title: Lung cancer-derived galectin-1 enhances tumorigenic potentiation of tumor-associated dendritic cells by expressing heparin-binding EGF-like growth factor.
abstract: The interaction between cancer cells and their microenvironment is a vicious cycle that enhances the survival and progression of cancer, resulting in metastasis. This study is the first to indicate that lung cancer-derived galectin-1 secretion is responsible for stimulating tumor-associated dendritic cells (TADCs) production of mature heparin-binding EGF-like growth factor (HB-EGF), which, in turn, increases cancer progression. Treatment of galectin-1, present in large amounts in lung cancer conditioned medium and lung cancer patient sera, mimicked the inductive effect of lung cancer conditioned medium on the expression and ectodomain shedding of HB-EGF by TNFα-converting enzyme/a disintegrin and metalloproteinase 9 (ADAM9) and ADAM17. Significant up-regulation of HB-EGF has been seen in tumor-infiltrating CD11c(+) dendritic cells in human lung cancer samples. Active cleavage of HB-EGF in TADCs by ADAM9 and ADAM17 is associated with increased protein kinase C δ and Lyn signaling. Enhancement of HB-EGF production in TADCs increased the proliferation, migration, and epithelial-to-mesenchymal transition abilities of lung cancer. In contrast, inhibiting HB-EGF by siRNA suppressed TADC-mediated cancer progression. Moreover, mice injected with galectin-1 knockdown Lewis lung carcinoma showed decreased expression and ectodomain shedding of HB-EGF and reduced incidence of cancer development, resulting in increased survival rates. We demonstrate here for the first time that human and mouse DCs are a source of HB-EGF, an EGFR ligand with tumorigenic properties. Antagonists of the effect of lung cancer-derived galectin-1 on DCs and anti-HB-EGF blocking antibodies could, therefore, have therapeutic potential as antitumor agents.
authors.affiliation: Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan,; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. Electronic address: kuopolin@seed.net.tw.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, and.
authors.forename: Da-En
authors.initials: DE
authors.lastname: Cheng
authors.affiliation: Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan,; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, and.
authors.forename: Jen-Yu
authors.initials: JY
authors.lastname: Hung
authors.affiliation: Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan,; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, and.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Department of Chest Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Shah-Hwa
authors.initials: SH
authors.lastname: Chou
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D037483:Galectin 1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; 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; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000912:Antibodies, Neoplasm; D057134:Antibodies, Neutralizing; D039521:CD11c Antigen; D037483:Galectin 1; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C445499:LGALS1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D051745:Protein Kinase C-delta; D051722:ADAM Proteins; C098339:ADAM9 protein, human; C498316:Adam9 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse