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Article ; Online: Author Correction: Systematic profiling of conditional pathway activation identifies context-dependent synthetic lethalities.

Chang, Liang / Jung, Nancy Y / Atari, Adel / Rodriguez, Diego J / Kesar, Devishi / Song, Tian-Yu / Rees, Matthew G / Ronan, Melissa / Li, Ruitong / Ruiz, Paloma / Chaturantabut, Saireudee / Ito, Takahiro / van Tienen, Laurens M / Tseng, Yuen-Yi / Roth, Jennifer A / Sellers, William R

Nature genetics

2024 Volume 56, Issue 3, Page(s) 553

Language	English
Publishing date	2024-02-24
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-024-01680-3
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 46: Show issues

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Article ; Online: Systematic profiling of conditional pathway activation identifies context-dependent synthetic lethalities.

Nature genetics

2023 Volume 55, Issue 10, Page(s) 1709–1720

Abstract: The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In ...

Abstract	The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct β-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.
MeSH term(s)	Humans ; Colorectal Neoplasms/pathology ; Phosphatidylinositol 3-Kinases ; beta Catenin/genetics ; Wnt Signaling Pathway/genetics ; Cell Proliferation ; Cell Line, Tumor
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; beta Catenin
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01515-7
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Article ; Online: Cortisol Levels in Childhood Associated With Emergence of Attenuated Psychotic Symptoms in Early Adulthood.

Cullen, Alexis E / Fisher, Helen L / Gullet, Nancy / Fraser, Elizabeth R / Roberts, Ruth E / Zahid, Uzma / To, Melody / Yap, Natalie Huijing / Zunszain, Patricia A / Pariante, Carmine M / Wood, Stephen J / McGuire, Philip / Murray, Robin M / Mondelli, Valeria / Laurens, Kristin R

Biological psychiatry

2021 Volume 91, Issue 2, Page(s) 226–235

Abstract: Background: In individuals at clinical high-risk for psychosis, elevated cortisol levels predict subsequent onset of psychotic disorder. However, it is unclear whether cortisol alterations are evident at an earlier clinical stage and promote progression ...

Abstract	Background: In individuals at clinical high-risk for psychosis, elevated cortisol levels predict subsequent onset of psychotic disorder. However, it is unclear whether cortisol alterations are evident at an earlier clinical stage and promote progression of psychosis expression. This study aimed to address this issue by investigating whether cortisol levels in childhood were associated with the emergence of attenuated psychotic symptoms in early adulthood. In exploratory analyses, we examined whether cortisol and psychosocial stress measures interacted in predicting attenuated psychotic symptoms. Methods: A sample of children (N = 109) enriched for psychosis risk factors were recruited at age 9-12 years and assessed at age 11-14 years (T1) and 17-21 years (T2). Measures of psychopathology, psychosocial stressors, and salivary cortisol were obtained at T1. Attenuated psychotic symptoms were assessed at T2 using the Prodromal Questionnaire. Results: Diurnal cortisol (β = 0.915, 95% CI: 0.062-1.769) and daily stressors (β = 0.379, 95% CI: 0.034-0.723) at T1 were independently associated with total Prodromal Questionnaire scores at T2 after accounting for demographic factors and T1 psychopathology. Exploratory analyses indicated a significant interaction between T1 diurnal cortisol and daily stressors (β = 0.743, 95% CI: 0.081-1.405), with the highest predicted T2 total Prodromal Questionnaire scores occurring when both diurnal cortisol and daily stressors were increased. Conclusions: Our findings suggest that daily stressors and elevations in diurnal cortisol in late childhood/early adolescence increases risk for developing attenuated psychotic symptoms. These findings emphasize the importance of assessing environmental and biological risk factors for psychosis during neurodevelopmentally vulnerable time periods.
MeSH term(s)	Adolescent ; Adult ; Child ; Humans ; Hydrocortisone ; Hypothalamo-Hypophyseal System ; Psychotic Disorders ; Risk Factors ; Saliva ; Stress, Psychological
Chemical Substances	Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2021-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2021.08.009
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Zs.A 720: Show issues

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Article ; Online: Glucose control using fast-acting insulin aspart in a real-world setting: A 1-year, two-centre study in people with type 1 diabetes using continuous glucose monitoring.

Billion, Lisa / Charleer, Sara / Verbraeken, Laurens / Sterckx, Mira / Vangelabbeek, Kato / De Block, Nathalie / Janssen, Charlien / Van Dessel, Kristof / Dirinck, Eveline / Peiffer, Frida / Bolsens, Nancy / Mathieu, Chantal / Gillard, Pieter / De Block, Christophe

Diabetes, obesity & metabolism

2021 Volume 23, Issue 12, Page(s) 2716–2727

Abstract: Aim: To evaluate the efficacy and safety of switching from traditional mealtime insulins to fast-acting insulin aspart (Fiasp) in a "real-world" clinical practice setting in adult people with type 1 diabetes (PWD1) who were using intermittently scanned ... ...

Abstract	Aim: To evaluate the efficacy and safety of switching from traditional mealtime insulins to fast-acting insulin aspart (Fiasp) in a "real-world" clinical practice setting in adult people with type 1 diabetes (PWD1) who were using intermittently scanned or real-time continuous glucose monitoring (isCGM or rtCGM, respectively). Materials and methods: Data from 438 adult PWD1 (60% men, age 44.6 ± 16.2 years, diabetes duration 21.5 ± 14.0 years, isCGM/rtCGM: 391/47, multiple daily injections/continuous subcutaneous insulin infusion: 409/29), who initiated Fiasp from January 2018 to May 2020, were analysed. The primary objective was the evolution of time in range (TIR; 70-180 mg/dL) at 6 and 12 months. Secondary objectives included change in HbA1c, body mass index (BMI), insulin doses, time below range (<70 and <54 mg/dL), and time above range (>180 and >250 mg/dL). Results: TIR improved from 50.3% ± 15.6% to 54.3% ± 15.1% at 6 months (n = 425) and to 55.5% ± 15.2% at 12 months (n = 385) (P < .001), corresponding to 57 min/d at 6 months and 75 min/d at 12 months. Time spent below 54 mg/dL evolved from 3.1% ± 3.3% to 3.1% ± 3.7% and 2.5% ± 3.0% at 6 and 12 months, respectively (P = .011). Also, time spent above 180 mg/dL decreased from 42.3% ± 16.7% at start by 4.2% at 6 months and by 4.6% at 12 months (P < .001). The proportion of people reaching TIR more than 70% increased from 11.0% to 14.8% (P = .002), and those spending less than 4% at time less than 70 mg/dL increased from 36.1% to 42.1% (P = .002). After 12 months, HbA1c, insulin doses, and BMI did not change significantly. Conclusions: In a Belgian real-world setting of adult PWD1, switching to Fiasp was associated with a 5% increased TIR after 12 months, corresponding to 75 min/d, in combination with less time spent below and above range.
MeSH term(s)	Adult ; Blood Glucose ; Blood Glucose Self-Monitoring ; Diabetes Mellitus, Type 1/drug therapy ; Female ; Glycated Hemoglobin A/analysis ; Humans ; Hypoglycemic Agents ; Insulin ; Insulin Aspart ; Male ; Middle Aged
Chemical Substances	Blood Glucose ; Glycated Hemoglobin A ; Hypoglycemic Agents ; Insulin ; Insulin Aspart (D933668QVX)
Language	English
Publishing date	2021-08-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.14527
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Zs.A 5442: Show issues

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Article ; Online: Bioconversion of natural gas to liquid fuel: opportunities and challenges.

Fei, Qiang / Guarnieri, Michael T / Tao, Ling / Laurens, Lieve M L / Dowe, Nancy / Pienkos, Philip T

Biotechnology advances

2014 Volume 32, Issue 3, Page(s) 596–614

Abstract: Natural gas is a mixture of low molecular weight hydrocarbon gases that can be generated from either fossil or anthropogenic resources. Although natural gas is used as a transportation fuel, constraints in storage, relatively low energy content (MJ/L), ... ...

