ELFN1-IL34-巨噬细胞形成环路促进结直肠癌血管生成和转移的机制研究

Metastasis is the leading cause of death in patients with colorectal cancer. Angiogenesis plays a key role in various stages of tumor growth and metastasis, but the molecular mechanisms and the key targets of angiogenesis in colorectal cancer are still unclear. Our previous studies showed that the expression of ELFN1 was significantly increased in metastatic colorectal cancer, which was positively correlated with microvessel density and macrophage infiltration. High expression of ELFN1 can activate NFκB pathway to promote the secretion of IL34, recruit and activate macrophages, leading to angiogenesis and metastasis of colorectal cancer. In turn, activation of macrophages up-regulates the expression of ELFN1 in colorectal cancer. We thus propose the hypothesis that ELFN1-IL34-macrophage loop promotes angiogenesis and metastasis of colorectal cancer. To confirm this hypothesis, this study intends (1) to clarify the role of ELFN1 in angiogenesis and metastasis of colorectal cancer; (2) to reveal the mechanisms that ELFN1 recruits and activates macrophages, and macrophages activation upregulates ELFN1 in feedback to promote angiogenesis and metastasis; and (3) to elucidate the role of ELFN1-IL34-macrophage loop in the regulation of angiogenesis and metastasis from cell, animal and clinical levels. This study aims to provide new ideas and therapeutic targets for clinical anti-colorectal cancer angiogenesis and metastasis.

转移是结直肠癌患者死亡的主要原因。血管生成在肿瘤生长及转移的各个阶段发挥关键作用，但目前调控结直肠癌血管生成的分子机制及关键靶点仍不清楚。我们前期研究发现转移性结直肠癌中ELFN1表达显著增高，且与微血管密度及巨噬细胞浸润呈正相关。ELFN1高表达激活NFκB通路促进IL34分泌，募集并激活巨噬细胞，促进结直肠癌血管生成和转移，同时巨噬细胞激活反馈性上调结直肠癌中ELFN1的表达。由此我们提出ELFN1-IL34-巨噬细胞形成环路促进结直肠癌血管生成和转移的假设。为证实该假设，本研究拟从细胞、动物和临床三个层次（1）明确ELFN1在结直肠癌血管生成和转移中的作用；（2）揭示ELFN1募集并激活巨噬细胞，巨噬细胞激活反馈性上调ELFN1促进血管生成和转移的分子机制；（3）阐明ELFN1-IL34-巨噬细胞环路在调控血管生成和转移中的作用，为临床抗结直肠癌血管生成和转移提供新思路及治疗靶点。

研究背景：转移是结直肠癌患者死亡的主要原因。血管生成在肿瘤生长及转移的各个阶段发挥关键作用，但目前调控结直肠癌血管生成的分子机制及关键靶点仍不清楚。.研究结果：我们研究发现转移性结直肠癌中ELFN1表达显著增高，且与微血管密度及巨噬细胞浸润呈正相关，ELFN1高表达结直肠癌细胞促进巨噬细胞迁移并发生M2型极化，一方面促进巨噬细胞分泌VEGFA、CXCL8表达，促进血管生成及肿瘤转移；另一方面ELFN1上调巨噬细胞表面PD-L1表达，抑制CD8+T细胞免疫功能；机制上，ELFN1高表达通过结合并抑制PP1磷酸酶活性，激活NFκB通路并促进IL34分泌；IL34通过结合CSF1R激活巨噬细胞中的ERK通路，上调VEGFA、CXCL8及PD-L1；同时，M2型极化的巨噬细胞反馈性上调结直肠癌中ELFN1的表达，小鼠体内实验证实，抑制ELFN1-IL34-巨噬细胞环路可抑制结直肠癌血管生成和转移。.科学意义：本研究提出ELFN1-IL34-巨噬细胞环路为临床抗结直肠癌血管生成和转移的新靶点。