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Träfflista för sökning "AMNE:(MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology) ;pers:(Claesson Welsh Lena)"

Search: AMNE:(MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology) > Claesson Welsh Lena

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1.
  • Hagberg, Carolina E, et al. (author)
  • Vascular endothelial growth factor B controls endothelial fatty acid uptake.
  • 2010
  • In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 464:7290, s. 917-21
  • Journal article (peer-reviewed)abstract
    • The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.
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2.
  • Dieterich, Lothar (author)
  • Molecular Regulation of Inflammation and Angiogenesis in the Tumor Microenvironment
  • 2011
  • Doctoral thesis (other academic/artistic)abstract
    • Tumor growth and progression not only depend on properties of the malignant cells but are strongly influenced by the tumor microenvironment. The tumor stroma consists of various cell types such as inflammatory cells, endothelial cells and fibroblasts, which can either inhibit or promote tumor growth. Consequently, therapeutic targeting of the tumor stroma is increasingly recognized as an important tool to fight cancer. Two particularly important processes that contribute to the pathology of most types of tumors are angiogenesis and inflammation. In order to target these processes specifically and efficiently, it is fundamental to identify and understand the factors and signaling pathways involved. This thesis initially describes the multiple functions of the small heat shock protein αB-crystallin in the tumor microenvironment. αB-crystallin was first identified in a screen of proteins specifically up-regulated in endothelial cells forming vessel-like structures. We found that αB-crystallin is expressed in a subset of tumor vessels and promotes angiogenesis by inhibiting endothelial apoptosis, suggesting that targeting of αB-crystallin might inhibit angiogenesis and thereby decrease tumor growth. However, we also discovered an important role of αB-crystallin in regulation of inflammatory processes. We show that αB-crystallin increases the surface levels of E-selectin, an important leukocyte-endothelial adhesion molecule. Thereby, αB-crystallin may alter leukocyte recruitment to inflamed tissues such as the tumor stroma. In addition, we found that αB-crystallin is expressed in immature myeloid cells that accumulate in the periphery and at the tumor site during tumor development. Importantly, lack of αB-crystallin resulted in increased accumulation of immature myeloid cells, which might increase tumor associated inflammation. Finally, through combining laser microdissection of vessels from human tissue and microarray analysis, we identified a gene expression signature specifically associated with vessels in high grade glioma. Blood vessels in malignant glioma are highly abnormal and contribute to the pathology of the disease. Thus, knowledge about the molecular set-up of these vessels might contribute to the development of future vascular normalizing treatments.
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3.
  • Bahram, Fuad, et al. (author)
  • VEGF-mediated signal transduction in lymphatic endothelial cells
  • 2010
  • In: Pathophysiology : the official journal of the International Society for Pathophysiology / ISP. - : Elsevier BV. - 0928-4680. ; 17:4, s. 253-261
  • Journal article (peer-reviewed)abstract
    • The VEGF family of angiogenic ligands consists of VEGFA, VEGFB, VEGFC, VEGFD and placenta growth factor, PlGF. These growth factors bind in an overlapping pattern to three receptor tyrosine kinases, denoted VEGFR1, VEGFR2 and VEGFR3. Originally, VEGFA (the prototype VEGF) was described as a master regulator of vascular endothelial cell biology in vitro and in vivo, transducing its effect through VEGFR2. VEGFA, VEGFB and PlGF bind to VEGFR1, which is a negative regulator of endothelial cell function at least during embryogenesis. VEGFC and VEGFD were identified as lymphatic endothelial factors, acting via VEGFR3. With time, the very clear distinction between the roles of the VEGF ligands in angiogenesis/lymphangiogenesis has given way for a more complex pattern. It seems that the biology of the different VEGFR2 and VEGFR3 ligands overlaps quite extensively and that both receptor types contribute to angiogenesis as well as lymphangiogenesis. This paradigm shift in our understanding is due to the access to more sophisticated reagents and techniques revealing dynamic and plastic expression of ligands and receptors in different physiological and pathological conditions. Moreover, knowledge on the important role of VEGF coreceptors, the neuropilins, in regulating the responsiveness to VEGF has changed our perception on the mechanism of VEGF signal transduction. This review will primarily focus on the properties of VEGR3, its signal transduction and the resulting biology.
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4.
  • Schmidt, Linnéa, et al. (author)
  • Case-specific potentiation of glioblastoma drugs by pterostilbene
  • 2016
  • In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:45, s. 73200-73215
  • Journal article (peer-reviewed)abstract
    • Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene's effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.
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5.
  • Berge, Tone, et al. (author)
  • T cell specific adapter protein (TSAd) interacts with Tec kinase ITK to promote CXCL12 induced migration of human and murine T cells
  • 2010
  • In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:3, s. e9761-
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The chemokine CXCL12/SDF-1alpha interacts with its G-protein coupled receptor CXCR4 to induce migration of lymphoid and endothelial cells. T cell specific adapter protein (TSAd) has been found to promote migration of Jurkat T cells through interaction with the G protein beta subunit. However, the molecular mechanisms for how TSAd influences cellular migration have not been characterized in detail. PRINCIPAL FINDINGS: We show that TSAd is required for tyrosine phosphorylation of the Lck substrate IL2-inducible T cell kinase (Itk). Presence of Itk Y511 was necessary to boost TSAd's effect on CXCL12 induced migration of Jurkat T cells. In addition, TSAd's ability to promote CXCL12-induced actin polymerization and migration of Jurkat T lymphocytes was dependent on the Itk-interaction site in the proline-rich region of TSAd. Furthermore, TSAd-deficient murine thymocytes failed to respond to CXCL12 with increased Itk phosphorylation, and displayed reduced actin polymerization and cell migration responses. CONCLUSION: We propose that TSAd, through its interaction with both Itk and Lck, primes Itk for Lck mediated phosphorylation and thereby regulates CXCL12 induced T cell migration and actin cytoskeleton rearrangements.
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6.
  • Georganaki, Maria (author)
  • Vascular targeting for enhanced cancer immunotherapy
  • 2018
  • Doctoral thesis (other academic/artistic)abstract
    • Induced angiogenesis and chronic inflammation are major components of tumor immunosuppression. The scope of this thesis is to understand the role of the vasculature in anti-tumor immunity and thereby to improve cancer immunotherapy.The anti-tumor effects of anti-angiogenic therapies range from vessel normalization to directly affecting immune responses. In Paper I, we demonstrate that VEGF, a major pro-angiogenic factor, inhibits TNFα-induced endothelial activation via interfering with the NF-κB pathway and suppressing T-cell chemoattractants. Sunitinib, an anti-angiogenic tyrosine kinase inhibitor targeting VEGFR2 signaling, enhanced T-cell recruitment and reverted endothelial cell anergy by upregulating pro-inflammatory cytokines in murine melanomas. Therefore, in Paper II, we study the anti-tumor potential of combining sunitinib treatment with CD40-stimulating immunotherapy. CD40 activation leads to increased anti-tumor T-cell responses. The combination therapy was superior in restricting tumor growth and enhancing survival, associated with decreased immunosuppression and increased endothelial activation leading to improved T-cell recruitment. In Paper III, RNA-sequencing reveals that tumor endothelial cells are capable of acquiring negative feedback mechanisms secondary to CD40 immunotherapy by upregulating immunosuppressive genes such as IDO1. Co-administration of agonistic CD40 antibody treatment with an IDO1 inhibitor delayed tumor growth, associated with increased intratumoral T-cell activation.In Paper IV, we investigate ELTD1, an orphan adhesion G protein-coupled receptor, which is upregulated in high-grade glioma vessels. ELTD1 deficiency did not affect developmental angiogenesis in mice but increased tumor growth. Interestingly, ELTD1 loss improved glioma vessel perfusion and reduced permeability and hypoxia. Thus, ELTD1 targeting may normalize tumor vessels, potentially enhancing drug delivery.In Paper V, we demonstrate that ectopic expression of specific cytokines in murine gliomas induces tertiary lymphoid organ- (TLO-) TLO-like structures in the brain. TLOs, mainly composed of T- and B-cell clusters and high endothelial venules, are onsite preservers of robust immune responses. In line with this, increased survival of mice with gliomas overexpressing either LT-αβ or LIGHT was associated with alleviated tumor immunosuppresion. This suggests that TLO-inducing agents may improve cancer immunotherapy for glioma treatment.Collectively, this thesis demonstrates that the tumor vasculature is crucial for anti-tumor immune responses and that vascular targeting can enhance cancer immunotherapy.
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7.
