Large-scale Real-time Reverse Transcription-PCR Approach of Angiogenic Pathways in Human Transitional Cell Carcinoma of the Bladder: Identification of VEGFA as a Major Independent Prognostic Marker (original) (raw)
Related papers
1997
Tumor development is angiogenesis dependent, and vascular endothe 11*1 growth factor (VEGF) is a key growth factor in this process. We demonstrate that high expression of VEGF mRNA in 55 superficIal blad der cancers was associated with earlier recurrence (P = 0.001; hazard ratio, 3.09) and progression to a more invasive phenotype (P = 0.02; hazard ratio, 533). VEGF mRNA expression correlated with protein levels in superficial tumors (r 0.59, P 0.003) and normal bladder (r 0.65, P < 0.05), although the ratio of VEGF protein to mRNA was elevated In tumors compared to normal bladder (P = 0.004), suggesting posttranscriptional regulation. In this study, VEGF is implicated as a major downstream mediator of the effects of the p5.3 tumor suppressor gene by the association between high p53 protein (determined immuno chemically) and high VEGF protein and mRNA expression (P < 0.02), although in cases without high p53 protein expression, high VEGF mRNA also predicts a poor prognosis. The relationship between VEGF and early twnor recurrence suggests that seeding via angiogenesis may be a major mechanism in the pathogenesis of recurrence. These studies indicate that VEGF can predict the behavior of superfidal bladder tumors and is a therapeutic target for intravesical therapy.
Correlation Between VEGF and EGFR Expression in Urothelial Carcinoma of Bladder
2021
Bladder cancer is the ninth malignancy of the genitourinary system in the world. Urothelial cell carcinoma is the commonest histological type. There are no good therapeutic options to date. Vascular endothelial growth factor (VEGF) is a growth factor that is essential to stimulate angiogenesis. Tumor growth relies on angiogenesis and determines the therapy. The epidermal growth factor receptor (EGFR) is known as a tyrosine kinase transmembrane receptor. EGFR is involved in the regulation of VEGF. Several researches have shown that EGFR stimulation induces VEGF expression. Therefore, this research was conducted to analyze the relationship between VEGF and EGFR, as the basis of therapy using anti-VEGF and anti-EGFR. An observational research was conducted on 53 formalin fixed paraffin-embedded tissue from Radical Cystectomy patients urothelial carcinoma of bladder which was at Dr. Soetomo General Academic Hospital Surabaya, Indonesia during 2010 2019. Immunohistochemistry was conducte...
Oncology Reports, 2012
The objective of this study was to analyze the expression profile of the angiogenic components, vascular endothelial growth factor-A (VEGFA), basic fibroblast growth factor-2 (FGF2), osteopontin (OPN) and ras homolog gene family, member C (RHOC), in urothelial cell carcinoma (UCC) of the urinary bladder and to examine their role as candidate diagnostic biomarkers. Using qPCR, 77 samples of UCC of the urinary bladder and 77 matched tumor-associated normal samples were investigated to determine the expression of the four angiogenic components. The correlation between gene expression, patient survival and pathological features of the tumors was also examined. The VEGFA and OPN transcript levels were greater in the bladder cancer tissue than in the normal urothelium (P<0.001). Patients with higher VEGFA mRNA levels showed a tendency towards shorter cancerspecific survival. OPN levels showed a gradual increase, the lowest levels being found in non-invasive carcinoma and the highest in muscle invasive tumors. Elevated OPN levels indicated poor prognosis in connection with advanced disease stage (P<0.001). Both superficially invasive and muscle inva-sive tumors had significantly higher FGF2 levels compared to the control tissues (P=0.018 and P=0.050, respectively). Moreover, FGF2 was significantly higher in the metastatic vs. the non-metastatic tumors (P=0.0097). FGF2 levels exhibited a trend towards a correlation with worse patient survival. RHOC mRNA levels were higher in muscle invasive compared to superficially invasive tumors, as well as in grade III vs. grade I/II tumors. Furthermore, we detected worse overall survival for patients with high RHOC expression levels. VEGFA and FGF2 exhibited the best linear combination in the ROC curves for specificity and sensitivity. Thus, VEGFA and FGF2 may serve as candidate biomarkers for diagnostic purposes. Higher OPN expression may be used as a potential biomarker to predict patient survival relative to advanced tumor stage. However, further studies are required to investigate its role in urinary bladder carcinogenesis.
Clinical significance of the VEGF level in urinary bladder carcinoma
Cancer biomarkers : section A of Disease markers, 2015
To investigate the correlation of Vascular Endothelial Growth Factor (VEGF) and micro-vessel density (MVD) with urinary bladder tumor and its stage. The study was conducted between January 2010 and December 2012. The study included screening of 122 patients at elevated risk for bladder cancer, of which 35 patients were finally enrolled in the study. Diagnosis was made on the basis of urine cytology, radiological investigation (ultrasound KUB, and CT-scan) and histopathology. Thirty-five normal cancer-free individuals were enrolled as controls. Human VEGF levels were measured using an enzyme linked immunoassay and protein content (pg/mg protein) by Lowry method. SPSS for Windows version 10.0.7 (SPSS, Chicago, IL, USA) was used for statistical analysis of the data. Mean urine VEGF level in the cases was significantly higher in comparison to the control group. There was a direct correlation between VEGF level and tumor stage. Mean urine VEGF values were minimum in the control group (22...
Expression and Significance of Vascular Endothelial Growth Factor Receptor 2 in Bladder Cancer
Journal of Urology, 2006
Vascular endothelial growth factor has a critical role in maintaining tumor microvasculature and, as such, is an attractive target for anti-angiogenic therapy. Aberrant expression of VEGF receptors, especially VEGFR2, on epithelial tumor cells allows VEGF to stimulate growth and migration of tumor cells in an autocrine and/or paracrine manner. Therefore, we studied the expression of VEGF and VEGFR2 in bladder cancer, and the relationship to disease characteristics.Expression of VEGF and VEGFR2 was studied in a cohort of 72 patients with transitional cell cancer of the bladder. Tumor tissues from all patients were analyzed by immunohistochemistry and examined by a pathologist blinded to patient outcome. Patient demographics and disease outcome were correlated with expression of these markers. Bladder cancer cell lines that express VEGFR2 were studied in vitro and in vivo to establish the significance of VEGF/VEGFR2 signaling.Expression of VEGF and VEGFR2 was observed in 58% and 50% of urothelial tumor cells, respectively. VEGF expression failed to correlate with clinical variables. However, VEGFR2 expression correlated with disease stage (coefficient 0.23, p = 0.05). In addition, VEGFR2 expression increased with tumor invasion into the muscle (p <0.01). Experiments with VEGFR2 positive bladder cancer cell lines in vitro demonstrated increased invasion in response to VEGF. In addition, VEGF inhibition augmented the effect of docetaxel in a murine xenograft model of bladder cancer with a significant inhibition in proliferative index and microvascular density, and induction of apoptosis.Increased VEGFR2 expression correlates with several features that predict progression of urothelial cancer, including disease stage and invasive phenotype. VEGF targeted therapy may enhance the efficacy of standard therapy for bladder cancer.
