CSF1调节肿瘤浸润巨噬细胞COX代谢对结直肠癌细胞EMT的影响和机制研究

Epithelial-mesenchymal transition (EMT) plays important roles in prognosis of colorectal cancer, but its regulatory mechanisms remain not fully understood. CSF1 is over-expressed in colorectal cancer, and the abnormal activity of CSF1/CSF1R signaling regulates EMT process. Our previous study showed that cancer cell-derived CSF1 was involved in the recruitment of macrophages into tumor and their phenotypes and functions. Lipid metabolism is an important character between macrophage subgroups and also the basis of their function. Abnormal COX metabolism occurs in colorectal cancer and is closely related with the cytoskeleton rearrangement, which finally leads to EMT process. Therefore, we assume that CSF1 over-expression microenvironment may affect the COX metabolism in tumor-infiltrated macrophages. The COX metabolites regulated EMT in colorectal cancer through KIF-Wnt/β-catenin pathway. Our study would help to understand the role of tumor-infiltrated macrophages in EMT of colorectal cancer, and provide new evidences for CSF1-dependent macrophage-targeting therapy, which shed new light on the lower metastasis risk and improved prognosis of colorectal cancer patients.

上皮-间充质转化是影响结直肠癌预后的重要因素，但其调控机制目前尚未完全阐明。结直肠癌局部存在CSF1过表达微环境，异常CSF1/CSF1R信号通路可能调控结直肠癌EMT发生。本课题组前期研究发现，结直肠癌过表达CSF1可募集巨噬细胞至肿瘤局部并影响巨噬细胞表型。脂代谢是巨噬细胞亚群的区分特征和功能发挥的基础，结直肠癌局部存在异常COX代谢现象。COX代谢产物在肿瘤局部的积累可造成肿瘤细胞骨架的改变，诱导EMT发生。因此，我们推测CSF1过表达微环境可能调节肿瘤浸润巨噬细胞COX代谢过程。异常表达的COX代谢产物通过KIF-Wnt/β-catenin通路影响结直肠癌细胞的EMT。本研究有助于理解肿瘤浸润巨噬细胞对结直肠癌EMT行为的调控作用，进一步丰富CSF1介导的巨噬细胞靶向疗法的理论依据，最终为降低结直肠癌患者复发及转移风险、改善预后提供新思路。

组织浸润免疫细胞是局部微环境的重要组成部分，在微环境特性的调控中发挥突出作用。本项目从非免疫细胞与免疫细胞的交互对话机制入手，先后探究了结直肠癌和宫颈癌这两个特殊的病理微环境对局部浸润免疫细胞的影响。首先，申请人发现结直肠癌患者外周血单核细胞CXCR2表达水平异常降低，且与患者肿瘤分期和肿瘤局部免疫状态密切相关。利用细胞实验和动物模型，证实了CXCR2参与单核细胞向肿瘤局部的迁移，并影响肿瘤相关巨噬细胞促炎细胞因子的分泌，从而影响肿瘤局部免疫微环境的构成。该研究结果将为结直肠癌患者肿瘤进展和预后提供重要指标，并为CXCR2为靶点的抗肿瘤免疫治疗提供重要的支持依据。其次，申请人探究了宫颈癌局部微环境对肿瘤浸润巨噬细胞功能活性的影响。结果显示，与结直肠癌组织相似，宫颈癌诱导巨噬细胞向M2方向极化；而加入炎性介质poly(I:C）后，宫颈癌细胞IL-6分泌显著上调，逆转巨噬细胞极化倾向。两部分研究成果相互应证、互为补充，为深入理解肿瘤局部微环境中细胞之间的交互对话机制和调节因素做出了良好的研究范例。