Expression of the VEGF and angiopoietin genes in endometrial atypical hyperplasia and endometrial cancer

Holland, Cathrine; Day, Kate; Evans, Alice; Smith, Stephen K.

doi:10.1038/sj.bjc.6601194

Cited by 48 publications

(46 citation statements)

References 44 publications

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“…These findings are supported by a limited number of previous smaller studies. Holland et al showed VEGF expression in 100% of the endometrial cancer specimens examined using in situ hybridization (23). Furthermore, they found no expression of VEGF in benign endometrial tissue and in only 20% of tissue samples with atypical hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Biological Significance of Vascular Endothelial Growth Factor in Endometrial Cancer

Kamat

Merritt

Coffey

et al. 2007

Clinical Cancer Research

165

107

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Purpose: Vascular endothelial growth factor (VEGF) is critical for angiogenesis and tumor progression; however, its role in endometrial cancer is not fully known. Therefore, we examined the clinical and therapeutic significance of VEGF in endometrial carcinoma using patient samples and an endometrioid orthotopic mouse model. Experimental Design: Following Institutional Review Board approval, VEGF expression and microvessel density (MVD) counts were evaluated using immunohistochemistry in 111 invasive endometrioid endometrial cancers by two independent investigators. Results were correlated with clinicopathologic characteristics. For the animal model, Ishikawa or Hec-1A cancer cell lines were injected directly into the uterine horn. Therapy experiments with bevacizumab alone or in combination with docetaxel were done and samples were analyzed for markers of angiogenesis and proliferation. Results: Of 111endometrial cancers, high expression of VEGF was seen in 56% of tumors. There was a strong correlation betweenVEGF expression and MVD (P < 0.001). On multivariate analysis, stage (P = 0.04), grade (P = 0.003),VEGF levels (P = 0.03), and MVD (P = 0.037) were independent predictors of shorter disease-specific survival. In the murine model, whereas docetaxel and bevacizumab alone resulted in 61% to 77% tumor growth inhibition over controls, combination therapy had the greatest efficacy (85-97% inhibition over controls; P < 0.01) in both models.In treated tumors, combination therapy significantly reduced MVD counts (50-70% reduction over controls; P < 0.01) and percent proliferation (39% reduction over controls; P < 0.001).Conclusions: Increased levels of VEGF and angiogenic markers are associated with poor outcome in endometrioid endometrial cancer patients. Using a novel orthotopic model of endometrioid endometrial cancer, we showed that combination of antivascular therapy with docetaxel is highly efficacious and should be considered for future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Clinical and Biological Significance of Vascular Endothelial Growth Factor in Endometrial Cancer

Kamat

Merritt

Coffey

et al. 2007

Clinical Cancer Research

165

107

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“…Compared with the blank group, ERK, Akt, mTOR and Bcl-2 mRNA and protein expressions were decreased in the pMIR-miR-29b group and increased in the LNA-miR-29b inhibitors group. As Holland et al demonstrated, once VEGFA signaling is blocked by VEGF dominant negative receptors or neutralizing antibodies, tumor angiogenesis and proliferation are damaged [31]. Biroccio et al also found that the overexpression of Bcl-2 enhanced the metastatic potential of human breast cancer cells [35].…”

Section: Discussionmentioning

confidence: 99%

“…According to Liu et al, miR-29b targeted VEGFA and could be used as novel biomarkers in diagnosis of glioma [30]. Of the angiogenic factors, VEGFA is a dimeric glycoprotein that plays a crucial role in promoting the proliferation and migration of endothelial cells and increasing the permeability of tumor-related blood vessels through binding the tyrosine kinase receptors flt-1 (VEGFR-1) and KDR (VEGFR-2) [31]. Largely consistent with our results, Aghajanian et al advocated the positive association between high circulating VEGF-A levels with the poor outcome of EC patients [32].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

