Multiple direct and indirect mechanisms drive estrogen-induced tumor growth in high grade serous ovarian cancers

Gian Franco Zannoni, Lucia Lisi, Giovanni Scambia, Marianna Buttarelli, Daniele Travaglia, Enrica Martinelli, Daniela Gallo Guido

Risultato della ricerca: Contributo in rivistaArticolo in rivista

22 Citazioni (Scopus)

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 E2modulates the growth of high grade serous ovarian cancer (HGSOC). Results showed that ERa 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 ERa-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 E2on 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.
Lingua originaleEnglish
pagine (da-a)8155-8171
Numero di pagine17
RivistaOncotarget
Volume7
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Blotting, Western
  • Case-Control Studies
  • Cell Proliferation
  • Cystadenocarcinoma, Serous
  • ER
  • Estradiol
  • Estrogens
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Grading
  • Oncology
  • Ovarian Neoplasms
  • Ovary
  • Prognosis
  • RNA, Messenger
  • Real-Time Polymerase Chain Reaction
  • Receptors, Estrogen
  • Retrospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • Tumor microenvironment
  • Tumor-associated macrophages
  • Xenograft Model Antitumor Assays
  • Young Adult

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