scholarly journals Reversal of vasohibin-driven negative feedback loop of vascular endothelial growth factor/angiogenesis axis promises a novel antifibrotic therapeutic strategy for liver diseases

Hepatology ◽  
2014 ◽  
Vol 60 (2) ◽  
pp. 458-460 ◽  
Author(s):  
Suvro Chatterjee
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Negative Feedback ◽  
Liver Diseases ◽  
Feedback Loop ◽  
Therapeutic Strategy ◽  
Negative Feedback Loop ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Vascular Endothelial Growth Factor (VEGF) Acts Via Auto- and Paracrine Mechanisms as a Critical Microenvironmental Factor for the Survival of Chronic Lymphocytic Leukemia (CLL) Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4376-4376
Author(s):  
Iris Gehrke ◽  
Julian Paesler ◽  
Rajesh Kumar Gandhirajan ◽  
Regina Razavi ◽  
Simon Jonas Poll-Wolbeck ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
B Cells ◽  
Growth Factor ◽  
Feedback Loop ◽  
Stromal Cell ◽  
Lymphocytic Leukemia ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Abstract Abstract 4376 The major pathophysiological characteristic of chronic lymphocytic leukemia (CLL) is the accumulation of malignant, immuno-incomptetent B-cells, which is commonly known as the apoptotic block. Recently, it was speculated that vascular endothelial growth factor (VEGF) might be involved in this process. Whereas most of the available studies are solely descriptive, functional data are largely missing. The aim of this study was therefore to describe the effect and functional background of VEGF on CLL cells for the identification of potential strategies for a targeted CLL therapy. We identified an autocrine VEGF feedback loop in CLL cells, but not healthy B-cells. Recombinant human (rh) VEGF stimulation lead to increased expression of the anti-apoptotic proteins Mcl1 and XIAP, but was not sufficient to prolong survival. When CLL cells were cocultured with the bone marrow derived stromal cell line HS5, survival was significantly enhanced 28.5 ± 6.5% after 72h relative to monoculture, whereas healthy B-cells did not profit from coculture (-0.5 ± 4.7%). HS5 cells produce and secrete high amounts of VEGF themselves. When cocultured with HS5 CLL cells also showed an increased VEGF expression, indicating the existence of a paracrine VEGF feedback loop. The actual relevance of VEGF in the coculture mediated survival support was proofed by siRNA experiments. When VEGF expression and secretion was downregulated in HS5 cell by siRNA, the survival advantage CLL cells obtained from the coculture was reduced down to that in monoculture. Also the addition of a VEGF-neutralizing monoclonal antibody largely reversed the survival supporting effect of the coculture, clearly indicating the critical role of VEGF in bone marrow stromal cell-mediated CLL cell survival. We further found rhVEGF to induce upregulation and activation of STAT3 via Tyr705-phosphorylation and a subsequent expression of STAT3 targets such as Cyclin D1 and BclXL. VEGF-stimulation further induced downregulation of the tumor suppressor RB1 and E2F1, which act as proapoptotic factors. Vice versa inhibition of VEGF by using selective VEGF-R inhibitors reduced both, Tyr705 phosphorylation and expression of STAT3 target genes. We therefore, propose a dual mechanism of VEGF-mediated CLL cell survival support via upregulation of the potent oncogene STAT3 and downregulation of the tumor suppressor RB1/E2F1. Hence, VEGF might function as a potential new therapeutic target to overcome the apoptotic block in CLL cells. Disclosures: Hallek: BayerScheringAG: Honoraria, Research Funding.

scholarly journals Detection of Autoantibodies to Vascular Endothelial Growth Factor Receptor-3 in Bile Duct Ligated Rats and Correlations with a Panel of Traditional Markers of Liver Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Florent Duval ◽  
Delia Elva Cruz-Vega ◽  
Ivonne González-Gamboa ◽  
María Teresa González-Garza ◽  
Fernando Ponz ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Bile Duct ◽  
Liver Diseases ◽  
Total Bilirubin ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Duct Ligation ◽  
Endothelial Growth Factor

There is a need for new noninvasive biomarkers (NIBMs) able to assess cholestasis and fibrosis in chronic cholestatic liver diseases (CCLDs). Tumorigenesis can arise from CCLDs. Therefore, autoantibodies to tumor-associated antigens (TAA) may be early produced in response to abnormal self-antigen expression caused by cholestatic injury. Vascular endothelial growth factor receptor-3 (VEGFR-3) has TAA potential since it is involved in cholangiocytes and lymphatic vessels proliferations during CCLDs. This study aims to detect autoantibodies directed at VEGFR-3 during bile duct ligation- (BDL-) induced cholestatic injury in rat sera and investigate whether they could be associated with traditional markers of liver damage, cholestasis, and fibrosis. An ELISA was performed to detect anti-VEGFR-3 autoantibodies in sera of rats with different degree of liver injury and results were correlated with aminotransferases, total bilirubin, and the relative fibrotic area. Mean absorbances of anti-VEGFR-3 autoantibodies were significantly increased from week one to week five after BDL. The highest correlation was observed with total bilirubin (R2= 0.8450,P=3.04e-12). In conclusion, anti-VEGFR-3 autoantibodies are early produced during BDL-induced cholestatic injury, and they are closely related to cholestasis, suggesting the potential of anti-VEGFR-3 autoantibodies as NIBMs of cholestasis in CCLDs and justifying the need for further investigations in patients with CCLD.

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