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Vascular endothelial growth factor (VEGF) is important in the growth and metastasis of cancer cells. In 2001, another angiogenic factor, endocrine gland-derived VEGF (EG-VEGF), was characterized and sequenced. EG-VEGF activity appears to be restricted to endothelial cells derived from endocrine glands. At the molecular level, its expression is regulated by hypoxia and steroid hormones. Although VEGF and EG-VEGF are structurally different, they function in a coordinated fashion. Since the majority of mammary tumors are hormone-dependent, it was hypothesized that EG-VEGF would be expressed in these tumors, and therefore, represent a potential target for anti-angiogenic therapy. The aim of the present study was to assess the expression of VEGF, EG-VEGF and its receptor (prokineticin receptor-1), as well as that of breast cancer resistant protein, estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, in 50 breast samples of infiltrating canalicular carcinoma (ICC) and their correlation with tumor staging. The samples were analyzed using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. Both angiogenic growth factors were identified in all samples. However, in 90% of the samples, the expression level of VEGF was significantly higher than that of EG-VEGF (P=0.024). There was no association between the expression of VEGF, EG-VEGF or its receptor with tumor stage. In ICC, the predominant angiogenic factor expressed was VEGF. The expression level of either factor was not correlated with the tumor-node-metastasis stage. Although ICC is derived from endothelial cells, EG-VEGF expression was not the predominant angiogenic/growth factor in ICC. [ABSTRACT FROM AUTHOR]

PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EGVEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants (n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ+/- and PPAR mice. Major processes of placental development that are known to be controlled by PPAR, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ+/- mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion. [ABSTRACT FROM AUTHOR]

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is a newly cloned factor that selectively acts on the endothelium of endocrine gland cells. EG-VEGF was previously identified as an important cytokine, involved in the modulation of apoptosis in pancreatic cancer cell lines. The present study examined the effects of EG-VEGF proliferation and migration, in pancreatic cancer cells. To determine the potential for EG-VEGF as a therapeutic target for pancreatic cancer, the expression of EG-VEGF were measured in pancreatic cancer tissue, and the association between its expression and the clinicopathological characteristics of the pancreatic cancer patients was determined. The results of the present study suggest that EG-VEGF may act as a novel tumor gene in pancreatic cancer. EG-VEGF was rarely expressed in the normal pancreatic tissue, but was highly expressed in the pancreatic cancer tissue. These data suggest that EG-VEGF may be a cancer-specific, and possibly tissue-specific, survival factor in the pancreas. In the Mia PaCa-2 pancreatic cancer cell line, EG-VEGF was shown to promote proliferation and cellular invasion, and modulate the phosphorylation of mitogen-activated protein kinase, a modulator for the malignant phenotype. [ABSTRACT FROM AUTHOR]

In utero exposure to nicotine is associated with increased risk of numerous adverse fetal and neonatal outcomes, which suggests that it acts directly to affect placental development and the establishment of the fetomaternal circulation (FC). This study used both in vivo [Wistar rats treated with 1 mg/kg nicotine from 2 wk prior to mating until gestational day (GD) 15] and in vitro (RCHO-1 cell line; treated with 10-9 to 10-3M nicotine) models to examine the effects of nicotine on these pathways. At GD 15, control and treated placentas were examined for the impact of nicotine on 1) trophoblast invasion, proliferation, and degree of hypoxia, 2) labyrinth vascularization, 3) expression of key genes of placental development, and 4) expression of placental angiogenic factors. The RCHO-1 cell line was used to determine the direct effects of nicotine on trophoblast differentiation. Our in vivo experiments show that nicotine inhibits trophoblast interstitial invasion, increases placental hypoxia, downregulates labyrinth vascularization as well as key transcription factors Hand1 and GCM1, and decreases local and circulating EG-VEGF, a key placental angiogenic factor. The in vitro experiments confirmed the inhibitory effects of nicotine on the trophoblast migration, invasion, and differentiation processes and demonstrated that those effects are most likely due to a dysregulation in the expression of nicotine receptors and a decrease in MMP9 activity. Taken together, these data suggest that adverse effects of maternal smoking on pregnancy outcome are due in part to direct and endocrine effects of nicotine on the main processes of placental development and establishment of FC. [ABSTRACT FROM AUTHOR]

Objective: To assess the predictive value of endocrine gland–derived vascular endothelial growth factor (EG-VEGF) concentrations in follicular fluid (FF) and serum for ovarian hyperstimulation syndrome (OHSS) in patients undergoing controlled ovarian hyperstimulation. Design: Retrospective, case-control study. Setting: University hospital, IVF center. Patient(s): Seventeen women with OHSS and 61 controls. Intervention(s): None. Main Outcome Measure(s): FF and serum EG-VEGF and VEGF concentrations, IVF outcome. Result(s): FF and serum EG-VEGF concentrations showed a significant negative correlation with serum E2 concentration on the day of hCG administration. FF, but not serum, VEGF concentrations also showed a significant negative correlation with serum E2 concentrations on hCG day. The FF EG-VEGF, FF VEGF, and serum EG-VEFG concentrations were significantly lower in the OHSS group than in the non-OHSS group. There was no significant difference in serum VEGF concentrations. Among FF and serum EG-VEGF and VEGF concentrations, only FF EG-VEGF concentrations were significantly lower in patients with moderate OHSS than in those with mild OHSS. Conclusion(s): FF and serum EG-VEGF concentrations may predict OHSS occurrence. Furthermore, FF EG-VEGF concentrations were significantly correlated with OHSS severity; thus, EG-VEGF appears to be more valuable than VEGF for predicting OHSS. [ABSTRACT FROM AUTHOR]

Extravillous trophoblast (EVT) invasion is important for embryo implantation, placental development, and successful remodeling of the uterine spiral artery. Endocrine gland derived-vascular endothelial growth factor (EG-VEGF) and matrix metalloproteinases (MMPs) are implicated in EVT invasion; however, the high con-centrations found in pregnancy pathologies have not been investigated in non-tumor trophoblasts. The roles of EG-VEGF, prokineticin receptors (PROKR1/2), MMP-2, and MMP-9 in EVT invasion during spiral artery remodeling were evaluated using human EVT from HTR-8/SVneo cell lines. The expression of MMP-2, MMP-9, and mitogen-activated protein kinase (MAPK), and Akt pathways in HTR-8/SVneo cells treated with recom-binant EG-VEGF alongside anti-PROKR1 and/or anti-PROKR2 antibodies was evaluated using quantitative reverse transcription-PCR and western blotting. Wound-healing and cell invasion assays were performed to assess the migration and invasion of these treated cells. Interestingly, 20 nM EG-VEGF activated ERK1/2 sig-naling and upregulated MMP-2 and MMP-9. This effect was suppressed by anti-PROKR2 antibody via ERK1/2 downregulation. Anti-PROKR2 antibody inhibited the migration and invasion of EG-VEGF-stimulated HTR-8/SVneo cells. Elevated concentrations of EG-VEGF enhance EVT invasion in a human trophoblast cell line by upregulating MMP-2 and MMP-9 via PROKR2. These new insights into the regulation of epithelial cell invasion may help in developing therapeutic interventions for placental-related diseases during pregnancy., Competing Interests: No potential conflict of interest relevant to this article was reported.