Abstract	Natural gas is a mixture of low molecular weight hydrocarbon gases that can be generated from either fossil or anthropogenic resources. Although natural gas is used as a transportation fuel, constraints in storage, relatively low energy content (MJ/L), and delivery have limited widespread adoption. Advanced utilization of natural gas has been explored for biofuel production by microorganisms. In recent years, the aerobic bioconversion of natural gas (or primarily the methane content of natural gas) into liquid fuels (Bio-GTL) by biocatalysts (methanotrophs) has gained increasing attention as a promising alternative for drop-in biofuel production. Methanotrophic bacteria are capable of converting methane into microbial lipids, which can in turn be converted into renewable diesel via a hydrotreating process. In this paper, biodiversity, catalytic properties and key enzymes and pathways of these microbes are summarized. Bioprocess technologies are discussed based upon existing literature, including cultivation conditions, fermentation modes, bioreactor design, and lipid extraction and upgrading. This review also outlines the potential of Bio-GTL using methane as an alternative carbon source as well as the major challenges and future research needs of microbial lipid accumulation derived from methane, key performance index, and techno-economic analysis. An analysis of raw material costs suggests that methane-derived diesel fuel has the potential to be competitive with petroleum-derived diesel.
MeSH term(s)	Biofuels ; Bioreactors ; Industrial Microbiology ; Methane ; Natural Gas ; Phospholipids ; Proteobacteria
Chemical Substances	Biofuels ; Natural Gas ; Phospholipids ; Methane (OP0UW79H66)
Language	English
Publishing date	2014-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	47165-3
ISSN	1873-1899 ; 0734-9750
ISSN (online)	1873-1899
ISSN	0734-9750
DOI	10.1016/j.biotechadv.2014.03.011
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Zs.A 3730: Show issues

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Article: Bioconversion of natural gas to liquid fuel: Opportunities and challenges

Fei, Qiang / Lieve M.L. Laurens / Ling Tao / Michael T. Guarnieri / Nancy Dowe / Philip T. Pienkos

Biotechnology Advances. 2014 May, June, v. 32

2014

Abstract	Natural gas is a mixture of low molecular weight hydrocarbon gases that can be generated from either fossil or anthropogenic resources. Although natural gas is used as a transportation fuel, constraints in storage, relatively low energy content (MJ/L), and delivery have limited widespread adoption. Advanced utilization of natural gas has been explored for biofuel production by microorganisms. In recent years, the aerobic bioconversion of natural gas (or primarily the methane content of natural gas) into liquid fuels (Bio-GTL) by biocatalysts (methanotrophs) has gained increasing attention as a promising alternative for drop-in biofuel production. Methanotrophic bacteria are capable of converting methane into microbial lipids, which can in turn be converted into renewable diesel via a hydrotreating process. In this paper, biodiversity, catalytic properties and key enzymes and pathways of these microbes are summarized. Bioprocess technologies are discussed based upon existing literature, including cultivation conditions, fermentation modes, bioreactor design, and lipid extraction and upgrading. This review also outlines the potential of Bio-GTL using methane as an alternative carbon source as well as the major challenges and future research needs of microbial lipid accumulation derived from methane, key performance index, and techno-economic analysis. An analysis of raw material costs suggests that methane-derived diesel fuel has the potential to be competitive with petroleum-derived diesel.
Keywords	biocatalysts ; biodiversity ; biofuels ; bioprocessing ; bioreactors ; biotransformation ; carbon ; diesel fuel ; energy content ; enzymes ; fermentation ; fuel production ; gases ; lipids ; methane ; methanotrophs ; molecular weight ; natural gas ; raw materials
Language	English
Dates of publication	2014-06
Size	p. 596-614.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	47165-3
ISSN	0734-9750
ISSN	0734-9750
DOI	10.1016/j.biotechadv.2014.03.011
Database	NAL-Catalogue (AGRICOLA)

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Article: Differential gene expression analysis of tubule forming and non-tubule forming endothelial cells: CDC42GAP as a counter-regulator in tubule formation.

Engelse, Marten A / Laurens, Nancy / Verloop, Robert E / Koolwijk, Pieter / van Hinsbergh, Victor W M

Angiogenesis

2008 Volume 11, Issue 2, Page(s) 153–167

Abstract: The formation of new tubular structures from a quiescent endothelial lining is one of the hallmarks of sprouting angiogenesis. This process can be mimicked in vitro by inducing capillary-like tubular structures in a three-dimensional (3D) fibrin matrix. ... ...

