uPAR induces expression of transforming growth factor β and interleukin-4 in cancer cells to promote tumor-permissive conditioning of macrophages.

Abstract

Cancer cells condition macrophages and other inflammatory cells in the tumor microenvironment so that these cells are more permissive for cancer growth and metastasis. Conditioning of inflammatory cells reflects, at least in part, soluble mediators (such as transforming growth factor β and IL-4) that are released by cancer cells and alter the phenotype of cells of the innate immune system. Signaling pathways in cancer cells that potentiate this activity are incompletely understood. The urokinase receptor (uPAR) is a cell-signaling receptor known to promote cancer cell survival, proliferation, metastasis, and cancer stem cell-like properties. The present findings show that uPAR expression in diverse cancer cells, including breast cancer, pancreatic cancer, and glioblastoma cells, promotes the ability of these cells to condition co-cultured bone marrow-derived macrophages so that the macrophages express significantly increased levels of arginase 1, a biomarker of the alternatively activated M2 macrophage phenotype. Expression of transforming growth factor β was substantially increased in uPAR-expressing cancer cells via a mechanism that requires uPA-initiated cell signaling. uPAR also controlled expression of IL-4 in cancer cells via a mechanism that involves activation of ERK1/2. The ability of uPAR to induce expression of factors that condition macrophages in the tumor microenvironment may constitute an important mechanism by which uPAR promotes cancer progression.

• Authors: Jingjing Hu, Minji Jo, Boryana M Eastman, Andrew S Gilder, Jack D Bui, Steven L Gonias
• Journal: The American journal of pathology (Am J Pathol) Vol. 184 Issue 12 Pg. 3384-93 (Dec 2014) ISSN: 1525-2191 [Electronic] United States
• PMID: 25310970 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Receptors, Urokinase Plasminogen Activator
• Transforming Growth Factor beta
• Interleukin-4
• Arginase

Topics

• Animals
• Arginase (metabolism)
• Biomarkers, Tumor (metabolism)
• Brain Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Coculture Techniques
• Disease Progression
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Neoplastic
• Glioblastoma (metabolism)
• Humans
• Inflammation
• Interleukin-4 (metabolism)
• Macrophages (metabolism)
• Mice
• Neoplasm Metastasis
• Pancreatic Neoplasms (metabolism)
• Phenotype
• Receptors, Urokinase Plasminogen Activator (metabolism)
• Signal Transduction
• Transforming Growth Factor beta (metabolism)