文章：

TGF-β1–IGFBP7信号介导的癌细胞与癌症相关成纤维细胞之间的相互作用促进浸润性胃癌的进展

Crosstalk between Cancer Cells and Cancer-Associated Fibroblasts Mediated by TGF-β1–IGFBP7 Signaling Promotes the Progression of Infiltrative Gastric Cancer

原文发布日期：4 August 2023

DOI: 10.3390/cancers15153965

类型: Article

开放获取: 是

英文摘要：

Patients with infiltrative-type gastric cancer (GC) (Ming’s classification) have a poor prognosis due to more metastasis and recurrence. Cancer-associated fibroblasts (CAFs) in infiltrative-type extracellular matrix (ECM) have specific characteristics compared with those of expansive types with respect to metastasis, but the mechanism is still unclear. Based on our proteomics data, TCGA data analysis, and immunohistochemical staining results, significantly higher expression of IGFBP7 was observed in GC, especially in the infiltrative type, and was associated with a poor prognosis. Combining single-cell transcriptome data from GEO and multiple immunofluorescence staining on tissue showed that the differential expression of IGFBP7 mainly originated from myofibroblastic CAFs, the subgroup with higher expression of PDGFRB and α-SMA. After treating primary normal fibroblasts (NFs) with conditional medium or recombined protein, it was demonstrated that XGC-1-derived TGF-β1 upregulated the expression of IGFBP7 in the cells and its secretion via theP-Smad2/3 pathway and mediated its activation with higher FAP, PDGFRB, and α-SMA expression. Then, either conditional medium from CAFs with IGFBP7 overexpression or recombined IGFBP7 protein promoted the migration, invasion, colony formation, and sphere growth ability of XGC-1 and MGC-803, respectively. Moreover, IGFBP7 induced EMT in XGC-1. Therefore, our study clarified that in the tumor microenvironment, tumor-cell-derived TGF-β1 induces the appearance of the IGFBP7+CAF subgroup, and its higher IGFBP7 extracellular secretion level accelerates the progression of tumors.

摘要翻译： 

根据Ming分型，浸润型胃癌患者因更易发生转移和复发而预后不良。与膨胀型相比，浸润型细胞外基质中的癌相关成纤维细胞在转移方面具有特异性特征，但其机制尚不明确。基于我们的蛋白质组学数据、TCGA数据分析及免疫组化染色结果，发现IGFBP7在胃癌中表达显著升高（尤其于浸润型），且与不良预后相关。结合GEO单细胞转录组数据及组织多重免疫荧光染色显示，IGFBP7的差异表达主要来源于肌成纤维细胞性CAFs——即高表达PDGFRB和α-SMA的亚群。使用条件培养基或重组蛋白处理原代正常成纤维细胞后发现，XGC-1细胞来源的TGF-β1通过P-Smad2/3通路上调细胞内IGFBP7表达及其分泌，并介导其活化为高表达FAP、PDGFRB和α-SMA的状态。进一步实验表明，过表达IGFBP7的CAFs条件培养基或重组IGFBP7蛋白均可分别促进XGC-1和MGC-803细胞的迁移、侵袭、克隆形成及球体生长能力。此外，IGFBP7能诱导XGC-1发生上皮-间质转化。本研究由此阐明：在肿瘤微环境中，肿瘤细胞来源的TGF-β1诱导了IGFBP7+CAF亚群的出现，其更高的IGFBP7胞外分泌水平加速了肿瘤进展。

原文链接：

Crosstalk between Cancer Cells and Cancer-Associated Fibroblasts Mediated by TGF-β1–IGFBP7 Signaling Promotes the Progression of Infiltrative Gastric Cancer