scholarly journals Altered VEGF Splicing Isoform Balance in Tumor Endothelium Involves Activation of Splicing Factors Srpk1 and Srsf1 by the Wilms’ Tumor Suppressor Wt1

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 41 ◽  
Author(s):  
Kay-Dietrich Wagner ◽  
Mounir El Maï ◽  
Michael Ladomery ◽  
Tareg Belali ◽  
Nathalie Leccia ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Suppressor ◽  
Wilms Tumor ◽  
Splicing Factor ◽  
Normal Lung ◽  
Antiangiogenic Therapies ◽  
Tumor Endothelium ◽  
Tumor Types ◽  
Endothelial Growth Factor ◽  
Vegf Isoforms

Angiogenesis is one hallmark of cancer. Vascular endothelial growth factor (VEGF) is a known inducer of angiogenesis. Many patients benefit from antiangiogenic therapies, which however have limitations. Although VEGF is overexpressed in most tumors, different VEGF isoforms with distinct angiogenic properties are produced through alternative splicing. In podocytes, the Wilms’ tumor suppressor 1 (WT1) suppresses the Serine/arginine-rich protein-specific splicing factor kinase (SRPK1), and indirectly Serine/arginine-rich splicing factor 1 (Srsf1) activity, and alters VEGF splicing. We analyzed VEGF isoforms, Wt1, Srpk1, and Srsf1 in normal and tumor endothelium. Wt1, Srpk1, Srsf1, and the angiogenic VEGF164a isoform were highly expressed in tumor endothelium compared to normal lung endothelium. Nuclear expression of Srsf1 was detectable in the endothelium of various tumor types, but not in healthy tissues. Inducible conditional vessel-specific knockout of Wt1 reduced Wt1, Srpk1, and Srsf1 expression in endothelial cells and induced a shift towards the antiangiogenic VEGF120 isoform. Wt1(−KTS) directly binds and activates both the promoters of Srpk1 and Srsf1 in endothelial cells. In conclusion, Wt1 activates Srpk1 and Srsf1 and induces expression of angiogenic VEGF isoforms in tumor endothelium.

scholarly journals Isolation and Characterisation of Lymphatic Endothelial Cells from Lung Tissues Affected by Lymphangioleiomyomatosis

2021 ◽  
Author(s):  
Koichi Nishino ◽  
Yasuhiro Yoshimatsu ◽  
Tomoki Muramatsu ◽  
Yasuhito Sekimoto ◽  
Keiko Mitani ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Normal Lung ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
And Migration ◽  
Endothelial Growth Factor ◽  
Proliferation And Migration

Abstract Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.

scholarly journals An unexpected tail of VEGF and PlGF in pre-eclampsia

2011 ◽  
Vol 39 (6) ◽  
pp. 1576-1582 ◽  
Author(s):  
David O. Bates
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Endothelial Activation ◽  
Placental Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Physiological Changes ◽  
Vegf Family Members ◽  
Endothelial Growth Factor ◽  
Vegf Isoforms

PET (pre-eclamptic toxaemia), characterized by pregnancy-related hypertension and proteinuria, due to widespread endothelial dysfunction, is a primary cause of maternal morbidity. Altered circulating factors, particularly the VEGF (vascular endothelial growth factor) family of proteins and their receptors, are thought to be key contributors to this disease. Plasma from patients with PET induces numerous cellular and physiological changes in endothelial cells, indicating the presence of a circulating imbalance of the normal plasma constituents. These have been narrowed down to macromolecules of the VEGF family of proteins and receptors. It has been shown that responses of endothelial cells in intact vessels to plasma from patients with pre-eclampsia is VEGF-dependent. It has recently been shown that this may be specific to the VEGF165b isoform, and blocked by addition of recombinant human PlGF (placental growth factor). Taken together with results that show that sVEGFR1 (soluble VEGF receptor 1) levels are insufficient to bind VEGF-A in human plasma from patients with pre-eclampsia, and that other circulating macromolecules bind, but do not inactivate, VEGF-A, this suggests that novel hypotheses involving altered bioavailability of VEGF isoforms resulting from reduced or bound PlGF, or increased sVEGFR1 increasing biological activity of circulating plasma, could be tested. This suggests that knowing how to alter the balance of VEGF family members could prevent endothelial activation, and potentially some symptoms, of pre-eclampsia.

scholarly journals Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models

2020 ◽  
Vol 21 (4) ◽  
pp. 1388 ◽  
Author(s):  
Claudia Ceci ◽  
Maria Grazia Atzori ◽  
Pedro Miguel Lacal ◽  
Grazia Graziani
Keyword(s):  
Growth Factor ◽  
Immune Escape ◽  
Metastatic Cancer ◽  
Membrane Receptors ◽  
Pathological Angiogenesis ◽  
Tumor Endothelium ◽  
Vegf Family Members ◽  
Preclinical And Clinical Studies ◽  
Tumor Types ◽  
Endothelial Growth Factor