Abstract	The formation of new tubular structures from a quiescent endothelial lining is one of the hallmarks of sprouting angiogenesis. This process can be mimicked in vitro by inducing capillary-like tubular structures in a three-dimensional (3D) fibrin matrix. We aimed to analyze the differential mRNA expression in two phenotypically distinct cell populations from the same culture, namely in tubule-forming endothelial cells and monolayer endothelial cells not participating in tubule formation. A fibrin-rich 3D matrix derived from human plasma was used to facilitate tubule formation by human foreskin microvascular endothelial cells (hMVEC). After 7 days of stimulation with VEGF, bFGF, and TNF-alpha, the culture consisted of a monolayer and capillary-like sprouts that had grown into the fibrinous matrix. A method was developed to separate the monolayer and tubule-forming populations of hMVEC, keeping their cellular integrity intact to ensure mRNA extraction and cDNA production. Subsequent array analysis resulted in an inventory of differentially expressed genes that were associated with either tube-forming (angiogenic) or non-angiogenic capacity. Differential gene expression was verified by real-time PCR on the original RNA samples as well as on RNA obtained from laser-capture microdissected cross sections of monolayers and capillary structures in the 3D fibrinous matrix. The expression of CDC42GAP, an inhibitor of active-state small Rho GTPases, was reduced in tubular hMVEC. Overexpression of CDC42GAP in hMVEC attenuated endothelial tubule formation, while its suppression by siRNA slightly enhanced this process. Thus, CDC42GAP was identified as a counter-regulatory mediator for tubule formation.
MeSH term(s)	Biological Assay ; Biomarkers/metabolism ; Cell Movement ; Cells, Cultured ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Endothelium, Vascular/cytology ; Endothelium, Vascular/metabolism ; GTPase-Activating Proteins/biosynthesis ; GTPase-Activating Proteins/metabolism ; Gene Expression Profiling ; Humans ; Lasers ; Microdissection ; Neovascularization, Physiologic/genetics ; Phosphoproteins/biosynthesis
Chemical Substances	ARHGAP31 protein, human ; Biomarkers ; GTPase-Activating Proteins ; Phosphoproteins
Language	English
Publishing date	2008
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1484717-6
ISSN	0969-6970
ISSN	0969-6970
DOI	10.1007/s10456-007-9086-9
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Zs.A 5094: Show issues

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Article ; Online: Single and combined effects of alphavbeta3- and alpha5beta1-integrins on capillary tube formation in a human fibrinous matrix.

Laurens, Nancy / Engelse, Marten A / Jungerius, Clarissa / Löwik, Clemens W / van Hinsbergh, Victor W M / Koolwijk, Pieter

Angiogenesis

2009 Volume 12, Issue 3, Page(s) 275–285

Abstract: The fibrinous exudate of a wound or tumor stroma facilitates angiogenesis. We studied the involvement of RGD-binding integrins during tube formation in human plasma-derived fibrin clots and human purified fibrin matrices. Capillary-like tube formation by ...

Abstract	The fibrinous exudate of a wound or tumor stroma facilitates angiogenesis. We studied the involvement of RGD-binding integrins during tube formation in human plasma-derived fibrin clots and human purified fibrin matrices. Capillary-like tube formation by human microvascular endothelial cells in a 3D plasma-derived fibrinous matrix was induced by FGF-2 and TNF-alpha and depended largely on cell-bound u-PA and plasmin activities. While tube formation was minimally affected by the addition of either the alphavbeta3-integrin inhibiting mAb LM609 or the alpha5-integrin inhibiting mAb IIA1, the general RGD-antagonist echistatin completely inhibited this process. Remarkably, when alphavbeta3- and alpha5beta1-integrins were inhibited simultaneously, tube formation was reduced by 78%. It was accompanied by a 44% reduction of u-PA antigen accumulation and 41% less production of fibrin degradation products. alphavbeta5-integrin-blocking antibodies further enhanced the inhibition by mAb LM609 and mAb IIA1 to 94%, but had no effect by themselves. alphav-specific cRGD only inhibited angiogenesis when alpha5beta1-integrin was simultaneously blocked. Endostatin mimicked the effect of alpha5beta1-integrin and inhibited tube formation only in the presence of LM609 or cRGD (73 and 80%, respectively). Comparable results were obtained when purified fibrin matrices were used instead of the plasma-derived fibrinous matrices. These data show that blocking of tube formation in a fibrinous exudate requires the simultaneous inhibition of alphavbeta3- and alpha5beta1-integrins. This may bear impact on attempts to influence angiogenesis in a fibrinous environment.
MeSH term(s)	Angiogenesis Inhibitors/pharmacology ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacology ; Capillaries/drug effects ; Capillaries/growth & development ; Capillaries/metabolism ; Cell Culture Techniques ; Cells, Cultured ; Drug Combinations ; Drug Evaluation, Preclinical ; Endostatins/pharmacology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelial Cells/physiology ; Extracellular Matrix/chemistry ; Fibrin/chemistry ; Fibrin/pharmacology ; Humans ; Integrin alpha5beta1/antagonists & inhibitors ; Integrin alpha5beta1/immunology ; Integrin alpha5beta1/physiology ; Integrin alphaVbeta3/antagonists & inhibitors ; Integrin alphaVbeta3/immunology ; Integrin alphaVbeta3/physiology ; Neovascularization, Physiologic/drug effects ; Oligopeptides/metabolism ; Protein Binding ; Urokinase-Type Plasminogen Activator/metabolism
Chemical Substances	Angiogenesis Inhibitors ; Antibodies, Monoclonal ; Drug Combinations ; Endostatins ; Integrin alpha5beta1 ; Integrin alphaVbeta3 ; Oligopeptides ; arginyl-glycyl-aspartic acid (78VO7F77PN) ; Fibrin (9001-31-4) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)
Language	English
Publishing date	2009-05-16
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1484717-6
ISSN	1573-7209 ; 0969-6970
ISSN (online)	1573-7209
ISSN	0969-6970
DOI	10.1007/s10456-009-9150-8
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Article ; Online: TAFI and pancreatic carboxypeptidase B modulate in vitro capillary tube formation by human microvascular endothelial cells.

