Oncotarget

Research Papers:

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

Alessandra Ciucci _, Gian Franco Zannoni, Marianna Buttarelli, Lucia Lisi, Daniele Travaglia, Enrica Martinelli, Giovanni Scambia and Daniela Gallo

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Oncotarget. 2016; 7:8155-8171. https://doi.org/10.18632/oncotarget.6943

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Abstract

Alessandra Ciucci1, Gian Franco Zannoni2, Marianna Buttarelli1, Lucia Lisi3, Daniele Travaglia1, Enrica Martinelli1, Giovanni Scambia1, Daniela Gallo1

1Department of Obstetrics and Gynecology, Catholic University of The Sacred Heart, 00168 Rome, Italy

2Department of Histopathology, Catholic University of The Sacred Heart, 00168 Rome, Italy

3Institute of Pharmacology, Catholic University of The Sacred Heart, 00168 Rome, Italy

Correspondence to:

Daniela Gallo, e-mail: daniela.gallo@unicatt.it

Keywords: ER, estradiol, ovary, tumor-associated macrophages, tumor microenvironment

Received: October 30, 2015     Accepted: January 10, 2016     Published: January 18, 2016

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.


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