  • Morin, Eric (author)
  • Neuropilin-1 regulation of tumor vascularization and growth
  • 2018
  • Doctoral thesis (other academic/artistic)abstract
    • Angiogenesis, the formation of new blood vessels from existing ones, is dysregulated during tumor progression as a result of chronic hypoxia and inflammation. Such alterations lead to a lack of vessel hierarchy, and the formation of poorly perfused, leaky and blunt-ended vessels, contributing to disease progression. This thesis explores the impact of neuropilin-1 (NRP1) presentation of vascular endothelial growth factor-A (VEGF-A) to its cognate receptor, VEGFR2. NRP1 presentation of VEGF-A occurs in cis (when NRP1 and VEGFR2 are present on the same cell) or in trans (when molecules are present on adjacent cells). As shown in this thesis, the different modes of NRP1 presentation influence endothelial cell signaling and tumor angiogenesis. The overall aim with the studies has been to identify new biomarkers for cancer survival and potential therapeutic targets.In paper I, we explored if signaling downstream of VEGFR2 was affected by NRP1 presentation in cis compared to trans. Complex formation in trans was readily identified, however, the kinetics were delayed and prolonged, inhibiting VEGFR2 internalization and downstream signaling. Additionally, in vivo tumor studies in mice demonstrated that trans presentation of NRP1 led to early inhibition of angiogenesis and suppressed tumor initiation.In paper II, the presence and clinical impact of trans VEGFR2/NRP1 complexes in human cancer was investigated. We first identified gastric and pancreatic adenocarcinomas (PDAC) as candidates for further investigation. VEGFR2/NRP1 complexes were identified in both tumor types but were more prevalent in PDAC. Trans presentation of NRP1 in PDAC correlated with a reduction in several vessel parameters and tumor cell proliferation. Importantly, this study identified the presence of trans complexes as an independent marker of longer overall survival for PDAC patients.In paper III, we explored the impact of NRP1 presentation modes on renal cell carcinoma (RCC) patient survival. We performed in situ proximity ligation assay (PLA) and immunofluorescence staining on a RCC cohort. Tumor cell NRP1, either trans-complexed with endothelial cell-expressed VEGFR2 as detected by in situ PLA, or alternatively, detected by immunofluorescent staining, was identified as an independent predictor of increased overall survival. These data reinforce the importance of the cell type-specific expression of cancer biomarkers.
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8.
  • Testini, Chiara (author)
  • Regulation of VEGFR2 signaling in angiogenesis and vascular permeability
  • 2016
  • Doctoral thesis (other academic/artistic)abstract
    • Angiogenesis and vascular permeability occur in physiological and pathological conditions. Angiogenesis denotes the process of blood vessel formation from preexisting quiescent vessels. Angiogenesis is initiated by proangiogenic factors, inducing endothelial cell sprouting, migration and anastomosis, followed by regression of the new vessels or maturation into a quiescent status. Vascular permeability is the process where blood vessels exchange nutrients, solutes and inflammatory cells with the surrounding tissue. Small molecules freely cross the endothelial wall, however macromolecules and cells leak out from the vasculature only after stimulation by certain factors, including VEGF. Angiogenesis and vascular permeability are tightly regulated physiological processes, but uncontrolled angiogenesis and excessive leakage lead to pathological conditions and the progression of several diseases.VEGF and its receptor VEGFR2 are critical players in angiogenesis and in vascular permeability. The binding of the ligand to the receptor is not the only event involved in the activation and regulation of the signaling cascade. Coreceptors, kinases, phosphatases, and other proteins involved in the trafficking of the complex modulate the signal amplitude and duration.VEGF/VEGFR2 complex combined with the coreceptor NRP1 has a strong pro-angiogenic action and a critical role in angiogenesis. Both VEGFR2 and NRP1 bind VEGF and can present VEGF in cis, when both VEGFR2 and NRP1 are expressed on the same endothelial cell or in trans, when NRP1 is expressed on an adjacent endothelial cell or another type of cell.Y949 and Y1212 are two of the main phosphorylation sites of VEGFR2 induced by VEGFA. The binding of phosphorylated Y949 to the SH2 domain of TSAd regulates vascular permeability leading to Src activation and adherens junction opening in vitro. Phospho-Y1212 is implicated in actin stress fiber remodeling via the adapter Nck, affecting the actin cytoskeleton and endothelial cell migration in vitro.Paladin is a vascular-enriched phosphatase-domain containing protein without reported phosphatase activity and is a negative regulator of insulin receptor and Toll-like receptor 9 signaling.In this thesis work, I have investigated the spatial dynamics of NRP1/VEGFR2 complex formation (in cis and in trans) for coordinating VEGF-mediated angiogenesis in physiological and in pathological conditions (Paper I). I have studied, in vivo, the role of VEGFR2 Y949 in vascular permeability and metastatic spread (Paper II) and the role of VEGFR2 Y1212 in angiogenic remodeling and vessel stability (Paper III). Furthermore, I have examined paladin’s role in regulating VEGF/VEGFR2 signaling and VE-cadherin junction stability, in angiogenic sprouting and vascular permeability (Paper IV).In conclusion, VEGF/VEGFR2 signaling is regulated by a multifactor system and each individual regulatory mechanism leads to a specific outcome in angiogenesis, vascular permeability and vessel stability.
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9.
  • Mellberg, Sofie, et al. (author)
  • Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis.
