标提供理论基础。

我们新近发现在肝癌组织中存在着由血管内皮细胞包裹肿瘤细胞团的新生血管结构（ECTC），该结构很可能是引起肝癌血行转移的重要因素。本项目通过肝癌组织芯片筛选到肝癌血管内皮细胞上表达的CXCR4分子与ECTC结构的形成显著相关。体内和体外功能实验发现CXCR4分子可通过促进血管分支来影响ECTC结构的形成。机制研究发现，Mφ可通过分泌TNFα上调血管内皮细胞上CXCR4分子的表达。进一步动物实验显示内皮细胞上CXCR4分子的表达与索拉非尼治疗敏感性相关，并与患者接受索拉非尼治疗效果成负相关。以上所得的结果揭示了Mφ影响肝癌血管生成的新机制，将有助于为通过选择性调控肿瘤血管形态作为临床干预的潜在新靶标提供理论基础。