Browsing by Subject "Vascular Endothelial Growth Factor A"
Now showing 1 - 7 of 7
- Results Per Page
- Sort Options
Item Anti-VEGF Induced Reduction in Microvessel Density Does Not Correlate with Anti-Tumor Repsonse in Lung Cancer Xenografts(2013-01-22) Jacob, Antonia J.; Sullivan, Laura A.; Toombs, Jason E.; Minna, John D.; Brekken, Rolf A.Vascular endothelial growth factor-A (VEGF) is a primary stimulant of angiogenesis in pathological conditions including tumor progression. Strategies to block VEGF activity prevent or slow tumor growth in preclinical settings; however, clinical studies with bevacizumab, a monoclonal antibody (mAb) specific for VEGF have resulted in only modest benefit to a subset of patients with lung cancer. Previous studies in our laboratory defined the therapeutic efficacy of bevacizumab and an alternative anti-VEGF mAb (r84) in 12 non-small cell lung cancer (NSCLC) xenografts. Three NSCLC xenografts (Calu-6, A549 and Calu-3) showed intrinsic resistance to bevacizumab therapy. In the present study we evaluated whether microvessel density (MVD) could be used to 1) demonstrate if the anti-VEGF mAbs were effective at reducing VEGF-driven angiogenesis and 2) if MVD changes induced by bevacizumab or r84 correlated with overall therapeutic efficacy as determined by tumor size after chronic therapy. 3-5 tumors from animals bearing NSCLC xenografts treated with a control mAb (XTLl, bevacizumab or r84 were evaluated by immunohistochemistry for endothelial cells as a measure of microvessel density. Two independent endothelial cell markers were used, endomucin and CD31. In 11 of the 12 xenografts treatment with bevaclzumab or r84 significantly reduced MVD compared to XTL treatment, suggesting that bevacizumab and r84 do reduce VEGF-driven angiogenesis. However, the reduction in MVD induced by anti-VEGF therapy did not correlate with overall tumor response to therapy. These results strongly implicate resistance to anti-VEGF therapy is not mediated by activation af alternative angiogenic programs to compensate for VEGF blockade. Further the results suggest that tumor cell adaptation to therapy-induced hypoxia underlies poor therapeutic response to anti-VEGF strategies. Microarray of gene expression analysis of control treated tumors revealed several genes associated with metabolism, proliferation, and metastasis were significantly increased in tumors that displayed intrinsic resistant to bevacizumab. We conclude that response of tumor cells to therapy-induced hypoxia is a critical feature that drives the overall efficacy of anti-VEGF strategies.Item The Immunosuppressive Function of VEGF Signaling in the Tumor Microenvironment(December 2021) Zhang, Yuqing; Aguilera, Todd A.; Brekken, Rolf A.; Castrillon, Diego H.; Dellinger, Michael T.Angiogenesis, a hallmark of cancer, is induced by vascular endothelial growth factor-A (VEGF). As a result, anti-VEGF therapy is commonly employed for cancer treatment. However, anti-VEGF therapy generally provides modest efficacy in cancer patients and therapy-induced hypoxia results in a less differentiated mesenchymal-like tumor cell phenotype, which reinforces the need for effective companion therapies. Cyclooxygenase-2 (COX-2) inhibition has been shown to promote tumor cell differentiation and improve standard therapy response in pancreatic cancer. Here, I evaluate the efficacy of COX-2 inhibition and VEGF blockade in preclinical models of pancreatic cancer and identity it as a strategy to overcome therapy-induced resistance in pancreatic cancer. Combination therapy reverses anti-VEGF-induced epithelial-mesenchymal transition, collagen deposition and promotes an immune stimulatory microenvironment. Recent studies have also found that VEGF expression is also associated with immune suppression in cancer patients. This connection has been investigated in preclinical and clinical studies by evaluating the therapeutic effect of combining anti-angiogenic reagents with immune therapy. However, the mechanisms