Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis.
Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis.
复制标题
癌症相关成纤维细胞通过SDF-1/CXCR4轴促进子宫内膜癌的进展
DOI：
10.1186/s13045-015-0231-4
复制
发表时间：
2016-02-06
影响因子：
28.5
通讯作者：
Xue FX
中科院分区：
文献类型：
--
作者：
Teng F;Tian WY;Wang YM;Zhang YF;Guo F;Zhao J;Gao C;Xue FX
癌症相关成纤维细胞（CAF）被认为在癌症的发生和发展中发挥着重要作用。然而，很少有研究评估 CAF 在子宫内膜癌 (EC) 进展中的作用。我们的目标是检测 CAF 对促进 EC 进展的功能贡献。从子宫内膜样腺癌和正常子宫内膜组织中分离出基质成纤维细胞。收集培养的CAF和正常成纤维细胞（NF）的条件培养基，采用ELISA法检测基质细胞衍生因子1α（SDF-1α）、巨噬细胞趋化蛋白1（MCP-1）、迁移抑制因子（MIF）、集落刺激因子1（CSF-1）和白细胞介素1（IL-1）的水平。将 CAF 或 NF 与 EC 细胞系共培养，通过 MTT 测定和 Transwell 小室测定增殖、迁移和侵袭。使用异种移植模型来观察肿瘤生长。通过酶谱法评估基质金属蛋白酶 (MMP)-2 和 MMP-9 活性。 AMD3100（一种趋化因子受体 4 (CXCR4) 拮抗剂）用于阻断 SDF-1/CXCR4 轴。使用中和抗体通过蛋白质印迹法检测 PI3K/Akt 和 MAPK/Erk 通路。采用免疫组织化学方法分析异种移植肿瘤和348例中SDF-1α和CXCR4的表达。通过分泌 SDF-1α，CAF 比 NF 更能促进混合 EC 细胞的增殖、迁移和侵袭以及体内肿瘤发生。 AMD3100 显着抑制了这些效应。 CAF 通过 SDF-1α/CXCR4 轴促进 EC 进展，以旁分泌依赖性方式激活 PI3K/Akt 和 MAPK/Erk 信号传导，或以自分泌依赖性方式增加 MMP-2 和 MMP-9 分泌。 SDF-1α和CXCR4表达上调伴随着临床EC的发生和进展。 SDF-1α高表达水平与EC的深部肌层浸润、淋巴结转移和不良预后相关。我们的数据表明，源自 EC 组织的 CAF 通过 SDF-1/CXCR4 轴以旁分泌或自分泌依赖性方式促进 EC 进展。 SDF-1α是一种影响EC患者生存的新型独立不良预后因素。靶向 SDF-1/CXCR4 轴可能为 EC 治疗提供一种新的治疗策略。
Cancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development. However, little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC) progression. We aim to detect the functional contributions of CAFs to promote progression of EC. Stromal fibroblasts were isolated from endometrioid adenocarcinomas and normal endometrial tissues. The conditioned media of cultured CAFs and normal fibroblasts (NFs) were collected to detect the level of stromal cell-derived factor-1alpha (SDF-1α), macrophage chemoattractant protein-1 (MCP-1), migration inhibitory factor (MIF), colony stimulating factor-1 (CSF-1), and interleukin-1 (IL-1) by ELISA. The CAFs or NFs were cocultured with EC cell lines to determine the proliferation, migration, and invasion by MTT assays and transwell chambers. Xenograft models were used to observe tumor growth. Matrix metalloproteinases (MMP)-2 and MMP-9 activity was evaluated by zymography. AMD3100 (a chemokine receptor 4 (CXCR4) antagonist) was used to block the SDF-1/CXCR4 axis. Neutralizing antibodies were used to detect PI3K/Akt and MAPK/Erk pathways by western blotting. SDF-1α and CXCR4 expressions were analyzed in xenotransplanted tumors and 348 cases by immunohistochemistry. CAFs promoted proliferation, migration, and invasion as well as in vivo tumorigenesis of admixed EC cells significantly more than NFs by secreting SDF-1α. These effects were significantly inhibited by AMD3100. CAFs promoted EC progression via the SDF-1α/CXCR4 axis to activate the PI3K/Akt and MAPK/Erk signalings in a paracrine-dependent manner or increase MMP-2 and MMP-9 secretion in an autocrine-dependent manner. SDF-1α and CXCR4 expression upregulation accompanied clinical EC development and progression. High SDF-1α expression levels were associated with deep myometrial invasion, lymph node metastasis, and poor prognosis in EC. Our data indicated that CAFs derived from EC tissues promoted EC progression via the SDF-1/CXCR4 axis in a paracrine- or autocrine-dependent manner. SDF-1α is a novel independent poor prognostic factor for EC patients’ survival. Targeting the SDF-1/CXCR4 axis might provide a novel therapeutic strategy for EC treatment.