PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages.
PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages.
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DOI：
10.1038/s41374-020-00512-2
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Yokozaki H
中科院分区：
文献类型：
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作者：
Sakamoto H;Koma YI;Higashino N;Kodama T;Tanigawa K;Shimizu M;Fujikawa M;Nishio M;Shigeoka M;Kakeji Y;Yokozaki H
癌症相关成纤维细胞（CAF）有助于各种癌症的进展。先前，我们报道了CAFs在食管鳞状细胞癌（ESCC）中的意义;然而，CAFs在ESCC微环境中的功能仍然未知。为了研究CAFs的功能，我们建立了人骨髓间充质干细胞（MSCs）与食管鳞癌细胞间接共培养的方法。与单纯培养的MSCs相比，共培养的MSCs表达更多的成纤维细胞活化蛋白，这是CAFs的标志物之一。因此，我们将共培养的MSC定义为CAF样细胞。为了鉴定与CAFs中ESCC进展相关的分子，我们对单培养的MSC和CAFs样细胞进行了cDNA微阵列分析，以比较它们的基因表达谱。我们发现，编码纤溶酶原激活物抑制剂-1（派-1）的SERPINE 1在CAF-like细胞中的表达比在单一培养的MSCs中更丰富，并且CAF-like细胞来源的派-1通过低密度脂蛋白受体相关蛋白1（LRP 1）通过Akt和Erk 1/2信号通路诱导ESCC细胞和巨噬细胞的迁移和侵袭能力。基于ESCC组织的免疫组化检测，派-1和LRP 1的高表达水平与ESCC患者的不良预后相关。这些结果表明派-1/LRP 1轴有助于ESCC的进展，使其成为ESCC治疗的潜在靶点。作者表明，来自癌症相关成纤维细胞的纤溶酶原激活物抑制剂-1（派-1）通过脂蛋白受体相关蛋白1（LRP 1）促进食管鳞状细胞癌（ESCC）细胞的侵袭和巨噬细胞的迁移。派-1和/或LRP 1高表达与食管鳞癌患者预后不良相关，派-1/LRP 1轴可能成为食管鳞癌治疗的靶点。
Cancer-associated fibroblasts (CAFs) contribute to the progression of various cancers. Previously, we reported the significance of CAFs in esophageal squamous cell carcinoma (ESCC); however, the functions of CAFs in the ESCC microenvironment remain unknown. To investigate CAFs’ function, we established an indirect coculture assay between human bone marrow-derived mesenchymal stem cells (MSCs) and ESCC cells. Cocultured MSCs expressed more fibroblast activation protein, one of the markers of CAFs, compared with monocultured MSCs. Therefore, we defined cocultured MSCs as CAF-like cells. To identify molecules associated with the ESCC progression in CAFs, we conducted a cDNA microarray analysis on monocultured MSCs and CAF-like cells to compare their gene expression profiles. We found that SERPINE1, which encodes plasminogen activator inhibitor-1 (PAI-1), was more abundant in CAF-like cells than in monocultured MSCs, and the PAI-1 derived from CAF-like cells induced the abilities of migration and invasion in both ESCC cells and macrophages by the Akt and Erk1/2 signaling pathways via the low-density lipoprotein receptor-related protein 1 (LRP1), which is a PAI-1 receptor. Based on immunohistochemistry assays of ESCC tissues, higher expression levels of PAI-1 and LRP1 were correlated with poor prognosis in ESCC patients. These results suggest that the PAI-1/LRP1 axis contributes to the progression of ESCC, making it a potential target for ESCC therapy. The authors show that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts promotes the invasion of esophageal squamous cell carcinoma (ESCC) cells and the migration of macrophages via lipoprotein receptor-related protein 1 (LRP1). High expression of PAI-1 and/or LRP1 is associated with poor prognosis in patients with ESCC, and the PAI-1/LRP1 axis could be a target of anticancer therapy.