Hypoxia-driven paracrine osteopontin/integrin αvβ3 signaling promotes pancreatic cancer cell epithelial-mesenchymal transition and cancer stem cell-like properties by modulating forkhead box protein M1

Pancreatic stellate cells (PSCs), a key component of the tumor microenvironment, contribute to tumor invasion, metastasis, and chemoresistance. Osteopontin (OPN), a phosphorylated glycoprotein, is overexpressed in pancreatic cancer. However, OPN expression in PSCs and its potential roles in tumor-stroma interactions remain unclear. The present study first showed that OPN is highly expressed and secreted in activated PSCs driven by hypoxia, and this process is in a ROS-dependent manner; in addition, OPN was shown to be involved in the PSC-induced epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties of pancreatic cancer cells (PCCs). Mechanistically, OPN from activated PSCs interacts with the transmembrane receptor integrin alpha v beta 3 on PCCs to upregulate forkhead box protein M1 (FOXM1) expression and induce malignant phenotypes of PCCs. Moreover, the Akt and Erk pathways participate in OPN/integrin alpha v beta 3 axis-induced FOXM1 expression of PCCs. Our further analysis showed that OPN and FOXM1 are significantly upregulated in pancreatic cancer tissues and are associated with poor clinical outcome, indicating that OPN and FOXM1 might be considered as diagnostic and prognostic biomarkers for patients with pancreatic cancer. In conclusion, we show here for the first time that OPN promotes the EMT and CSC-like properties of PCCs by activating the integrin alpha v beta 3-Akt/Erk-FOXM1 cascade in a paracrine manner, suggesting that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.