Progranulin靶向TNFR对结肠癌间质成纤维细胞的活化作用及其上调VEGF-A表达的分子机制

Fibroblasts in colon cancer environment promote cancer development, metastasis, invision, and vascular generation, which is a promising cell type for cancer targent treatment. Progranulin (PGRN), a growth factor like molecule, has been reported to play an important role in breast cancer, ovarian cancer, and other cancers; and is a predicting marker of patients’ poor prognosis. However, the role of PGRN in fibroblasts is less known. In our previous study, PGRN can activate fibroblasts through upregulating the expression of fibroblast activating protein (FAP) and vascular endothelial growth factor A (VEGF-A). In the presence of tumor necrosis factor receptor 2 (TNFR2) neutralizing antibody, fibroblasts can not be activated and extracellular signal-regulated kinase (ERK) pathway was inhibited. We hypothesized that PGRN would activate fibroblasts through interacting with TNFR and activating ERK signalling pathway. In this study, we will explore the role of PGRN in activating fibroblasts and analyze if it is mediated through PGRN interacting with TNFR-ERK signalling pathway. Besides, the molecular mechanisms that upregulate VEGF-A expression will be clarified in fibroblasts.

结肠癌间质成纤维细胞与肿瘤侵袭、转移、血管生成等各个环节具有密切关系，是肿瘤治疗的新兴靶点。类生长因子样分子Progranulin（PGRN）被报道在乳腺癌、卵巢癌等多种肿瘤中高表达，与病人的不良预后相关，但是尚缺乏PGRN对肿瘤间质成纤维细胞作用的研究。前期工作发现：PGRN促进了结肠间质成纤维细胞的增殖及活化基因FAP、血管内皮生长因子VEGF-A的表达；加入肿瘤坏死因子受体（TNFR2）中和抗体后，影响了PGRN对间质成纤维细胞ERK通路的激活及FAP、VEGF-A的表达。提示PGRN可能通过TNFR-ERK通路活化间质成纤维细胞，并上调VEGF-A的表达。拟通过体外PGRN刺激实验，观察PGRN对间质成纤维细胞迁移、收缩等活化能力的影响，分析间质成纤维细胞的活化是否与PGRN激活TNFR-ERK通路有关，进一步深入探讨PGRN通过TNFR-ERK通路上调VEGF-A的分子机制。

结肠癌是常见的消化道恶性肿瘤，在结肠癌发生发展过程中，肿瘤与微环境的相互作用涉及肿瘤生长、侵袭、转移等各个重要环节。因此，深入研究探讨结肠癌与其间质相互作用的机理，对提高结肠癌治疗的有效率、延长病人的无病生存期、改善预后是十分必要的。类生长因子样分子Progranulin （PGRN）被报道在乳腺癌、卵巢癌等多种肿瘤中高表达，但是尚缺乏PGRN在结肠癌中作用及其对间质微环境作用的研究。本研究发现：1.PGRN在结肠癌细胞中高表达，与患者的不良预后相关，与间质成纤维细胞活化因子α-SMA、组织微血管密度（MVD）、血管生成因子VEGF-A的表达正相关；2.结肠癌细胞来源的PGRN可以促进间质成纤维细胞的增殖、迁移和收缩等活化功能；3.PGRN可以一方面促进结肠癌细胞VEGF-A表达，另一方面直接刺激血管内皮细胞的增殖和小管形成，通过直接和间接作用促进了肿瘤血管生成；4. PGRN在间质成纤维细胞活化及血管生成中的作用依赖TNFR2/AKT和ERK信号通路实现。我们的研究丰富了肿瘤与微环境相互作用的理论内容，为结肠癌的诊断、预后判断及治疗提供了新的靶点。