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

Mol Oncol. 2019 Feb;13(2):228-245. doi: 10.1002/1878-0261.12399. Epub 2018 Dec 22.


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 OPN/integrin αvβ3 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 αvβ3-Akt/Erk-FOXM1 cascade in a paracrine manner, suggesting that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.

Keywords: cancer stem cell-like properties; epithelial-mesenchymal transition; hypoxia; pancreatic cancer; pancreatic stellate cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Forkhead Box Protein M1 / metabolism*
  • Humans
  • Integrin alphaVbeta3 / metabolism*
  • Male
  • Middle Aged
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Osteopontin / metabolism*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Stellate Cells / metabolism
  • Pancreatic Stellate Cells / pathology
  • Paracrine Communication*
  • Prognosis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Tumor Hypoxia*
  • Young Adult


  • Forkhead Box Protein M1
  • Integrin alphaVbeta3
  • Reactive Oxygen Species
  • Osteopontin
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases