Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features

BACKGROUND: Although uterine fibroids are very common, their pathogenesis and clinical behaviour are poorly understood. Since they may be prevalent in some families, we investigated whether such a prevalence was associated with distinctive clinical and molecular features. METHODS: A case-control questionnaire study of 300 multi-ethnic women with uterine fibroids at a London university hospital was undertaken, with review of case notes and immunohistochemical determination of vascular endothelial growth factor (VEGF-A) in fibroids. RESULTS: When compared with families with sporadic fibroids, familial prevalence of fibroids was associated with a higher incidence of abdominal swelling (59.1% versus 41.6%; P=0.037), menorrhagia (84.4% versus 51.9%; P=0.042), dysmenorrhoea (64.4% versus 46.3%; P=0.004), dyspareunia (43.2% versus 27.9%; P=0.012) and family history of cancers (52.3% versus 32.4%; P<0.01). The fibroids were also more multiple (mean +/- SEM: 7 +/- 0.86 versus 3 +/- 0.42; P<0.011) and strong VEGF-A expression in fibroids was more common in the familial group (64% versus 28%). Racial distribution was the same in both groups (blacks 49%, whites 33.4%, others 18.6%). CONCLUSIONS: Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features that differ from those found when fibroids occur sporadically in families.     

Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer

Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.     

IL-33 receptor ST2 deficiency attenuates renal ischaemia–reperfusion injury in euglycaemic,but not streptozotocin-induced hyperglycaemic mice

Aim

Kidney hypoxia can predispose to the development of acute and chronic renal failure in diabetes. Ischaemia–reperfusion injury (IRI) causes inflammation, and diabetes is known to exacerbate this inflammatory response in the kidney, whereas alarmin IL-33 could act as an innate immune mediator during kidney IRI. Thus, the present study examined the impact of genetic IL-33 receptor ST2 deficiency (ST2?/?) on renal IRI in euglycaemic and hyperglycaemic mice.

Inhibition of the liver expression of arylalkylamine N-acetyltransferase increases the expression of angiogenic factors in cholangiocytes

Background and aims

Reduction of biliary serotonin N-acetyltransferase (AANAT) expression and melatonin administration/secretion in cholangiocytes increases biliary proliferation and the expression of SR, CFTR and Cl^–/HCO₃^– AE2. The balance between biliary proliferation/damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor-A/C (VEGF-A/C). VEGFs are secreted by several epithelia, where they modulate cell growth by autocrine and paracrine mechanisms. No data exists regarding the effect of AANAT modulation on the expressions of VEGFs by cholangiocytes.

Methods

In this study, we evaluated the effect of local modulation of biliary AANAT expression on the cholangiocytes synthesis of VEGF-A/C.

Results

The decrease in AANAT expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of VEGF-A/C. Overexpression of AANAT in cholangiocyte lines decreased the expression of VEGF-A/C.

Conclusions

Modulation of melatonin synthesis may affect the expression of VEGF-A/C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of VEGF-A/C expression regulating biliary functions.     

The prognostic value of vascular endothelial growth factors (VEGFs)-A and -B and their receptor, VEGFR-1, in invasive breast carcinoma

OBJECTIVES: Vascular endothelial growth factors A and B (VEGF-A and VEGF-B) play a major role in angiogenesis and activate VEGF receptor 1 (VEGFR-1). However, the clinicopathologic and clinical value of VEGF-B and VEGFR-1 in invasive breast carcinoma remains unclear. METHODS: We immunohistochemically examined the expression pattern of VEGF-A, VEGF-B and VEGFR-1 in 177 invasive breast carcinomas in relation to clinicopathological parameters, p53, c-erbB2 proteins expression and patients' survival. RESULTS: VEGF-A, VEGF-B and VEGFR-1 were immunodetected predominantly in the cytoplasm of the malignant cells. None of the studied markers correlated with any of the clinicopathological parameters, other than stromal VEGFR-1 which inversely correlated with PR (p=0.021). Cancerous VEGF-A and stromal VEGFR-1 were positively related to p53 (p=0.016 and p=0.033, respectively). Cancerous VEGF-B was positively associated with c-erbB-2 (p=0.045) and was found to exert an unfavorable impact on both disease-free and the overall survival of the node-positive patients (p=0.05 and p=0.029, respectively). Cancerous VEGFR-1 was recognized as being an independent poor prognostic indicator (p=0.037). CONCLUSION: These findings suggest that, while VEGF-B seems to be useful as a prognostic indicator only in node-positive patients, VEGFR-1 may be an independent poor prognosticator in patients with invasive breast carcinoma.     

皮肤黑素瘤中miRNA-34c的表达对促血管新生因子VEGF-A、VEGFR-1的影响

目的探讨皮肤黑素瘤中miRNA-34c的表达以及其对促血管新生因子VEGF-A和VEGFR-1的影响。方法 Northern blotting检测原代人黑素瘤细胞、黑素瘤细胞株A375和原代人表皮黑素细胞miRNA-34c表达。构建miRNA-34c基因过表达与基因敲低的黑素瘤细胞株A375细胞系即高表达miRNA-34c组和低表达miRNA-34c组,以空载体转染黑素瘤细胞株A375作为空载体对照组。CCK-8法检测各组细胞增殖活性。qRT-PCR和Western blotting分别检测各组VEGF-A、VEGFR-1 mRNA和蛋白表达。结果与原代人表皮黑素细胞相比,黑素瘤细胞株A375和原代人黑素瘤细胞中miRNA-34c的表达降低(P<0.05)。高表达miRNA-34c组、低表达miRNA-34c组和空载体对照组细胞增殖活性无明显差异(P>0.05)。高表达miRNA-34c组VEGF-A、VEGFR-1的mRNA和蛋白表达较空载体对照组降低(P<0.05)。低表达miRNA-34c组VEGF-A、VEGFR-1的mRNA和蛋白表达较空载体组升高(P<0.05)。结论 miRNA-34c在皮肤黑素瘤中呈现特异性下调,miRNA-34c可能通过对促血管新生因子VEGF-A、VEGFR-1的下调参与皮肤黑素瘤的发生与发展。     

Placental gene expression patterns of epidermal growth factor in intrauterine growth restriction

Objective

In this study, we compared human placental gene expression patterns of epidermal growth factor (EGF) in pregnancies with intrauterine growth restriction (IUGR) vs. normal pregnancies as control.

Study design

Gene expression of EGF was determined from human placental samples collected from all pregnancies presenting with IUGR at our institution during the study period January 1, 2010–January 1, 2011. Multiple clinical variables were also assessed including maternal age, gestational weight gain, increase of BMI during pregnancy and fetal gender.

Results

A total of 241 samples were obtained (101 in the IUGR pregnancy group, 140 in the normal pregnancy group). EGF was found to be underexpressed in the IUGR group compared to normal pregnancy (Ln2^α: −1.54; p < 0.04). Within the IUGR group no fetal gender-dependent difference was seen in EGF gene expression (Ln2^α: 0.44; p < 0.06). Similarly, no significant difference in EGF expression was noted in cases with more vs. less severe forms of IUGR (Ln2^α: −0.08; p = 0.05). IUGR pregnancies were significantly more common in the maternal age group 35–44 years compared to other age groups. Gestational weight gain and gestational BMI increase were significantly lower in IUGR pregnancies compared to controls.

Conclusions

Placental expression of EGF was found to be reduced in IUGR pregnancies vs. normal pregnancies. This may partly explain the smaller placental size and placental dysfunction commonly seen with IUGR. An increased incidence of IUGR was observed with maternal age exceeding 35 years. The probability of IUGR correlated with lower gestational weight gain and lower BMI increase during pregnancy.     

Tumor Specific VEGF-A and VEGFR2/KDR Protein are Co-expressed in Breast Cancer

Angiogenesis is a prognostic indicator in primary breast cancer regulated by specific angiogenic factors and their receptors. Vascular endothelial growth factor-A (VEGF-A), so far considered the most important, acts through dimerization of the receptor VEGFR2/KDR within the receptor tyrosine kinase family of VEGF receptors. In order to study the interplay between VEGF-A and VEGFR2/KDR in breast cancer we evaluated their expression by immunohistochemistry in 102 breast cancers organized in a tumor tissue array system allowing semi-quantitative evaluation of cytoplasmatic staining intensity. In addition, VEGF-A165 was analyzed by an enzyme immuno assay (ELISA) in protein extracts prepared from frozen tissue from 98 of 102 tumors included in the array. Cytoplasmatic staining of VEGF of varying intensity was observed in all samples and correlated with the ELISA results of VEGF content (p = 0.007). Interestingly, VEGFR2/KDR expression correlated with VEGF expression using immunohistochemistry, indicating that VEGF and VEGFR2/KDR may be co-expressed in breast cancer. Furthermore, high levels of VEGF-A165 in the protein extracts was associated with impaired short time survival but not long term survival whereas immunohistochemically assessed VEGF and VEGFR2/KDR were not significantly associated with survival. In summary, immunohistochemically based analysis of VEGF using a tumor tissue array system seems to be a useful method for VEGF quantification in breast cancer here validated using an ELISA based method. The tumor tissue array system enables opportunities of simultaneous analysis of markers engaged in angiogenesis justifying further studies using larger series of tumors.