title: 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.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.forename: Jen-Yu
authors.initials: JY
authors.lastname: Hung
authors.forename: Shah-Hwa
authors.initials: SH
authors.lastname: Chou
authors.forename: Shin-Yi
authors.initials: SY
authors.lastname: Chiang
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Huang
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.forename: Ming-Ju
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Wei-An
authors.initials: WA
authors.lastname: Chang
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hsu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D054365:Chemokine CXCL5 / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006360:Heat-Shock Proteins; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; C587883:HBEGF protein, human; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; C587884:Hbegf protein, mouse; D006360:Heat-Shock Proteins; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors
keywords: CXCL5; HB-EGF; cancer progression; dendritic cells; lung cancer