Association of Angiopoietin-2 and Ki-67 Expression with Vascular Density and Sunitinib Response in Metastatic Renal Cell Carcinoma (original) (raw)
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Acta oncologica (Stockholm, Sweden), 2018
Clear-cell renal cell carcinomas (ccRCC) are characterized by hyper-vascularization and can respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. We aimed to study the predictive value of the expression of genes in the hypoxia induced factor (HIF) - vascular endothelial growth factor (VEGF) - VEGFR-pro-angiogenic pathway in metastatic ccRCC (m-ccRCC) patients treated with sunitinib and the correlation between the expression of these genes and the molecular ccrcc-classification, the expression of genes involved in the immune-suppressive microenvironment and Von Hippel-Lindau (VHL) - and Polybromo-1 (PBRM1) - mutational status. m-ccRCC patients treated with sunitinib as first-line targeted therapy were included. Gene expression was studied in the primary nephrectomy sample by qRT-PCR, VHL- and PBRM1-mutational status by sequencing. Response rate by RECIST, progression-free survival (PFS) and overall survival (OS) were study endpoints. One hundred...
International journal of oncology, 2009
Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signaling in tumors induces remodeling in surviving vessels, and link increased expression of angiopoietin-1 (Ang-1) with this process. However, overexpression of Ang-1 in different tumors has yielded divergent results, restricting angiogenesis in some systems while promoting it in others. These data raise the possibility that effects of Ang-1/Tie-2 may be context-dependent. Expression of an Ang-1 construct (Ang1*) did not significantly change tumor growth in our model prior to treatment, although vess...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018
The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in metastatic renal-cell carcinoma (mRCC) patients. This French multicentre, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS). Thirty-two patients were enrolled. Median PFS was 4.5 months and median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; =0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ³10% decrease in PRT size. Baseline biomarkers significantly ...
British journal of cancer, 2013
We aimed to study key signalling proteins involved in angiogenesis and proliferation on the response to inhibitors of tyrosine kinases and mammalian target of rapamycin in first- and in second-line treatment of renal cell carcinoma (RCC). In a panel of human RCC tumours, in vitro and in nude mice, we evaluated the effect of sunitinib, sorafenib and everolimus, alone and in sequence, on tumour growth and expression of signalling proteins involved in proliferation and resistance to treatment. We demonstrated that, as single agents, sunitinib, sorafenib and everolimus share similar activity in inhibiting cell proliferation, signal transduction and vascular endothelial growth factor (VEGF) secretion in different RCC models, both in vitro and in tumour xenografts. Pre-treatment with sunitinib reduced the response to subsequent sunitinib and sorafenib but not to everolimus. Inability by sunitinib to persistently inhibit HIF-1, VEGF and pMAPK anticipated treatment resistance in xenografted...
ANALYTICAL AND QUANTITATIVE CYTOPATHOLOGY AND HISTOPATHOLOGY, 2018
Objective: To investigate the correlation between the expression of vascular epidermal growth factor (VEGF), angiotensin II (Ang II), and the therapeutic effect of VEGF inhibitor sunitinib in clear cell renal cell carcinoma (ccRCC). Study Design: Expression levels of VEGF and Ang II were assessed in 40 patients with ccRCC by immunohistochemistry (IHC). Their associations with cancer clinical variables were further analyzed. The therapeutic efficacy of VEGF inhibitor sunitinib in ccRCC was also investigated. Statistical analysis was conducted using SPSS 19.0 software. Results: The IHC results showed that both VEGF and Ang II were overexpressed in ccRCC and were associated with tumor differentiation and lymph node metastasis. No significant associations were detected in other clinical features such as gender, age, and tumor volume, etc. The effective rate of sunitinib in treating ccRCC was 85.7%—significantly higher than that of the control group. Moreover, its adverse effects rate was relatively low. Conclusion: VEGF and Ang II, whose expressions were closely related to tumorigenesis and progression of ccRCC, could promote tumor growth together. VEGF may serve as a predictive factor for sunitinib in the therapeutic effect of ccRCC.
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
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.
British Journal of Cancer
BACKGROUND: Vascular endothelial (VE)-cadherin is an endothelial cell-specific protein responsible for endothelium integrity. Its adhesive properties are regulated by post-translational processing, such as tyrosine phosphorylation at site Y 685 in its cytoplasmic domain, and cleavage of its extracellular domain (sVE). In hormone-refractory metastatic breast cancer, we recently demonstrated that sVE levels correlate to poor survival. In the present study, we determine whether kidney cancer therapies had an effect on VEcadherin structural modifications and their clinical interest to monitor patient outcome. METHODS: The effects of kidney cancer biotherapies were tested on an endothelial monolayer model mimicking the endothelium lining blood vessels and on a homotypic and heterotypic 3D cell model mimicking tumour growth. sVE was quantified by ELISA in renal cell carcinoma patients initiating sunitinib (48 patients) or bevacizumab (83 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). RESULTS: Human VE-cadherin is a direct target for sunitinib which inhibits its VEGF-induced phosphorylation and cleavage on endothelial monolayer and endothelial cell migration in the 3D model. The tumour cell environment modulates VE-cadherin functions through MMPs and VEGF. We demonstrate the presence of soluble VE-cadherin in the sera of mRCC patients (n = 131) which level at baseline, is higher than in a healthy donor group (n = 96). Analysis of sVE level after 4 weeks of treatment showed that a decrease in sVE level discriminates the responders vs. non-responders to sunitinib, but not bevacizumab. CONCLUSIONS: These data highlight the interest for the sVE bioassay in future follow-up of cancer patients treated with targeted therapies such as tyrosine-kinase inhibitors.
BMC Cancer, 2009
Background: Sunitinib is a protein tyrosine kinase-inhibitor targeting VEGFR, c-kit and PDGFR. It has been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumors. Although it has been shown to prolong disease-free and overall survival in renalcell carcinoma patients, only 70% of the treated population receive a clinical benefit (CB) from the treatment. Markers that could predict clinical benefit to sunitinib would be an important aid in monitoring and following their treatment. We assessed the outcome and plasma proangiogenic factors in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib in our institution.