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 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.

Anti-inflammatory effects of lavender and eucalyptus essential oils on the in vitro cell culture model of bladder pain syndrome using T24 cells

“…Utilization of EOs against bacterial infections is emerging due to the increased occurrence of antibiotic resistance. Hybrid lavender EOs seem to be promising candidates as new therapies against the multidrug-resistant Pseudomonas aeruginosa due to their low cytotoxicity and high effectiveness [ 38 ]. Lavender oils from true lavender, spike lavender and hybrid lavenders differ in the constitution and therefore in biological and therapeutic activities.…”

“…After each treatment of cells, the culture supernatant of control and treated cells was collected and kept at − 80 °C until measurements. The concentration of IL-8 secreted in the culture media was determined using human IL-8 ELISA kit (Thermo Fisher Scientific Inc., Waltham, MA) following the manufacturer’s instructions [ 38 ].…”

Association of plasma proteins with rate of cognitive decline and dementia: 20-year follow-up of the Whitehall II and ARIC cohort studies

“…75 Elevated N-terminal pro-BNP levels are also linked with increased risk of vascular and Alzheimer’s dementia. 28, 29, 76, 77 Of the proteins not previously linked to dementia, SVEP1 is known to promote thrombosis, 78, 79 and HE4 and CRDL1 participate in angiogenesis in response to ischemia 80-82 and might contribute to the abnormal angiogenesis observed in vascular and Alzheimer’s dementia. 6, 83 These results provide a variety of mechanisms that could predispose to cerebrovascular dysfunction in dementias.…”

The Prognostic Value of Integrated Analysis of Inflammation and Hypoxia-Related Genes in Idiopathic Pulmonary Fibrosis

“…Previous studies suggest that HS3ST1 was significantly correlated with inflammation and hypoxia, which is consistent with our results and thereby indicates that HS3ST1 could be a promising target for IPF. WFDC2, also called HE4, was identified as a prognostic biomarker for various cancer types and is involved in the regulation of multiple pathways, including EGFR and STAT3 (47)(48)(49). A recent clinical study shows that aberrant HE4 expression of patients with IPF was associated with a poor clinical outcome; however, this aspect requires further investigation (50).…”