Synergistic effect of lung tumor-associated dendritic cell-derived HB-EGF and CXCL5 on cancer progression.

Abstract

The interaction between cancer cells and their microenvironment is a paradoxical cycle that exacerbates cancer progression and results in metastasis. Our study investigated the mechanism underlying the synergistic enhancement of release of soluble factors from tumor-associated dendritic cells and its effect on cancer development. The combination of HB-EGF (heparin-binding EGF-like growth factor) and CXCL5 (CXCL5/epithelial neutrophil-activating peptide-78) produced a strong synergistic effect on cancer proliferation, epithelial-mesenchymal transition, migration and invasion. CXCL5 not only potentiated the classical EGFR pathway and the AKT and ERK/RSK1/2 signaling pathways but also increased the phosphorylation of heat shock protein 27 (HSP27), which was slightly increased in A549 cells treated with either HB-EGF or CXCL5 only. Phosphorylated HSP27 stabilized sustained AKT activity by direct interaction, leading to enhanced tumor spheroid formation. Knockdown of HSP27 by shRNA decreased HB-EGF plus CXCL5-mediated tumor spheroid formation in a three-dimensional culture system, suggesting that AKT/HSP27 was required for HB-EGF/CXCL5-mediated cancer progression. Inhibiting RSK also reduces the modulation of c-Fos phosphorylation, Snail upregulation and cell migration by HB-EGF plus CXCL5, suggesting a synergistic effect of ERK/RSK and HB-EGF plus CXCL5 on cell migration. In mice, CXCL5 antibody synergistically enhances the efficiency of the tyrosine kinase inhibitor, gefitinib, without increasing its toxicity. These results provide evidence that elucidates potential cross-points between extracellular signals affecting lung cancer progression. Targeting CXCL5 may provide therapeutic benefits for lung cancer chemotherapy or immunotherapy.

• Authors: Po-Lin Kuo, Ming-Shyan Huang, Jen-Yu Hung, Shah-Hwa Chou, Shin-Yi Chiang, Ya-Fang Huang, Chih-Jen Yang, Ming-Ju Tsai, Wei-An Chang, Ya-Ling Hsu
• Journal: International journal of cancer (Int J Cancer) Vol. 135 Issue 1 Pg. 96-108 (Jul 01 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 24346967 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 UICC.

Chemical References

• CXCL5 protein, human
• Chemokine CXCL5
• HBEGF protein, human
• HSP27 Heat-Shock Proteins
• HSPB1 protein, human
• Hbegf protein, mouse
• Heat-Shock Proteins
• Heparin-binding EGF-like Growth Factor
• Intercellular Signaling Peptides and Proteins
• Molecular Chaperones
• Protein Kinase Inhibitors

Topics

• Animals
• Cell Movement (genetics)
• Cell Proliferation (drug effects)
• Chemokine CXCL5 (genetics, metabolism)
• Dendritic Cells (metabolism)
• Disease Progression
• Epithelial-Mesenchymal Transition (genetics)
• HSP27 Heat-Shock Proteins (antagonists & inhibitors, genetics)
• Heat-Shock Proteins
• Heparin-binding EGF-like Growth Factor
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Lung Neoplasms (genetics, metabolism, pathology)
• Mice
• Molecular Chaperones
• Protein Kinase Inhibitors (administration & dosage)
• Signal Transduction (genetics)
• Transcriptional Activation (drug effects, genetics)
• Tumor Microenvironment (drug effects, genetics)