of how anti-VEGF strategies enhance immune therapy are not fully understood. We and others have shown selective elevation of VEGFR2 expression on tumor-associated myeloid cells in tumor-bearing animals. I further investigate the function of VEGFR2+ myeloid cells in regulating tumor immunity and find VEGF induces an immunosuppressive phenotype in VEGFR2+ myeloid cells including directly upregulating the expression of programmed cell death 1-ligand 1 (PD-L1). Moreover, I demonstrate that VEGF blockade inhibits the immunosuppressive phenotype of VEGFR2+ myeloid cells, increases T cell activation and enhances the efficacy of immune checkpoint blockade. These studies highlight the function of VEGFR2 on myeloid cells and provide mechanistic insight on how VEGF inhibition potentiates immune checkpoint blockade.Item In Cell Stress Conditions, VEGFR2 Exerts Pronounced Effects on Cell Growth in Dysplastic Barrett's Epithelial Cells(2015-01-26) Belli, Olivia; Zhang, Qiuyang; Souza, Rhonda F.BACKGROUND & AIMS: Vascular endothelial growth factor (VEGF), a potent inducer of angiogenesis, recently has been shown to exert direct pro-proliferative and pro-survival effects on cancer cells through binding to its receptors, VEGFR1 and VEGFR2. In earlier studies, we showed that VEGF/VEGFR2 signaling exerts direct pro-proliferative effects on transformed Barrett's and adenocarcinoma cells in an autocrine fashion, with no significant effects on apoptosis. To explore the potential contribution of VEGFR signaling to cell growth of dysplastic Barrett's cells, we knocked down the VEGFR1 or VEGFR2 and studied the effects on cell morphology, cell number, proliferation, and apoptosis. METHODS: We used 3 high-grade dysplastic Barrett's epithelial cell lines (CP-B, CP-C, and CP-D). VEGFR1 and VEGFR2 were knocked down through stable infection with retroviral shRNA vectors. Knockdown was assessed through qRT-PCR for VEGFR1 and Western blot for VEGFR2. Cell morphology was assessed by optic microscopy. Cell numbers were assessed by cell counts at 48 hours in full growth media (FM) and under cell stress conditions (1% FM); proliferation was assessed by BrdU incorporation and apoptosis was assessed by a cell death Elisa in 1%FM. RESULTS: Knockdown of VEGFR1 was seen in 34% of CP-C, 22% of CP-D, and 0% of CP-B. Thus, we used CP-C only to assess effects of VEGFR1 knockdown. By Western blotting, we observed knockdown of VEGFR2 in CP-B and in CP-D, but not in CP-C. Thus, we used CP-B and CP-D to assess effects of VEGFR2 knockdown. We did not observed any morphology changes in the VEGFR knockdown cell lines compared to controls. In FM, dysplastic cells containing either VEGFR1 or VEGFR2 knockdown had higher cell numbers compared to control cells. In 1%FM, there was no significant difference in cell number between CP-C cells containing VEGFR1 knockdown and controls. In contrast, at 48 hours in 1%FM, CP-B and CP-D containing VEGFR2 knockdown had lower cell numbers (19.9 ± 1.3 X 104 and 10.5± 1.4 cells, respectively) compared to controls (41.4 ± 4.4 and 16.9 ± 1.6 cells). Compared to controls, VEGFR2 knockdown significantly increased BrdU incorporation in CP-B cells, even though overall cell number was decreased, whereas in CP-D, BrdU incorporation was decreased (p=0.059) along with overall cell number. Compared to controls, VEGFR2 knockdown increased apoptosis in CP-B and CP-D cells. CONCLUSIONS: VEGFR2, but not VEGFR1, contributes to cell growth of dysplastic Barrett's cells, but only under conditions of cell stress, with both pro-survival and pro-proliferative effects. These findings support a potential role for anti-VEGFR2 therapies in the treatment of high grade dysplasia in Barrett's esophagus.Item [Southwestern News](2001-08-17) Genusa, AngelaItem Targeted therapy 101: a primer for clinicians(2008-12-05) Gerber, David E.Item Targeted therapy: what does the internist really need to know?(2017-09-29) Dowell, Jonathan E.Item [UT Southwestern Medical Center News](2007-01-08) Heinzl, Toni