Guimarães, Ana H C / Laurens, Nancy / Weijers, Ester M / Koolwijk, Pieter / van Hinsbergh, Victor W M / Rijken, Dingeman C

Arteriosclerosis, thrombosis, and vascular biology

2007 Volume 27, Issue 10, Page(s) 2157–2162

Abstract: Objective: Besides having a key role in fibrinolysis, the plasminogen system has been implicated in cell migration and angiogenesis. A common mechanism is the binding of plasminogen to carboxy-terminal lysine residues in partially degraded fibrin or on ... ...

Abstract	Objective: Besides having a key role in fibrinolysis, the plasminogen system has been implicated in cell migration and angiogenesis. A common mechanism is the binding of plasminogen to carboxy-terminal lysine residues in partially degraded fibrin or on cellular surfaces. Here we examined the involvement of thrombin activatable fibrinolysis inhibitor (TAFI) and pancreatic carboxypeptidase B (CPB) in an in vitro capillary tube formation system, which is largely plasminogen-dependent. Methods and results: Human microvascular endothelial cells (hMVECs) were seeded on a 3D plasma clot matrix and subsequently stimulated with bFGF/tumor necrosis factor (TNF)-alpha. Tube formation was analyzed and fibrin degradation products (FbDP) were determined in the medium. Supplementation of the matrix with additional TAFI or CPB produced a reduction in tube formation. Pretreatment of hMVECs with CPB before seeding resulted in a similar effect. FbDP-levels indicated a concomitant reduction in matrix proteolysis. A TAFIa inhibitor increased tube formation and FbDP release into the medium. In separate assays, CPB impaired the migration of hMVECs in a dose-dependent manner, whereas proliferation and adhesion remained unaffected. Conclusions: Overall, these results demonstrate that TAFI and CPB in these systems modulate the plasminogen system both in the matrix and on the cell surface, thus leading to the inhibition of endothelial cell movement and tube formation.
MeSH term(s)	Angiogenesis Inhibitors/metabolism ; Angiogenesis Inhibitors/pharmacology ; Atherosclerosis/enzymology ; Capillaries/cytology ; Carboxypeptidase B/metabolism ; Carboxypeptidase B/pharmacology ; Carboxypeptidase B2/antagonists & inhibitors ; Carboxypeptidase B2/metabolism ; Cell Adhesion ; Cell Culture Techniques ; Cell Movement/drug effects ; Cell Proliferation ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Endothelial Cells/enzymology ; Endothelial Cells/metabolism ; Fibrin/metabolism ; Fibrin Fibrinogen Degradation Products/metabolism ; Fibroblast Growth Factor 2/metabolism ; Humans ; Neovascularization, Physiologic/drug effects ; Plant Proteins/pharmacology ; Plasminogen/metabolism ; Protease Inhibitors/pharmacology ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; Urokinase-Type Plasminogen Activator/metabolism ; Wound Healing
Chemical Substances	Angiogenesis Inhibitors ; Fibrin Fibrinogen Degradation Products ; Plant Proteins ; Protease Inhibitors ; Tumor Necrosis Factor-alpha ; Fibroblast Growth Factor 2 (103107-01-3) ; Fibrin (9001-31-4) ; Plasminogen (9001-91-6) ; Carboxypeptidase B (EC 3.4.17.2) ; Carboxypeptidase B2 (EC 3.4.17.20) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)
Language	English
Publishing date	2007-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.107.150144
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Zs.A 1705: Show issues

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Article: Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton.

