title: Activation of a positive feedback loop involving IL-6 and aromatase promotes intratumoral 17β-estradiol biosynthesis in endometrial carcinoma microenvironment.
abstract: Tumor-stroma interactions contribute greatly to intratumoral estrogen biosynthesis in endometrial carcinoma, but the mechanisms involved remain largely unknown. Previous study demonstrated that intratumoral aromatase upregulation in stromal cells participated in this process, but the specific aromatase-regulators have not been reported. In the present study, we found that aromatase expression in intratumoral stroma, but not in tumor epithelium, correlated positively with interleukin 6 (IL-6) expression in cancer epithelial cells by immunohistochemistry, which was confirmed using laser capture microdissection/real-time reverse transcription-PCR. With stimulation by exogenous IL-6, aromarase expression was increased in stromal cells not but not in cancer cells. Aromatase mRNA levels in endometrial cancer cells were not influenced by cocultivation with intratumoral stromal cells. When cocultured with 17β-estradiol (E2 )-treated cancer cells, aromatase mRNA in stromal cells was significantly elevated and increased IL-6 protein levels were detected in E2 -treated culture medium. Next, we demonstrated that E2 -induced IL-6 production was through cooperation between estrogen receptor α and nuclear factor-kappa B. Furthermore, an IL-6 receptor blocking antibody could attenuate the upregulation of aromatase expression in stromal cells and the E2 concentration in coculture systems of cancer and stromal cells. The results were confirmed by an orthotopic nude endometrial carcinoma model in vivo. These studies elucidated the activation of a positive feedback loop, that is, IL-6 stimulated by E2 in endometrial cancer cells induced aromatase expression in stromal cells, promoting enhanced intratumoral E2 synthesis. Blocking of this tumor-stroma interaction may be a therapeutic strategy to overcome in situ estrogen biosynthesis in endometrial carcinoma.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Che
authors.forename: Bin-Ya
authors.initials: BY
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Liao
authors.forename: Hui-Juan
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Yang
authors.forename: Yin-Yan
authors.initials: YY
authors.lastname: He
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Xia
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: He
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Wang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Wan
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D015153:Blotting, Western; D018920:Coculture Techniques; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000096:biosynthesis*; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism*; D061346:Laser Capture Microdissection; D051379:Mice; D008819:Mice, Nude; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D004958:Estradiol; D001141:Aromatase
keywords: IL-6; aromatase; endometrial carcinoma; estrogen; tumor microenvironment