FAP + gastric cancer mesenchymal stromal cells via paracrining INHBA and remodeling ECM promote tumor progression.

Autor: Liu T; 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., Huang C; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China., Sun L; Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu Province, 215300, China., Chen Z; Department of Gastrointestinal Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China., Ge Y; Department of Gastrointestinal Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China., Ji W; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China., Chen S; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China., Zhao Y; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China., Wang M; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China., Wang D; Department of Oncology, Digestive Disease Institute & Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China. Electronic address: deqiang_wang@aliyun.com., Zhu W; 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. Electronic address: zhuwei@ujs.edu.cn.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2025 Jan 10; Vol. 144, pp. 113697. Date of Electronic Publication: 2024 Nov 29.
DOI: 10.1016/j.intimp.2024.113697
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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