Bijman, Marcel N A / van Nieuw Amerongen, Geerten P / Laurens, Nancy / van Hinsbergh, Victor W M / Boven, Epie

Molecular cancer therapeutics

2006 Volume 5, Issue 9, Page(s) 2348–2357

Abstract: Conventional anticancer agents may display antiangiogenic effects, but the underlying mechanism is poorly understood. We determined the antiangiogenic properties of cisplatin, doxorubicin, and the microtubule-targeting agents docetaxel, epothilone B, and ...

Abstract	Conventional anticancer agents may display antiangiogenic effects, but the underlying mechanism is poorly understood. We determined the antiangiogenic properties of cisplatin, doxorubicin, and the microtubule-targeting agents docetaxel, epothilone B, and vinblastine at concentrations not affecting cell proliferation. We also assessed tubulin and actin morphology and the activity of two key molecules in cell motility, the small Rho GTPases Cdc42 and Rac1. The highest non-toxic concentration (HNTC) of each drug was defined as the concentration inhibiting a maximum of 10% human umbilical vein endothelial cell growth on a 1-hour drug exposure, being for cisplatin 10 micromol/L, doxorubicin 100 nmol/L, docetaxel 10 nmol/L, epothilone B 1 nmol/L, and vinblastine 10 nmol/L. Comparative endothelial cell functional assays using HNTCs for an exposure time of 1 hour indicated that endothelial cell migration in the wound assay, endothelial cell invasion in a transwell invasion system, and endothelial cell formation into tubelike structures on a layer of Matrigel were significantly inhibited by docetaxel, epothilone B, and vinblastine (P < 0.05), but not by cisplatin and doxorubicin. Docetaxel was slightly more efficient in the inhibition of endothelial cell motility than epothilone B and vinblastine. Fluorescence microscopy revealed that only the microtubule-targeting agents affected the integrity of the tubulin and F-actin cytoskeleton, which showed disturbed microtubule structures, less F-actin stress fiber formation, and appearance of nuclear F-actin rings. These observations were associated with early inhibition of Rac1 and Cdc42 activity. In conclusion, HNTCs of microtubule-targeting agents efficiently reduce endothelial cell motility by interference with microtubule dynamics preventing the activation of Rac1/Cdc42 and disorganizing the actin cytoskeleton.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Actin Cytoskeleton/physiology ; Angiogenesis Inhibitors/pharmacology ; Animals ; Cisplatin/pharmacology ; Cytoskeleton/drug effects ; Cytoskeleton/metabolism ; Doxorubicin/immunology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Epothilones/pharmacology ; Humans ; Mice ; Microtubules/drug effects ; Neovascularization, Physiologic/drug effects ; Pseudopodia/metabolism ; Pseudopodia/physiology ; Stress Fibers/metabolism ; Stress Fibers/physiology ; Tubulin Modulators/pharmacology ; Vinblastine/pharmacology ; cdc42 GTP-Binding Protein/antagonists & inhibitors ; cdc42 GTP-Binding Protein/genetics ; cdc42 GTP-Binding Protein/metabolism ; rac1 GTP-Binding Protein/antagonists & inhibitors ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism
Chemical Substances	Angiogenesis Inhibitors ; Epothilones ; Tubulin Modulators ; Vinblastine (5V9KLZ54CY) ; Doxorubicin (80168379AG) ; cdc42 GTP-Binding Protein (EC 3.6.5.2) ; rac1 GTP-Binding Protein (EC 3.6.5.2) ; Cisplatin (Q20Q21Q62J) ; epothilone B (UEC0H0URSE)
Language	English
Publishing date	2006-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-06-0242
Database	MEDical Literature Analysis and Retrieval System OnLINE

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