Chen

Tan

et al. 2017

Cell Physiol Biochem

104

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Objective: The purpose of this study is to explore the effects of microRNA-29b (miR-29b) regulating MAPK/ERK and PI3K/Akt signaling pathways on angiogenesis in endometrial carcinoma (EC) by targeting VEGFA. Methods: Between February 2013 and April 2015, 126 EC patients admitted to the Second Affiliated Hospital of Nanchang University were randomly selected, with 126 EC tissues and the corresponding adjacent normal tissues collected after surgery. The human EC cell lines RL-95-2 and HEC-1-B and human endometrial cells were assigned to the normal group (human endometrial cells), the blank group (untransfected RL-95-2 or HEC-1-B cells), the pMIR-control group (RL-95-2 or HEC-1-B cells transfected with an empty vector), the pMIR-miR-29b group (RL-95-2 or HEC-1-B cells transfected with the miR-29b plasmid), LNA-control group (RL-95-2 or HEC-1-B cells transfected with an oligonucleotide inhibitors control), the LNA-miR-29b inhibitors group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors), the LNA-miR-29b inhibitors + PD98059 group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors and PD98059, an inhibitor of the MAPK/ERK signaling pathway) and the LNA-miR-29b inhibitors + wortmannin group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors and wortmannin, an inhibitor of the PI3K/Akt signaling pathway). qRT-PCR and Western blotting were conducted to detect the miR-29b expression and the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2. Immunohistochemistry (IHC) was performed to determine the microvessel density (MVD) expression in the EC tissues, adjacent normal tissues and nude-mice. Results: Compared with the adjacent normal tissues, miR-29b expression was down-regulated, the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated, and MVD expression was increased in the EC tissues. Compared with the normal group, miR-29b expression was down-regulated, while the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated in the other groups. Compared with the blank, pMIR-control and LNA-control groups, miR-29b expression was increased, while mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were decreased in the pMIR-miR-29b group. The LNA-miR-29b inhibitors group exhibited elevated miR-29b expression and decreased mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 (All P < 0.05). Additionally, miR-29b expression was reduced in the LNA-miR-29b inhibitors + PD98059 and LNA-miR-29b inhibitors + wortmannin groups. In comparison to the normal group, MVD expression was elevated in the other groups. Compared with the blank, pMIR-control, LNA-control, LNA-miR-29b inhibitors + PD98059 and LNA-miR-29b inhibitors + wortmannin groups, MVD expression was decreased in the pMIR-miR-29b group but increased in the LNA-miR-29b inhibitors group. Conclusion: Our results indicate that miR-29b negatively mo...

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“…Since angiogenesis is a critical event in the growth and spread of tumors during carcinogenesis [45], and VEGFs and the angiopoietins are key factors in angiogenesis [46] [47]. The VEGF-C and VEGF-D have both been correlated with poor prognosis in endometrial cancer and atypical complex hyperplasia (ACH), in low grade endometrial tumors, expression of VEGF-B is increased, and experiment showed VEGF-A and VEGF-B, are differentially expressed in benign postmenopausal endometrium and endometrioid endometrial cancer [48]. High expression of VEGF-D in carcinoma cells and stroma cells, are closely related with high level of VEGFR-3 in carcinoma cells and endothelial cells, suggested that VEGF/ VEGFR signaling pathway mediated by VEGF-D/VEGFR-3 plays a significant role to myometrial invasion and lymph node metastasis [49].…”

Section: Apc/β-catenin Signaling Pathwaymentioning

confidence: 99%

Endometrial Carcinogenesis and Molecular Signaling Pathways

Ma¹,

Charles²,

Wang³

2014

AJMB

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The Endometrial Cancer (EC) is the most common gynecologic malignancy that starts in the endometrium of women. Carcinogenesis of EC is associated with several critical regulatory molecules, which involve in different signaling pathways. A number of signaling pathways have been identified to be involved in the multiple-step development of EC, including PI3K/AKT/mTOR signaling pathway, WNT/β-catenin signal transduction cascades (including APC/β-catenin pathway), MAPK/ ERK pathway, VEGF/VEGFR ligand receptor signaling pathway, ErbB signaling pathway, P53/P21 and P16INK4a/pRB signaling pathways. This review mainly focuses on the molecular signaling pathways relevant to human endometrial cancer and discusses those critical capabilities of transforming endometrial cells, including evading apoptosis; enhancing cell proliferation; blocking differentiation; and inducing angiogenesis.

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Expression of the VEGF and angiopoietin genes in endometrial atypical hyperplasia and endometrial cancer

Cited by 48 publications

References 44 publications

Clinical and Biological Significance of Vascular Endothelial Growth Factor in Endometrial Cancer

Clinical and Biological Significance of Vascular Endothelial Growth Factor in Endometrial Cancer

MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

Endometrial Carcinogenesis and Molecular Signaling Pathways

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