title: Multiple direct and indirect mechanisms drive estrogen-induced tumor growth in high grade serous ovarian cancers.
abstract: The notion that menopausal estrogen replacement therapy increases ovarian cancer risk, but only for the two more common types (i.e. serous and endometrioid), while possibly decreasing risk for clear cell tumors, is strongly suggestive of causality. However, whether estradiol (E2) is tumorigenic or promotes development of occult preexisting disease is unknown. The present study investigated molecular and cellular mechanisms by which E2 modulates the growth of high grade serous ovarian cancer (HGSOC). Results showed that ERα expression was necessary and sufficient to induce the growth of HGSOC cells in in vitro models. Conversely, in vivo experimental studies demonstrated that increasing the levels of circulating estrogens resulted in a significant growth acceleration of ERα-negative HGSOC xenografts, as well. Tumors from E2-treated mice had significantly higher proliferation rate, angiogenesis, and density of tumor-associated macrophage (TAM) compared to ovariectomized females. Accordingly, immunohistochemical analysis of ERα-negative tissue specimens from HGSOC patients showed a significantly greater TAM infiltration in premenopausal compared to postmenopausal women. This study describes novel insights into the impact of E2 on tumor microenvironment, independently of its direct effect on tumor cell growth, thus supporting the idea that multiple direct and indirect mechanisms drive estrogen-induced tumor growth in HGSOC.
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of The Sacred Heart, 00168 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ciucci
authors.affiliation: Department of Histopathology, Catholic University of The Sacred Heart, 00168 Rome, Italy.
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Zannoni
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of The Sacred Heart, 00168 Rome, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Buttarelli
authors.affiliation: Institute of Pharmacology, Catholic University of The Sacred Heart, 00168 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Lisi
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of The Sacred Heart, 00168 Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Travaglia
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of The Sacred Heart, 00168 Rome, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Martinelli
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of The Sacred Heart, 00168 Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of The Sacred Heart, 00168 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gallo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D004967:Estrogens; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol
keywords: ER; estradiol; ovary; tumor microenvironment; tumor-associated macrophages