scholarly journals Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

2013 ◽  
Vol 210 (3) ◽  
pp. 563-579 ◽  
Author(s):  
Charlotte Anderberg ◽  
Sara I. Cunha ◽  
Zhenhua Zhai ◽  
Eliane Cortez ◽  
Evangelia Pardali ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Tumor Vasculature ◽  
Vascular Endothelial ◽  
Mesenchymal Transition ◽  
Multiple Tumor ◽  
Unknown Significance ◽  
Endothelial To Mesenchymal Transition ◽  
Endothelial Growth Factor ◽  
Deficient Mice

Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.

scholarly journals Vascular Endothelial Growth Factor Prevents Endothelial-to-Mesenchymal Transition in Hypertrophy

2017 ◽  
Vol 104 (3) ◽  
pp. 932-939 ◽  
Author(s):  
Ben M.-W. Illigens ◽  
Alejandra Casar Berazaluce ◽  
Dimitrios Poutias ◽  
Robert Gasser ◽  
Pedro J. del Nido ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Endothelial Growth Factor

Effects of Rapamycin on the Epithelial-to-mesenchymal Transition of Human Peritoneal Mesothelial Cells

2005 ◽  
Vol 28 (2) ◽  
pp. 164-169 ◽  
Author(s):  
A. Aguilera ◽  
L.S. Aroeira ◽  
M. Ramírez-Huesca ◽  
M.L. Pérez-Lozano ◽  
A. Cirugeda ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Mesothelial Cells ◽  
Vascular Endothelial ◽  
Term Survival ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Human Peritoneal Mesothelial Cells ◽  
Endothelial Growth Factor ◽  
E Cadherin

The preservation of the peritoneal membrane is crucial for long-term survival in peritoneal dialysis. Epithelial-to-mesenchymal transition (EMT) is a process demonstrated in mesothelial cells (MC), responsible for negative peritoneal changes and directly related to PD. EMT enables neovascularization and fibrogenic capabilities in MC. Vascular endothelial growth factor (VEGF) is the mediator for neo-vascularization. Rapamycin is a potent immunosuppressor with antifibrotic action in renal allografts and has a demonstrated anti-VEGF effect. We performed this study with the hypothesis that rapamycin may regulate the EMT of MC. MC from human omentum were cultured. When mesothelial cells reached confluence, some of them were stimulated with r-TGF-ß (1 ng/mL) to induce EMT, co-administered with rapamycin (0.2, 2, 4, 20 and 40 nM). Other groups of cells received similar doses of rapamycin or r-TGF-ß, separately. Cells were analyzed at 6, 24, 48 hours and 7 days. As markers of EMT we included α-SMA, E-cadherin and snail nuclear factor by quantitative RT-PCR. EMT markers and regulators demonstrated the following changes with rapamycin: E-cadherin (a protective gene for EMT) increased 2.5-fold relative to controls under 40 nM, at 24h. Importantly, rapamycin inhibited snail expression induced by TGF-ß at 6h, whereas TGF-ß increased snail 10fold. At day 7, rapamycin showed no anti-EMT properties. An important decrease in α-SMA expression by MC after rapamycin addition was observed. In conclusion, rapamycin shows a mild protective effect on EMT, as it increases E-cadherin and decreases α-SMA expression. Consequently, rapamycin might partially regulate the epithelial-to-mesenchymal transition of mesothelial cells.

scholarly journals Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

2016 ◽  
Vol 310 (11) ◽  
pp. L1185-L1198 ◽  
Author(s):  
Toshio Suzuki ◽  
Yuji Tada ◽  
Rintaro Nishimura ◽  
Takeshi Kawasaki ◽  
Ayumi Sekine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Vascular Endothelial Cells ◽  
Repair Process ◽  
Vascular Endothelial ◽  
Mesenchymal Transition ◽  
Oxidase Inhibition ◽  
Endothelial To Mesenchymal Transition

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c- kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

scholarly journals Vascular endothelial growth factor selectively targets boronated dendrimers to tumor vasculature

2005 ◽  
Vol 4 (9) ◽  
pp. 1423-1429 ◽  
Author(s):  
Marina V. Backer ◽  
Timur I. Gaynutdinov ◽  
Vimal Patel ◽  
Achintya K. Bandyopadhyaya ◽  
B.T.S. Thirumamagal ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Vasculature ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

scholarly journals Immunohistochemical evaluation for P53 and VEGF (Vascular Endothelial Growth Factor) is not prognostic for long term survival in end stage esophageal adenocarcinoma

2009 ◽  
Vol 36 (1) ◽  
pp. 24-34 ◽  
Author(s):  
Leandro Totti Cavazzola ◽  
André Ricardo Pereira da Rosa ◽  
Carlos Cauduro Schirmer ◽  
Richard Ricachenevski Gurski ◽  
João Pedro Bueno Telles ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Curative Resection ◽  
P53 Protein ◽  
Vascular Endothelial ◽  
Clinicopathological Factors ◽  
Term Survival ◽  
Long Term Survival ◽  
End Stage ◽  
Endothelial Growth Factor

OBJECTIVES: To correlate the expression of p53 protein and VEGF with the prognosis of patients submitted to curative resection to treat esophageal adenocarcinoma. METHODS: Forty-six patients with esophageal adenocarcinoma, submitted to curative resection, were studied. The expressions of p53 protein and VEGF were assessed by immunohistochemistry in 52.2% and 47.8% of tumors, respectively. RESULTS: P53 protein and VEGF expressions coincided in 26% of the cases, and no correlation between these expressions was observed. None of the clinicopathological factors showed a significant correlation with p53 protein or VEGF expressions. There was no significant association between p53 protein and VEGF expressions and long-term survival. CONCLUSION: The expression of p53 protein and VEGF did not correlate with prognosis in esophageal adenocarcinoma patients submitted to curative resection.

scholarly journals Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 210
Author(s):  
Silvia Graziani ◽  
Luca Scorrano ◽  
Giovanna Pontarin
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Protein Synthesis ◽  
Growth Factor ◽  
Drug Withdrawal ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
P53 Expression ◽  
Endothelial Growth Factor

Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how transient exposure to Dox leads to long-term downregulation of Endothelial Vascular Endothelial Growth Factor Receptor type2 (VEGFR2), essential for endothelial cells function. Using an in vitro model devised to study the long-lasting effects of brief endothelial cells exposure to Dox, we show that Dox leads to sustained protein synthesis inhibition and VEGFR2 downregulation. Transient Dox treatment led to the development of long-term senescence associated with a reduction in VEGFR2 levels that persisted days after drug withdrawal. By analyzing VEGFR2 turnover, we ruled out that its downregulation was depended on Dox-induced autophagy. Conversely, Dox induced p53 expression, reduced mTOR-dependent translation, and inhibited global protein synthesis. Our data contribute to a mechanistic basis to the permanent damage caused to endothelial cells by short-term Dox treatment.

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