Liu Ting, Huang Chao, Sun Li, Chen Zhihong, Ge Yan, Ji Weimeng, Chen Shihan, Zhao Yuanyuan, Wang Mei, Wang Deqiang, Zhu Wei
Department of Oncology, Digestive Disease Institute & Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
Int Immunopharmacol. 2025 Jan 10;144:113697. doi: 10.1016/j.intimp.2024.113697. Epub 2024 Nov 29.
Gastric cancer (GC) mesenchymal stromal cells (GCMSCs) are the predominant components of the tumor microenvironment (TME) and play a role in the occurrence, development, and metastasis of tumors. However, GCMSCs exhibit phenotypic and functional heterogeneity. The key population of GCMSCs which are vital to tumor progression remains elusive. The expression of fibroblast activation protein (FAP) in gastric cancer was analyzed and verified using clinical pathology data and single-cell RNA sequencing database of gastric cancer patients. FAP positive GCMSCs (FAP GCMSCs) were isolated via flow cytometry and characterized through transcriptomic sequencing. The impact of conditioned medium from FAP GCMSCs on gastric cancer cell lines was assessed using Enzyme-linked immunosorbent assay (ELISA) and Western blot analyses. Additionally, immunohistochemistry (IHC) and Masson's trichrome staining were employed to explore the association between FAP GCMSCs and extracellular matrix (ECM) deposition in gastric cancer tissues. Our study demonstrates that FAP is predominantly expressed in the mesenchymal stromal cells within the gastric cancer milieu. FAP GCMSCs exhibited enhanced proliferation, migration, contraction, and tumor-promoting capabilities compared to their FAP counterparts. These cells significantly increased proliferation and migration of gastric cancer cells through the paracrine secretion of Inhibin Subunit Beta A (INHBA) and activation of the SMAD2/3 signaling pathway. Moreover, FAP GCMSCs also induced collagen deposition in ECM and then up-regulated invasion and stemness of GC cells. Mechanistically, this process was mediated by the interaction of collagen with Integrin Subunit Beta 1 (ITGB1), triggering the phosphorylation of Focal Adhesion Kinase (FAK) and Yes Associated Transcriptional Regulator (YAP). Our findings reveal that FAP GCSMCs enhanced the GC progression via releasing cytokine INHBA and remodeling ECM providing a theoretical basis for further exploration of tumor stromal-targeting therapy of gastric cancer.
胃癌间充质基质细胞（GCMSCs）是肿瘤微环境（TME）的主要组成部分，在肿瘤的发生、发展和转移中发挥作用。然而，GCMSCs表现出表型和功能的异质性。对肿瘤进展至关重要的GCMSCs关键亚群仍不清楚。利用胃癌患者的临床病理数据和单细胞RNA测序数据库，分析并验证了成纤维细胞活化蛋白（FAP）在胃癌中的表达。通过流式细胞术分离出FAP阳性GCMSCs（FAP GCMSCs），并通过转录组测序对其进行表征。使用酶联免疫吸附测定（ELISA）和蛋白质免疫印迹分析评估FAP GCMSCs条件培养基对胃癌细胞系的影响。此外，采用免疫组织化学（IHC）和Masson三色染色法探讨FAP GCMSCs与胃癌组织中细胞外基质（ECM）沉积之间的关系。我们的研究表明，FAP主要在胃癌微环境中的间充质基质细胞中表达。与FAP阴性的GCMSCs相比，FAP GCMSCs表现出更强的增殖、迁移、收缩和促肿瘤能力。这些细胞通过旁分泌抑制素亚基βA（INHBA）和激活SMAD2/3信号通路，显著增加胃癌细胞的增殖和迁移。此外，FAP GCMSCs还诱导ECM中的胶原蛋白沉积，进而上调GC细胞的侵袭和干性。机制上，这一过程是由胶原蛋白与整合素亚基β1（ITGB1）的相互作用介导的，触发了粘着斑激酶（FAK）和Yes相关转录调节因子（YAP）的磷酸化。我们的研究结果表明，FAP GCSMCs通过释放细胞因子INHBA和重塑ECM促进了GC的进展，为进一步探索胃癌的肿瘤基质靶向治疗提供了理论依据。
