| Autor: |
James NE; Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA., Emerson JB; Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.; Warren-Alpert Medical School of Brown University, Providence, RI, USA., Borgstadt AD; Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.; Warren-Alpert Medical School of Brown University, Providence, RI, USA., Beffa L; Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.; Warren-Alpert Medical School of Brown University, Providence, RI, USA., Oliver MT; Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.; Warren-Alpert Medical School of Brown University, Providence, RI, USA., Hovanesian V; Rhode Island Hospital, Digital Imaging and Analysis Core Facility, Providence, RI, USA., Urh A; Northwell Health Physician Partners Gynecologic Oncology, Brightwaters, NY, USA., Singh RK; University of Rochester Medical Center, Rochester, NY, USA., Rowswell-Turner R; University of Rochester Medical Center, Rochester, NY, USA., DiSilvestro PA; Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.; Warren-Alpert Medical School of Brown University, Providence, RI, USA., Ou J; Warren-Alpert Medical School of Brown University, Providence, RI, USA.; Women and Infants Hospital, Department of Pathology, Providence, RI, USA., Moore RG; University of Rochester Medical Center, Rochester, NY, USA., Ribeiro JR; Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA. Jrribeiro@wihri.org.; Warren-Alpert Medical School of Brown University, Providence, RI, USA. Jrribeiro@wihri.org. |
| Abstrakt: |
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. |