The vascular endothelial growth factor (VEGF) family members, VEGF-A, placenta growth factor (PlGF), and to a lesser extent VEGF-B, play an essential role in tumor-associated angiogenesis, tissue infiltration, and metastasis formation. Although VEGF-A can activate both VEGFR-1 and VEGFR-2 membrane receptors, PlGF and VEGF-B exclusively interact with VEGFR-1. Differently from VEGFR-2, which is involved both in physiological and pathological angiogenesis, in the adult VEGFR-1 is required only for pathological angiogenesis. Besides this role in tumor endothelium, ligand-mediated stimulation of VEGFR-1 expressed in tumor cells may directly induce cell chemotaxis and extracellular matrix invasion. Furthermore, VEGFR-1 activation in myeloid progenitors and tumor-associated macrophages favors cancer immune escape through the release of immunosuppressive cytokines. These properties have prompted a number of preclinical and clinical studies to analyze VEGFR-1 involvement in the metastatic process. The aim of the present review is to highlight the contribution of VEGFs/VEGFR-1 signaling in the progression of different tumor types and to provide an overview of the therapeutic approaches targeting VEGFR-1 currently under investigation.

SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases

2012 ◽  
Vol 40 (4) ◽  
pp. 831-835 ◽  
Author(s):  
Sebastian Oltean ◽  
Melissa Gammons ◽  
Richard Hulse ◽  
Maryam Hamdollah-Zadeh ◽  
Athina Mavrou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Splice Site ◽  
Splicing Factor ◽  
Vascular Endothelial ◽  
Terminal Exon ◽  
Disease States ◽  
Endothelial Growth Factor ◽  
Vegf Isoforms ◽  
Splicing Factor 1

SRPK1 (serine–arginine protein kinase 1) is a protein kinase that specifically phosphorylates proteins containing serine–arginine-rich domains. Its substrates include a family of SR proteins that are key regulators of mRNA AS (alternative splicing). VEGF (vascular endothelial growth factor), a principal angiogenesis factor contains an alternative 3′ splice site in the terminal exon that defines a family of isoforms with a different amino acid sequence at the C-terminal end, resulting in anti-angiogenic activity in the context of VEGF165-driven neovascularization. It has been shown recently in our laboratories that SRPK1 regulates the choice of this splice site through phosphorylation of the splicing factor SRSF1 (serine/arginine-rich splicing factor 1). The present review summarizes progress that has been made to understand how SRPK1 inhibition may be used to manipulate the balance of pro- and anti-angiogenic VEGF isoforms in animal models in vivo and therefore control abnormal angiogenesis and other pathophysiological processes in multiple disease states.

scholarly journals Isolation and characterisation of lymphatic endothelial cells from lung tissues affected by lymphangioleiomyomatosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Koichi Nishino ◽  
Yasuhiro Yoshimatsu ◽  
Tomoki Muramatsu ◽  
Yasuhito Sekimoto ◽  
Keiko Mitani ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Normal Lung ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
And Migration ◽  
Endothelial Growth Factor ◽  
Proliferation And Migration

AbstractLymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.

Cellular Localization of Enzymatically Active Thrombin in Intact Human Tissues by Hirudin Binding

1995 ◽  
Vol 73 (05) ◽  
pp. 793-797 ◽  
Author(s):  
Leo R Zacharski ◽  
Vincent A Memoli ◽  
William D Morain ◽  
Jean-Marc Schlaeppi ◽  
Sandra M Rousseau
Keyword(s):  
Tumor Cell ◽  
Cell Carcinoma ◽  
Cellular Localization ◽  
Thrombin Generation ◽  
Normal Lung ◽  
Cancer Tissue ◽  
Immunohistochemical Techniques ◽  
Tumor Types ◽  
Negative Controls

SummaryCellular sites of coagulation activation within complex, intact tissues have been studied by immunohistochemical techniques. Hirudin, a specific and high affinity inihibitor of the active site of thrombin, together with antibody to hirudin were applied to sections of AMeX-fixed specimens of normal lung, kidney, placenta, freshly incised skin and unperturbed skin obtained at fresh autopsy; to rheumatoid synovial tissue; and to malignant tissue from a variety of tumor types. Staining for thrombin was observed selectively on pulmonary alveolar, rheumatoid synovial, and placental macrophages that express an intact extrinsic coagulation pathway. Staining was also observed restricted to the endothelium of capillaries in freshly incised skin but not in either unperturbed skin or in aged incisions. Staining of tumor cell bodies was observed in small cell carcinoma of the lung, renal cell carcinoma, and malignant melanoma tissues that we found previously to show tumor cell-associated procoagulant activity. This staining occurred commonly on cells within the tumor mass that were distant from stromal fibrinogen/fibrin. By contrast, tumor-associated macrophage but not tumor cell staining was seen in adenocarcinoma and squamous cell carcinoma of the lung, and little or no staining was seen in colon cancer tissue. Negative controls in which either the hirudin probe or its antibody were omitted failed to show staining. These results are in accord with previous findings and suggest that such techniques may be useful for studying the cellular sites of thrombin generation in intact tissues. We postulate that administration of potent and specific thrombin antagonists, such as hirudin, to patients with relevant tumor types might be followed by homing of hirudin to tumor cells in vivo so that effects of local thrombin generation on malignant progression can be determined.

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