Inhibition of PAI‐1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer‐associated fibroblasts

Abstract

Plasminogen activator inhibitor‐1 (PAI‐1) promotes pulmonary fibrosis through increasing myofibroblast (MF) characteristics, expressing alpha‐smooth muscle actin (α‐SMA) in fibroblasts. Fibroblasts in the tumour stroma are called cancer‐associated fibroblasts (CAFs). Some CAFs have MF characteristics and substantially promote tumour progression and chemotherapy resistance. This study determined whether inhibition of PAI‐1 suppressed MF characteristics of CAFs and limited chemotherapy resistance in lung cancer. To investigate cellular PAI‐1 expression and its correlation with α‐SMA expression of CAFs, 34 patients’ paraffin‐embedded lung adenocarcinoma tissue sections were immunohistochemically stained for PAI‐1 and α‐SMA. Immunohistochemical analysis of lung adenocarcinoma tissues showed that PAI‐1 expression was correlated with that of α‐SMA ( r = 0.71, p < 0.001). Furthermore, in vitro, α‐SMA expression of CAFs was limited by PAI‐1 inhibition, and apoptosis of CAFs was increased. In addition, the effectiveness of cisplatin on lung cancer cells co‐cultured with CAFs was increased by suppressing α‐SMA expression using PAI‐1 inhibitor. In lung adenocarcinoma tissues, PAI‐1 expression was associated with T factor and TNM stage. Our data suggest that inhibition of PAI‐1 increased the chemotherapeutic effect on lung cancer through suppressing the MF characteristics of CAFs. Hence, PAI‐1 might be a promising therapeutic target for patients with chemotherapeutic‐resistant lung cancer with CAFs.

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

“…Masuda et al showed that stromal cells express higher levels of PAI-1 than cancer cells in lung adenocarcinoma tissues and that PAI-1 expression correlated with αSMA levels and depth of tumor invasion [43]. These findings are consistent with our results.…”

Cancer-Associated Fibroblasts as a Common Orchestrator of Therapy Resistance in Lung and Pancreatic Cancer

“…Suppressing alpha-smooth muscle actin (α-SMA) myofibroblastic CAFs—which share the phenotypic traits of fibroblasts and smooth muscle cells, secrete ECM, and generate mechanical tension within tissue through cell contraction [ 46 ]—through the inhibition of plasminogen activator inhibitor-1 (PAI-1) limits resistance to cisplatin in lung cancer [ 47 ]. CAFs in tissue sections from lung carcinomas incubated with or without cisplatin turned out to be much less sensitive to cisplatin when compared to isolated CAFs, indicating that the TME also attenuates the sensitivity of lung cancer CAFs to cisplatin [ 48 ].…”

Role of cancer‑associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non‑small cell lung cancer (Review)

“…These FAP-specific T cells recognize and destroy FAP+CAFs with subsequent antitumor effects ( 113 ). Some CAFs possess myofibroblast characteristics and express α-SMA, which can significantly promote NSCLC resistance to chemotherapy via the expression of high levels of inflammatory cytokines and chemokines ( 114 ). Plasminogen activator inhibitor-1 (PAI-1) can promote the MF characteristics of CAFs, and the expression of PAI-1 in CAFs is correlated with the expression of α-SMA ( 114 ).…”

“…Some CAFs possess myofibroblast characteristics and express α-SMA, which can significantly promote NSCLC resistance to chemotherapy via the expression of high levels of inflammatory cytokines and chemokines ( 114 ). Plasminogen activator inhibitor-1 (PAI-1) can promote the MF characteristics of CAFs, and the expression of PAI-1 in CAFs is correlated with the expression of α-SMA ( 114 ). PAI-1 inhibitors also decrease the expression levels of α-SMA and inhibit the MF characteristics of CAFs, improving chemotherapeutic efficacy in NSCLC ( 114 ).…”

“…Plasminogen activator inhibitor-1 (PAI-1) can promote the MF characteristics of CAFs, and the expression of PAI-1 in CAFs is correlated with the expression of α-SMA ( 114 ). PAI-1 inhibitors also decrease the expression levels of α-SMA and inhibit the MF characteristics of CAFs, improving chemotherapeutic efficacy in NSCLC ( 114 ). Thus inhibiting the MF properties of CAFs may be a novel therapeutic strategy for the treatment of chemotherapy-resistant NSCLC ( 114 ).…”