Serum levels of angiogenic factors and their prognostic relevance in bladder cancer (original) (raw)
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Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer
Clinical Cancer Research, 2008
Purpose: Vascular endothelial growth factor (VEGF), angiopoietins (Ang-1and Ang-2), and their receptor Tie2 are critically involved in both normal and pathologic angiogenesis. The aim of this study was to explore the role of Ang-1, Ang-2,VEGF, andTie2 in the development and progression of bladder cancer as well as to examine their prognostic value in this tumor type. Experimental Design:Tumor samples of 113 bladder cancer patients, normal bladder epithelium of 5 noncancer patients, and two low-grade (UMUC3 and RT4) and two high-grade (J82 and T24) bladder cancer cell lines were analyzed by quantitative real-time PCR. The expression data were analyzed performing Wilcoxon rank-sum and Kaplan-Meier log-rank tests as well as univariate Cox analyses and Cox proportional hazards regression model. Results: In tissues of noninvasive bladder tumors, Ang-1 expression was significantly lower (P < 0.001), whereasVEGF expression was significantly higher (P = 0.031) than in normal bladder tissue. These findings were also confirmed at the protein level by immunohistochemistry. In contrast, Tie2 and Ang-2 abundance in tumor did not differ significantly from that in normal bladder tissue. Multivariate analysis identified Ang-2 as a strong and independent predictor of tumor recurrence [hazard ratio (HR), 10.18; 95% confidence interval (95% CI), 2.69-38.49; P < 0.001] andTie2 expression as an independent favorable prognostic factor for both metastasis (HR, 0.31; 95% CI, 0.11-0.89; P = 0.029) and disease-specific survival (HR, 0.25; 95% CI, 0.10-0.62; P = 0.003). Conclusions: These data show the strongest change in expression of VEGF and Ang-1 in superficial bladder cancer in comparison with normal bladder epithelium and the invasive tumor stages. The prognostic significance of Ang-2 and Tie2 underlines the essential role of angiopoietins-Tie2 system in progression of bladder cancer. 7 http://cancertrials.nci.nih.gov
European Urology, 2009
Background: Actors of the angiogenesis pathways are targets for the new promising targeted therapies already used in several malignancies. In bladder cancer, antiangiogenic molecules could also add to already existing treatment options. Objective: To evaluate the involvement of angiogenesis pathways in bladder carcinogenesis and identify new molecular markers having a clinical implication. Design, setting, and participants: Expression levels of 40 genes involved in angiogenesis were assessed by quantitative real time RT-PCR in 157 urothelial tumour bladder samples obtained from patients who underwent transurethral bladder resection or radical cystectomy between 2001 and 2005. Pathologic tumour staging showed: 73 nonmuscle-invasive bladder tumours (30 low-grade pTa, 14 high-grade pTa, and 29 highgrade pT1), and 84 muscle-invasive tumours (! pT2), all of high grade. RT-PCR results were associated with a survival analysis. Results and limitations: VEGFA, MET, CXCR4, and IL8 were significantly overexpressed in tumour samples as compared to normal bladder tissue. VEGFA overexpressions were found in 89% of non-muscle-invasive and 66% of muscle-invasive tumour samples. In univariate analysis, for invasive tumours, VEGFA overexpression was associated with a poorer outcome in both overall and disease-free survival ( p = 0.011 and 0.026 respectively) at a 13-mo median follow-up. Multivariate analysis retained T stage, N status, and VEGFA overexpression as independent prognostic factors in both overall and disease-free survival ( p = 0.02 and p = 0.04, respectively, for VEGFA).
International Journal of Molecular Sciences, 2012
Background: Gastro-entero-pancreatic/neuroendocrine (NET) tumors are highly vascularized neoplasms. However, our knowledge concerning circulating levels of the angiogenic factors in NET patients still remains insufficient. Methods: The aim of this study was to measure plasma concentrations of VEGF, angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), soluble Tie-2, endostatin, osteopontin (OPN) and chromogranin A (CgA) in 36 NET patients and 16 controls. Results: Only the plasma concentrations of Tie-2 and CgA were higher in NET patients as compared to controls. These levels were within the reference range in controls; however one control demonstrated slightly elevated Tie-2 and 4 elevated CgA. Similarly, in the subgroup of patients with carcinoid syndrome, only Tie-2 and CgA concentrations were higher than those in patients with non-functioning NETs. In turn, in the subgroup of metastatic patients, only Ang-2 levels were higher than in those with localized disease. A positive correlation was found between Ang-2 and Tie-2 levels in metastatic patients and between Ang-1 and Tie-2 in localized NETs. Conclusions: The plasma concentration of Tie-2 is proposed as an additional marker for NET patients OPEN ACCESS plasma levels of Ang-2 together with the positive correlation between Ang-2 and Tie-2 levels in metastatic subjects, implies that cases with a Tie-2 level above the upper limits, together with higher level of Ang-2 seem to be highly predictive of metastases.
Novel angiogenesis markers as long-term prognostic factors in renal cell cancer patients
Clinical Genitourinary Cancer, 2017
Objective • To evaluate Ang-2 expression alone and in combination with expression of cell proliferation and cell survival markers (MIB-1 and Bcl-2) and angiogenesis markers (VEGFR3 and CD31), and the associations of these markers with renal cell cancer (RCC) patients' long-term survival. Patients and methods • Our study included 224 RCC patients who were treated before of the availability of anti-angiogenic agents between 1985 and 1995, at the Pirkanmaa Hospital District in Finland. • All tumor samples were reclassified and re-evaluated by an experienced uropathologist, and parallel tissue microarrays (TMA) were performed for immunohistochemical analysis. • Kaplan-Meier's survival estimation method and Cox proportional hazard models were used for survival analysis. Results • The percentage of Ang-2 expression in the tumor area varied from 0.07 to 25.65. • Ang-2 expression was significantly associated with the tumor grade and stage, as well as the MIB-1, Bcl-2 and VEGFR3 expression (p=0.042, p=0.018, p=0.039, p=0.013 and p=0.005, respectively). • The highest Ang-2 expression predicted better survival, p<0.05. • High Bcl-2 and low MIB-1 expression combined with Ang-2 expression associated with better survival. • Multivariate analysis showed poorer survival in patients with low Ang-2 or high MIB-1 expressions; HR 2.24, 95% CI [1.28-3.90] p=0.005 and HR 2.20, 95% CI [1.36-3.54] p=0.001, respectively. Conclusions • Very high Ang-2 expression was associated with better survival in RCC patients. Ang-2 expression correlated with tumor stage and grade, but it was still an independent prognostic factor in a multivariate analysis.
The diagnostic and prognostic value of tumor angiogenesis
European Journal of Surgery, 2003
The "angiogenic switch" and tumor angiogenesis play a critical role in the growth and metastasis of solid tumors. Tumor angiogenesis is regulated by a balance of stimulators (e.g., VEGF, bFGF) and inhibitors of angiogenesis (e.g., angiostatin, endostatin, angiostatic steroids). Measuring angiogenesis (blood vessel density) and/or its main regulators such as VEGF and bFGF in solid tumors, or the levels of these growth factors in the serum or urine provides new and sensitive markers for tumor progression, metastasis and prognosis.
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.
Quantification of angiogenesis as a prognostic marker in human carcinomas
European Journal of Cancer, 2003
Chalkley counts have been suggested as the primary method for immunohistochemical evaluation of angiogenesis, however, most studies have used microvessel density (MVD). We present paired Chalkley and MVD estimates in carcinomas of the prostate, breast, bladder and lung. The clinical data has previously been reported. In prostate carcinomas, high MVD indicated poor prognosis, whereas high Chalkley counts in breast carcinoma were associated with a poor prognosis. In bladder carcinoma, high estimates using both methods showed good prognosis and were associated with a high degree of inflammation. Neither of the counts revealed prognostic value in lung carcinomas, where the vascular pattern indicated that this cancer was non-angiogenic. We highlight methodological problems with both counting methods. Since angiogenic processes in lung and bladder cancers may be different from those occuring in prostate cancer, we suggest that future analyses also focus on measuring angiogenic factors to obtain more information on the biology of angiogenesis. #
International Journal of Oncology, 2005
The degree of angiogenesis in breast cancer has previously been shown to be an indicator of prognosis, and tumor microvasculature is a candidate target for new antiangiogenic therapies. The aim of this study was to investigate the prognostic value of vascular endothelial growth factor (VEGF) receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and Tie2/tek receptor tyrosine kinase in breast carcinoma. VEGF receptors and Tie2 expression was investigated using immunohistochemical assays with monoclonal antibodies on frozen sections in a series of 918 and 909 patients respectively. VEGFR-1 and VEGFR-2 and Tie2 were correlated with long-term (median, 11.3 years) patients' outcome. Univariate (Kaplan-Meier) analysis showed that VEGFR-1 positive tumor surface (cutoff = 5%) was significantly correlated with high metastasis risk (p=0.03) and relapse (p<0.01) in all patients, and in those with node negative tumors (p<0.001 and p<0.01 respectively), but not with overall survival. ...