title: Lung tumor-associated dendritic cell-derived amphiregulin increased cancer progression.
abstract: The interaction of cancer within a microenvironment is an important factor determining cancer development. This study analyzed the soluble factors secreted by tumor-associated dendritic cells (TADCs), which are responsible for increasing lung cancer growth, migration, invasion, and epithelial-to-mesenchymal transition. Addition of amphiregulin, present in large amounts in TADC-conditioned medium (CM), mimicked the inductive effect of TADC-CM on lung cancer progression, supported by the enhancement of cell proliferation, migration, and invasion as well as osteolytic bone metastases phenotypes. In contrast, neutralization of amphiregulin from TADC-CM decreased the advanced malignancy-inductive properties of TADC-CM. Significant upregulation of amphiregulin has been seen in tumor-infiltrating CD11c(+) DCs in human lung cancer samples and patients' sera. The enhancement of amphiregulin in TADCs has also been noted in mice transplanted with lung cancer cells. Induction of lung cancer progression by TADC-derived amphiregulin is associated with increased STAT3 and AKT activation, which subsequently increases the expression of cyclin D, Twist, and Snail. Blocking AKT significantly decreases TADC-CM and amphiregulin-mediated migration by decreasing the upregulation of Snail, whereas inhibition of STAT3 reduced the modulation of TADC-derived amphiregulin on Twist and cyclin D expression, suggesting that cooperation of STAT3 and AKT plays a critical role in TADC-mediated cancer progression. Moreover, mice treated with anti-amphiregulin Abs showed decreased incidence of cancer development and increased survival rates. Our study suggests that inhibition of amphiregulin or amphiregulin-related signaling is an attractive therapeutic target in lung cancer patients.
authors: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Ya-Ling
authors: YL
authors: Hsu
authors: Ming-Shyan
authors: MS
authors: Huang
authors: Da-En
authors: DE
authors: Cheng
authors: Jen-Yu
authors: JY
authors: Hung
authors: Chih-Jen
authors: CJ
authors: Yang
authors: Shah-Hwa
authors: SH
authors: Chou
authors: Po-Lin
authors: PL
authors: Kuo
mesh_terms: D066258:Amphiregulin; D000818:Animals; D001859:Bone Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary / Q000628:therapy; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D056741:Cyclin D / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D066255:EGF Family of Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051879:Twist-Related Protein 1 / Q000096:biosynthesis / Q000276:immunology
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D039521:CD11c Antigen; D056741:Cyclin D; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt