The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes

Abstract Epithelial ovarian cancer (EOC) is a highly lethal gynecologic malignancy arising from the fallopian tubes that has a high rate of chemoresistant recurrence and low five-year survival rate. The ovarian cancer biomarker HE4 is known to promote proliferation, metastasis, chemoresistance, and...

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Autores principales:	Nicole E. James, Jenna B. Emerson, Ashley D. Borgstadt, Lindsey Beffa, Matthew T. Oliver, Virginia Hovanesian, Anze Urh, Rakesh K. Singh, Rachael Rowswell-Turner, Paul A. DiSilvestro, Joyce Ou, Richard G. Moore, Jennifer R. Ribeiro
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1e2034decd7b4213a5c0a5824478d5c9
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spelling	oai:doaj.org-article:1e2034decd7b4213a5c0a5824478d5c92021-12-02T14:58:45ZThe biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes10.1038/s41598-020-65353-x2045-2322https://doaj.org/article/1e2034decd7b4213a5c0a5824478d5c92020-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-65353-xhttps://doaj.org/toc/2045-2322Abstract Epithelial ovarian cancer (EOC) is a highly lethal gynecologic malignancy arising from the fallopian tubes that has a high rate of chemoresistant recurrence and low five-year survival rate. The ovarian cancer biomarker HE4 is known to promote proliferation, metastasis, chemoresistance, and suppression of cytotoxic lymphocytes. In this study, we sought to examine the effects of HE4 on signaling within diverse cell types that compose the tumor microenvironment. HE4 was found to activate STAT3 signaling and promote upregulation of the pro-angiogenic STAT3 target genes IL8 and HIF1A in immune cells, ovarian cancer cells, and endothelial cells. Moreover, HE4 promoted increases in tube formation in an in vitro model of angiogenesis, which was also dependent upon STAT3 signaling. Clinically, HE4 and IL8 levels positively correlated in ovarian cancer patient tissue. Furthermore, HE4 serum levels correlated with microvascular density in EOC tissue and inversely correlated with cytotoxic T cell infiltration, suggesting that HE4 may cause deregulated blood vessel formation and suppress proper T cell trafficking in tumors. Collectively, this study shows for the first time that HE4 has the ability to affect signaling events and gene expression in multiple cell types of the tumor microenvironment, which could contribute to angiogenesis and altered immunogenic responses in ovarian cancer.Nicole E. JamesJenna B. EmersonAshley D. BorgstadtLindsey BeffaMatthew T. OliverVirginia HovanesianAnze UrhRakesh K. SinghRachael Rowswell-TurnerPaul A. DiSilvestroJoyce OuRichard G. MooreJennifer R. RibeiroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nicole E. James Jenna B. Emerson Ashley D. Borgstadt Lindsey Beffa Matthew T. Oliver Virginia Hovanesian Anze Urh Rakesh K. Singh Rachael Rowswell-Turner Paul A. DiSilvestro Joyce Ou Richard G. Moore Jennifer R. Ribeiro The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes
description	Abstract Epithelial ovarian cancer (EOC) is a highly lethal gynecologic malignancy arising from the fallopian tubes that has a high rate of chemoresistant recurrence and low five-year survival rate. The ovarian cancer biomarker HE4 is known to promote proliferation, metastasis, chemoresistance, and suppression of cytotoxic lymphocytes. In this study, we sought to examine the effects of HE4 on signaling within diverse cell types that compose the tumor microenvironment. HE4 was found to activate STAT3 signaling and promote upregulation of the pro-angiogenic STAT3 target genes IL8 and HIF1A in immune cells, ovarian cancer cells, and endothelial cells. Moreover, HE4 promoted increases in tube formation in an in vitro model of angiogenesis, which was also dependent upon STAT3 signaling. Clinically, HE4 and IL8 levels positively correlated in ovarian cancer patient tissue. Furthermore, HE4 serum levels correlated with microvascular density in EOC tissue and inversely correlated with cytotoxic T cell infiltration, suggesting that HE4 may cause deregulated blood vessel formation and suppress proper T cell trafficking in tumors. Collectively, this study shows for the first time that HE4 has the ability to affect signaling events and gene expression in multiple cell types of the tumor microenvironment, which could contribute to angiogenesis and altered immunogenic responses in ovarian cancer.
format	article
author	Nicole E. James Jenna B. Emerson Ashley D. Borgstadt Lindsey Beffa Matthew T. Oliver Virginia Hovanesian Anze Urh Rakesh K. Singh Rachael Rowswell-Turner Paul A. DiSilvestro Joyce Ou Richard G. Moore Jennifer R. Ribeiro
author_facet	Nicole E. James Jenna B. Emerson Ashley D. Borgstadt Lindsey Beffa Matthew T. Oliver Virginia Hovanesian Anze Urh Rakesh K. Singh Rachael Rowswell-Turner Paul A. DiSilvestro Joyce Ou Richard G. Moore Jennifer R. Ribeiro
author_sort	Nicole E. James
title	The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes
title_short	The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes
title_full	The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes
title_fullStr	The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes
title_full_unstemmed	The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes
title_sort	biomarker he4 (wfdc2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of stat3 target genes
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/1e2034decd7b4213a5c0a5824478d5c9
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The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes

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