PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages

• Published in: Laboratory investigation Vol. 101; no. 3; pp. 353 - 368
• Main Authors: Sakamoto, Hiroki, Koma, Yu-ichiro, Higashino, Nobuhide, Kodama, Takayuki, Tanigawa, Kohei, Shimizu, Masaki, Fujikawa, Masataka, Nishio, Mari, Shigeoka, Manabu, Kakeji, Yoshihiro, Yokozaki, Hiroshi
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.03.2021; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/1; 13/21; 13/51; 13/89; 38/61; 38/77; 631/67/1504/1477; 631/67/327; 692/420/755; 82/80; 96/63; 96/95; Aged; AKT protein; Bone marrow; Cancer; Cancer-Associated Fibroblasts - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cells, Cultured; DNA microarrays; Esophageal cancer; Esophageal Neoplasms - metabolism; Esophageal Squamous Cell Carcinoma - metabolism; Esophagus; Female; Fibroblast activation protein; Fibroblasts; Gene expression; Humans; Immunohistochemistry; Inhibitors; Laboratory Medicine; Leukocyte migration; Macrophages; Macrophages - drug effects; Macrophages - physiology; Male; Medicine; Medicine & Public Health; Mesenchyme; Microenvironments; Middle Aged; Monoculture; Neoplasm Invasiveness; Pathology; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen Activator Inhibitor 1 - pharmacology; Plasminogen activator inhibitors; Prognosis; Proteins; Receptor density; Receptors; Squamous cell carcinoma; Stem cells
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-020-00512-2

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.