  • 2009
  • In: The FASEB journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 23:5, s. 1490-1502
  • Journal article (peer-reviewed)abstract
    • To define molecular events accompanying formation of the 3-dimensional (3D) vascular tube, we have characterized gene expression during vascular endothelial growth factor (VEGF)-induced tubular morphogenesis of endothelial cells. Microarray analyses were performed comparing gene induction in growth-arrested, tube-forming endothelial cells harvested from 3D collagen cultures to that in proliferating endothelial cells cultured on fibronectin. Differentially expressed genes were clustered and analyzed for specific endothelial expression through publicly available datasets. We validated the contribution of one of the identified genes, vascular endothelial protein tyrosine phosphatase (VE-PTP), to endothelial morphogenesis. Silencing of VE-PTP expression was accompanied by increased VEGF receptor-2 (VEGFR2) tyrosine phosphorylation and activation of downstream signaling pathways. The increased VEGFR2 activity promoted endothelial cell cycle progression, overcoming the G(0)/G(1) arrest associated with organization into tubular structures in the 3D cultures. Proximity ligation showed close association between VEGFR2 and VE-PTP in resting cells. Activation of VEGFR2 by VEGF led to rapid loss of association, which was resumed with time in parallel with decreased receptor activity. In conclusion, we have identified genes, which may serve critical functions in formation of the vascular tube. One of these, VE-PTP, regulates VEGFR2 activity thereby modulating the VEGF-response during angiogenesis.
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10.
  • Ragunathrao, Vijay Avin Balaji, et al. (author)
  • Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling
  • 2019
  • In: Cell Reports. - : CELL PRESS. - 2211-1247. ; 29:11, s. 3472-3487
  • Journal article (peer-reviewed)abstract
    • The vascular endothelial growth factor-A (VEGF-A)-VEGFR2 pathway drives tumor vascularization by activating proangiogenic signaling in endothelial cells (ECs). Here, we show that EC-sphingosine-1-phosphate receptor 1 (S1PR1) amplifies VEGFR2-mediated angiogenic signaling to enhance tumor growth. We show that cancer cells induce S1 PR1 activity in ECs, and thereby, conditional deletion of Si PR1 in ECs (EC-Slpr1(-/-) mice) impairs tumor vascularization and growth. Mechanistically, we show that S1 PR1 engages the heterotrimeric G-protein Gi, which amplifies VEGF-VEGFR2 signaling due to an increase in the activity of the tyrosine kinase c-Abl1. c-Abl1, by phosphorylating VEGFR2 at tyrosine-951, prolongs VEGFR2 retention on the plasmalemma to sustain Rac1 activity and EC migration. Thus, S1 PR1 or VEGFR2 antagonists, alone or in combination, reverse the tumor growth in control mice to the level seen in EC-Slpr1(-/-) mice. Our findings suggest that blocking S1 PR1 activity in ECs has the potential to suppress tumor growth by preventing amplification of VEGF-VEGFR2 signaling.
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  • Result 1-10 of 64
Type of publication
journal article (43)
doctoral thesis (11)
other publication (7)
research review (2)
book chapter (1)
Type of content
peer-reviewed (38)
other academic/artistic (26)
Author/Editor
Dejana, Elisabetta (9)
Richards, Mark (8)
Testini, Chiara (8)
Jin, Yi (7)
Claesson-Welsh, Lena ... (7)
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Vestweber, Dietmar (6)
Gordon, Emma (6)
Sjöberg, Elin (6)
Li, Xiujuan (5)
Martinsson, Pernilla (5)
Shibuya, Masabumi (5)
Betsholtz, Christer (4)
Dimberg, Anna (4)
Morin, Eric (4)
Hellström, Mats (4)
Simons, Michael (4)
Smith, Ross O. (4)
Padhan, Narendra (4)
Andre, Helder (3)
McDonald, Donald M (3)
Bentley, Katie (3)
Hedlund, Marie (3)
Fukuhara, Daisuke (3)
Honkura, Naoki (3)
Kvanta, Anders (2)
Lindskog, Cecilia (2)
Tolmachev, Vladimir (2)
Larsson, Erik, 1975 (2)
He, Liqun (2)
Pietras, Kristian (2)
Ashrafzadeh, Parham (2)
Alitalo, Kari (2)
Bahram, Fuad (2)
Barbera, Stefano (2)
Orlandini, Maurizio (2)
Spurkland, Anne (2)
Lindahl, Per, 1967 (2)
Nordling, Sofia, 198 ... (2)
Eichmann, Anne (2)
Adams, Ralf H. (2)
Ballmer-Hofer, Kurt (2)
Orsenigo, Fabrizio (2)
Gerwins, Pär (2)
Kaakinen, Mika (2)
Eklund, Lauri (2)
Franco, Claudio A. (2)
Sjöström, Elisabet O ... (2)
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University
Uppsala University (62)
Karolinska Institutet (8)
University of Gothenburg (4)
Lund University (2)
Umeå University (1)
Royal Institute of Technology (1)
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Örebro University (1)
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Language
English (64)
Research subject (UKÄ/SCB)
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Natural sciences (9)

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