title: Interaction between non-small-cell lung cancer cells and fibroblasts via enhancement of TGF-β signaling by IL-6.
abstract: BACKGROUND
  Fibroblasts are key components of the tumor microenvironment. We clarified the role of transforming growth factor (TGF)-β and interleukin (IL)-6 in the interaction between fibroblasts and non-small-cell lung cancer (NSCLC) cells.
  
  
  METHODS
  We used NSCLC cells (A549, NCI-H358) and normal human lung fibroblast (NHLF) cells to evaluate phenotypic changes in the presence of human IL-6, TGF-β1, and conditioned media (CM) from these cells. Possible pathways were evaluated with SB431542, a TGF-β receptor inhibitor, or an anti-human IL-6 receptor neutralizing antibody (IL-6R-Ab).
  
  
  RESULTS
  A549 and NCI-H358 cells incubated with IL-6 (50 ng/mL) and TGF-β1 (2 ng/mL) showed significantly increased epithelial-mesenchymal transition (EMT) signaling compared to those treated with TGF-β1 alone. Furthermore, NHLF cells were synergistically activated by IL-6 and TGF-β1. IL-6 increased the expression of TGF-β type I receptors on the surface of A549, NCI-H358 and NHLF cells and enhanced TGF-β signaling. TGF-β1 induced phenotypic changes were attenuated by IL-6R-Ab. NHLF cells were activated and A549 cells showed induction of EMT in response to CM from the other cell type. These activities were attenuated by SB431542 or IL-6R-Ab, suggesting that interplay between NSCLC cells and NHLF may lead to increased EMT signaling in NSCLC cells and activation of NHLF cells through TGF-β and IL-6 signaling. Subcutaneous co-injection of A549 and NHLF cells into mice resulted in a high rate of tumor formation compared with injection of A549 cells without NHLF cells. SB431542 or IL-6R-Ab also attenuated the tumor formation enhanced by co-injection of the two cell types.
  
  
  CONCLUSIONS
  IL-6 enhanced epithelial cell EMT and stimulated tumor progression by enhancing TGF-β signaling. IL-6 and TGF-β may play a contributing role in maintenance of the paracrine loop between these two cytokines in the communication between fibroblasts and NSCLC cells for tumor progression.
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Abulimiti
authors.initials: A
authors.lastname: Abulaiti
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shintani
authors.forename: Soichiro
authors.initials: S
authors.lastname: Funaki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakagiri
authors.forename: Masayohi
authors.initials: M
authors.lastname: Inoue
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Sawabata
authors.forename: Masato
authors.initials: M
authors.lastname: Minami
authors.forename: Meinoshin
authors.initials: M
authors.lastname: Okumura
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D016212:Transforming Growth Factor beta
keywords: Epithelial–mesenchymal transition; Fibroblasts; IL-6; Non-small-cell lung cancer; TGF-β