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.

Ciucci, A., Zannoni, G. F., Buttarelli, M., Lisi, L., Travaglia, D., Martinelli, E., Scambia, G., Gallo, D., Multiple direct and indirect mechanisms drive estrogen-induced tumor growth in high grade serous ovarian cancers, <<ONCOTARGET>>, 2016; 7 (7): 8155-8171. [doi:10.18632/oncotarget.6943] [http://hdl.handle.net/10807/120176]

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

Zannoni, Gian Franco;Buttarelli, Marianna;Lisi, Lucia;Travaglia, Daniele;Martinelli, Enrica;Scambia, Giovanni;Gallo, Daniela
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 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.
2016
Inglese
Ciucci, A., Zannoni, G. F., Buttarelli, M., Lisi, L., Travaglia, D., Martinelli, E., Scambia, G., Gallo, D., Multiple direct and indirect mechanisms drive estrogen-induced tumor growth in high grade serous ovarian cancers, <<ONCOTARGET>>, 2016; 7 (7): 8155-8171. [doi:10.18632/oncotarget.6943] [http://hdl.handle.net/10807/120176]
File in questo prodotto:
File Dimensione Formato  
120176.pdf

accesso aperto

Tipologia file ?: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 3.88 MB
Formato Unknown
3.88 MB Unknown Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/120176
Citazioni
  • ???jsp.display-item.citation.pmc??? 19
  • Scopus 38
  • ???jsp.display-item.citation.isi??? 39
social impact