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

摘要

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 αvβ3 on PCCs to upregulate forkhead box protein M1 (FOXM1) expression and induce malignant phenotypes of PCCs. Moreover, the Akt and Erk pathways participate in style="fixed-case">OPN/integrin αvβ3 axis‐induced style="fixed-case">FOXM1 expression of style="fixed-case">PCCs. Our further analysis showed that style="fixed-case">OPN and style="fixed-case">FOXM1 are significantly upregulated in pancreatic cancer tissues and are associated with poor clinical outcome, indicating that style="fixed-case">OPN and style="fixed-case">FOXM1 might be considered as diagnostic and prognostic biomarkers for patients with pancreatic cancer. In conclusion, we show here for the first time that style="fixed-case">OPN promotes the style="fixed-case">EMT and style="fixed-case">CSC‐like properties of style="fixed-case">PCCs by activating the integrin αvβ3‐Akt/Erk‐ style="fixed-case">FOXM1 cascade in a paracrine manner, suggesting that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.