title: The cell-cell interaction between tumor-associated macrophages and small cell lung cancer cells is involved in tumor progression via STAT3 activation.
abstract: Small cell lung cancer (SCLC) is an aggressive tumor with a poor prognosis. It is well known that various stromal cells, including macrophages, play a role in tumor progression in several types of malignant tumors; however, the significance of tumor-associated macrophages (TAMs) in SCLC has not been fully elucidated. Signal transducer and activator of transcription 3 (STAT3) is a molecule well-known to be related to tumor progression. In the present study, we investigated the relationship of TAMs and SCLC cells to test the hypothesis that TAMs induce tumor progression in SCLC via STAT3 activation.
  
  
  
  We performed immunohistochemical analysis using surgically resected tumor specimens and in vitro co-culture experiments using human SCLC cell lines and human monocyte-derived macrophages.
  
  
  
  We first demonstrated via immunostaining that STAT3 activation in tumor cells was predominantly observed in the peripheral areas of tumor nests existing near TAMs in stroma. The indirect co-culture of SCLC cells and macrophages induced STAT3 activation in both cell types, and macrophage-derived culture supernatant (CS) significantly activated STAT3 in SCLC cells. Macrophage-derived CS induced tumor cell proliferation and invasion via STAT3 activation. In addition, chemo-resistance and sphere formation were also increased by macrophage-derived CS. Macrophage-derived interleukin-6 and CC chemokine ligand 4 (CCL4/MIP-1β) were suggested to be associated with STAT3 activation in SCLC cells. CS-induced STAT3 activation in SCLC cells was suppressed by anti-IL-6 receptor antibody, but not by anti-CCL4/MIP-1β antibody.
  
  
  
  These results suggest that TAMs are likely involved in SCLC progression via STAT3 activation and TAM-derived IL-6 is indicated to be one of molecules related to STAT3 activation in SCLC cells. Thus, the cell-cell interaction between TAMs and SCLC cells might be a target for therapy.
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Toyohisa
authors.initials: T
authors.lastname: Iriki
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohnishi
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hasita
authors.initials: H
authors.lastname: Horlad
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Cheng
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Koei
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichiyasu
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kohrogi
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: ycomo@kumamoto-u.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
mesh_terms: D002450:Cell Communication / Q000276:immunology*; D045744:Cell Line, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D054407:Chemokine CCL4 / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology / Q000601:surgery; D008264:Macrophages / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D055752:Small Cell Lung Carcinoma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery
chemical_list: D054407:Chemokine CCL4; C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Interleukin-6; Signal transducer and activator of transcription 3; Small cell lung cancer; Tumor-associated macrophage