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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| Format: | Article |
| Language: | English |
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Nature Portfolio
2020-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-65353-x |
| _version_ | 1819127181181190144 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-22T08:07:50Z |
| format | Article |
| id | doaj.art-1e2034decd7b4213a5c0a5824478d5c9 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-22T08:07:50Z |
| publishDate | 2020-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1e2034decd7b4213a5c0a5824478d5c92022-12-21T18:33:06ZengNature PortfolioScientific Reports2045-23222020-05-0110111210.1038/s41598-020-65353-xThe biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genesNicole E. James0Jenna B. Emerson1Ashley D. Borgstadt2Lindsey Beffa3Matthew T. Oliver4Virginia Hovanesian5Anze Urh6Rakesh K. Singh7Rachael Rowswell-Turner8Paul A. DiSilvestro9Joyce Ou10Richard G. Moore11Jennifer R. Ribeiro12Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women’s OncologyWomen and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women’s OncologyWomen and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women’s OncologyWomen and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women’s OncologyWomen and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women’s OncologyRhode Island Hospital, Digital Imaging and Analysis Core FacilityNorthwell Health Physician Partners Gynecologic OncologyUniversity of Rochester Medical CenterUniversity of Rochester Medical CenterWomen and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women’s OncologyWarren-Alpert Medical School of Brown UniversityUniversity of Rochester Medical CenterWomen and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women’s OncologyAbstract 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.https://doi.org/10.1038/s41598-020-65353-x |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-020-65353-x |
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