Serum levels of angiogenic factors and their prognostic relevance in bladder cancer
2009
Angiogenesis plays a critical role in tumor growth. VEGF, angiopoietins (Ang-1, Ang-2) and their tyrosine kinase receptor Tie2 are major regulators of angiogenesis. The aim of this study was to evaluate the prognostic value of the serum levels of these factors in bladder cancer. We analyzed the serum samples of 117 bladder cancer patients and 64 healthy volunteers by enzyme linked immunosorbent assay (ELISA) for Ang-1, Ang-2, VEGF and the extracellular domain of Tie2. The statistical evaluation of the obtained data was performed via Kaplan-Meier log-rank test, univariate Cox analyses as well as Cox proportional hazards regression model. Serum Ang-1 levels of bladder cancer patients were significantly higher (p<0.001), while soluble Ang-2 and Tie2 levels were significantly lower (p=0.016 and p=0.001 respectively) in patients than those in controls. Cox univariate analysis revealed high sTie2 serum level as a risk factor for metastasis and as a borderline significant risk factor for disease related death (p=0.022 and p=0.081 respectively). These correlations were independent from tumor stage and grade in a Cox multivariate model (p=0.016 and p=0.069). These data indicate that the serum levels of analyzed angiogenic factors do change characteristically in bladder cancer. The soluble extracellular serum level of Tie2 may provide a stage and grade independent diagnostic tool to select a high risk group of bladder cancer patients. Keywords Bladder cancer . Serum . Angiopoietin . Tie2 . VEGF . Prognosis Abbreviations HR hazard ratio CI confidence interval TEM Tie2-expressing monocyte TCC transitional cell carcinoma Pathol. Oncol. Res.
Archives of Medical Research, 2011
Background and Aims. We proved the feasibility of radical transurethral resection in selected patients with muscle-invasive bladder cancer with a minimum follow-up of O5 years. A follow-up schedule was developed based on progression and recurrence during this period. Methods. The study included 93 patients with invasive bladder cancer treated by radical transurethral resection. Student t test was used for continuous variables to establish clinical progression predictive factors. VEGF-C protein expressions were tested by immunohistochemistry postsurgery.
Prognostic significance of angiogenesis in superficial bladder cancer
International Urology and Nephrology, 2004
Objective: To assess the prognostic significance of angiogenesis parameters such as microvessel density (MVD) and vascular endothelial growth factor (VEGF) in superficial bladder cancer. Patients and methods: We studied 127 superficial bladder cancer samples immunohistochemically for the above factors. We compared them with standard clinicopathological features (grade, stage, concurrent in situ, multifocality, primary or recurrent status) as well as with p53 expression, recurrence and progression to muscle infiltrating disease. Results: During a 36 months median follow up of 109 patients with superficial primary tumors (min. 3, max. 69 months), 80 of them recurred (73.4%), while 8 patients (7.3%) progressed to muscle invading disease. A significant correlation was noted between MVD and VEGF in all 127 samples (p = 0.019). No association was noted between MVD or VEGF with the other clinicopathological features, recurrence or progression. Although progression free survival rates of categorized microvessel density (up to and higher than median value) differed significantly only in grade 3 patients, no independent prognostic significance could be attributed to MVD. No correlation was observed between MVD or VEGF with p53 protein. Conclusions: Based on our data we suggest that VEGF is not useful for predicting recurrence or progression in superficial bladder cancer. Microvessel density determination may help to predict progression of grade 3 patients to muscle invasive disease but not as an independent prognostic factor.
Anticancer research
Vascular endothelial growth factor-C (VEGF-C) has been associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis and was reported to have an anti-apoptotic and proliferative role. An immunohistochemical study was applied to 123 specimens of bladder urothelial carcinoma (BUC) to detect VEGF-C and investigate its clinicopathological and prognostic value. VEGF-C-immunostained BUC specimens (123) were statistically correlated with histological grade and stage, patient overall survival and immuno-expression of Ki-67 and bax proteins. VEGF-C immunopositivity (27/123 BUCs, 22.0%) was inversely correlated with tumor stage and bax immunoexpression (p = 0.007 and p = 0.032, respectively). VEGF-C-positive BUCs tended to have better prognosis (univariate analysis). VEGF-C might be associated with an anti-apoptotic phenotype. Our controversial results regarding patient survival suggest that the role of VEGF-C in BUC progression and prognosis remains to be clarified.