title: Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation.
abstract: Ascites macrophages in advanced epithelial ovarian cancer (AdEOC) are involved in cancer metastasis and progression by modifying the tumor microenvironment. However, the precise mechanisms of cell-to-cell interaction between macrophages and tumor cells are still unclear. This study focused on the activation of signal transducer and activator of transcription 3 (Stat3) which is a critical signal transduction molecule at a point of convergence for numerous oncogenic signaling pathways as well as controlling the M2-poralization of macrophages. AdEOC ascites, in which high concentration of interleukin (IL)-6, IL-10, growth-related oncogene-alpha and vascular endothelial growth factor were detected, stimulated the proliferation of SKOV3 cells, a human ovarian cancer cell line. The simultaneous blocking of IL-6 and IL-10 by neutralizing antibodies suppressed ascites-induced tumor cell proliferation. Stat3 activation in SKOV3 cells was induced by co-culture with macrophages especially with macrophage colony stimulating factor-primed M2 macrophages but lesser extent with granulocyte-macrophage colony stimulating factor-primed immature macrophages. Cyclin-D1 expression in SKOV3 cells was also significantly induced by co-culture with macrophages. Blocking of Stat3 in macrophages by small interfering RNA inhibited the production of IL-6 and IL-10 by macrophages, and suppressed Stat3 activation and cyclin-D1 induction in co-cultured SKOV3 cells. Stat3 activation in SKOV3 cells was abrogated by simultaneous neutralization of IL-6 and IL-10. These results indicate that Stat3 activation by IL-6 and IL-10 plays an important role in cell-to-cell interaction between tumor cells and macrophages in the ascites of AdEOC.
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Takaishi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.forename: Hironori
authors.initials: H
authors.lastname: Tashiro
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ohtake
authors.forename: Takenobu
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Katabuchi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
mesh_terms: D001201:Ascites / Q000473:pathology*; D002277:Carcinoma / Q000473:pathology*; D002450:Cell Communication; D016764:Cell Polarity; D054360:Chemokine CXCL1 / Q000032:analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10