abstrak penelitian tentang endoglin di tahun 2010

8/7/2019 Abstrak Penelitian Tentang Endoglin Di Tahun 2010

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Endometriosis dan endoglin 2011.enl Page 1

Reference Type: Journal ArticleRecord Number: 39

Estrogen therapy for hereditary haemorrhagic

telangiectasia (HHT): Effects of raloxifene, onEndoglin and ALK1 expression in endothelial cells

Year: 2010

Author: V. Albinana, M. E. Bernabeu-Herrero, R. Zarrabeitia, C. Bernabeu and L.M. Botella

Journal: Thromb HaemostVolume: 103

Issue: 3Pages: 525-34

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, isan autosomal dominant vascular disease. The clinical manifestations are epistaxis,mucocutaneous and gastrointestinal telangiectases, and arteriovenousmalformations. There are two predominant types of HHT caused by mutations inEndoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1and HHT2, respectively. No cure for HHT has been found and there is a currentneed to find new effective drug treatments for the disease. Some patients showsevere epistaxis which interferes with their quality of life. We report preliminaryresults obtained with Raloxifene to treat epistaxis in postmenopausal HHT womendiagnosed with osteoporosis. We tried to unravel the molecular mechanismsinvolved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code forproteins involved in the transforming growth factor beta pathway and it is widelyaccepted that haploinsufficiency is the origin for the pathogenicity of HHT.Therefore, identification of drugs able to increase the expression of those genes isessential to propose new therapies for HHT. In vitro results show that raloxifeneincreases the protein and mRNA expression of ENG and ALK1 in culturedendothelial cells. Raloxifene also stimulates the promoter activity of these genes,suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene

improved endothelial cell functions like tubulogenesis and migration in agreementwith the reported functional roles of Endoglin and ALK1. Our pilot study provides afurther hint that oral administration of raloxifene may be beneficial for epistaxistreatment in HHT menopausal women. The molecular mechanisms of raloxifeneinvolve counteracting the haploinsufficiency of ENG and ALK1.



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Dynamic expression of Endoglin, a TGF-betaco-receptor, during pre-circulation vasculardevelopment in chick

Year: 2010

Author: C. Alev, B. A. McIntyre, K. Ota and G. Sheng

Journal: Int J Dev BiolVolume: 54Issue: 4Pages: 737-42

Mutations in the human Endoglin gene, encoding a dimeric TGF-beta co-receptor,

lead to type 1 hereditary hemorrhagic telangiectasia. Studies in mice have revealedimportant roles of Endoglin in endothelial cell proliferation, differentiation andintegrity. Endoglin(-/-) mouse embryos die at mid-gestation due to cardiac defectsand vessel rupture. Its role during early vasculogenesis is unclear, as the initialphase of vascular endothelial cell formation appears unaffected in Endoglin(-/-)embryos. In order to understand possible roles of Endoglin in early vasculardevelopment, we used the chick model and analyzed the temporal and spatialexpression pattern of Endoglin during vasculogenesis in pre-circulation stage chickembryos. Weak Endoglin expression was detected at HH4 in the node and in theextraembryonic mesoderm. The node-specific expression is transitory anddisappears after HH5. Strong up-regulation of Endoglin expression is seen at HH8

in all endothelial progenitors undergoing morphological changes to becomeendothelial cells. Most extraembryonic splanchnopleural vascular endothelial cellsdown-regulate Endoglin after their morphological differentiation, whereas lateralplate and cardiac endothelial cells remain positive until HH12, followed by a cleardrop after circulation starts at HH13. Progenitors for the pronephric duct are positivefrom HH10 to HH12, but down-regulate Endoglin after epithelialization of duct cells.Overall, these data reveal a dynamic expression pattern of Endoglin inpre-circulation chick development and indicate that Endoglin may play an importantrole in the transition from endothelial progenitors to functional endothelial cellsduring early vascular development.


Cellular basis of diabetic nephropathy: V. Endoglinexpression levels and diabetic nephropathy risk inpatients with Type 1 diabetes

Year: 2010


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Author: P. Alvarez-Munoz, M. Mauer, Y. Kim, S. S. Rich, M. E. Miller, G. B. Russell,J. M. Lopez-Novoa and M. L. Caramori

Journal: J Diabetes ComplicationsVolume: 24


Endoglin is an accessory receptor molecule that, in association with transforminggrowth factor beta (TGF-beta) family receptors Types I and II, binds TGF-beta1,TGF-beta3, activin A, bone morphogenetic protein (BMP)-2 and BMP-7, regulatingTGF-beta dependent cellular responses. Relevant to diabetic nephropathy,endoglin, expressed in vascular endothelial and smooth muscle cells, fibroblasts,and mesangial cells, negatively regulates extracellular matrix (ECM). The aim of thisstudy was to evaluate endoglin expression in cultured skin fibroblasts from patientswith Type 1 diabetes with and without diabetic nephropathy. Kidney and skinbiopsies were performed in 125 Type 1 diabetic patients. The 20 with the fastestrate of mesangial expansion (estimated by electron microscopy) and proteinuria("fast-track") and the 20 with the slowest rate and normoalbuminuria ("slow-track"),along with 20 controls were studied. Endoglin mRNA expression was assessed bymicroarray and quantitative real-time polymerase chain reaction (QRT-PCR) andprotein expression by Western blot. Age and sex distribution were similar amonggroups. Diabetes duration was similar (20+/-8 vs. 24+/-7 years), hemoglobin A1clower (8.4+/-1.2% vs. 9.4+/-1.5%), and glomerular filtration rate higher (115+/-13 vs.72+/-20 ml/min per 1.73 m2) in slow-track vs. fast-track patients. Microarrayendoglin mRNA expression levels were higher in slow-track (1516.0+/-349.9) than

fast-track (1211.0+/-274.9; P=.008) patients or controls (1223.1+/-422.9; P=.018).This was confirmed by QRT-PCR. Endoglin protein expression levels correlated withmicroarray (r=0.59; P=.044) and QRTPCR (r=0.61; P=.034) endoglin mRNAexpression. These studies are compatible with the hypothesis that slow-track Type 1diabetic patients, strongly protected from diabetic nephropathy, have distinct cellularbehaviors that may be associated with reduced ECM production.


Endoglin: A marker of neoplasias or rather ofneo-angiogenesis?

Year: 2010

Author: V. Barresi and G. Barresi

Journal: Head NeckVolume: 32Issue: 7Pages: 970-1; author reply 971


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Reference Type: Journal Article

Record Number: 14

Abnormal expression of Endoglin and its receptorcomplex (TGF-beta1 and TGF-beta receptor II) asearly angiogenic switch indicator in premalignantlesions of the colon mucosa

Year: 2010

Author: G. Bellone, C. Gramigni, B. Vizio, F. A. Mauri, A. Prati, D. Solerio, L.Dughera, E. Ruffini, G. Gasparri and M. Camandona

Journal: Int J OncolVolume: 37Issue: 5Pages: 1153-65

The precise timing of the angiogenic switch in colorectal cancer development is stillunclear. The simultaneous expression of Endoglin (CD105), transforming growth

factor (TGF)-beta1 and TGF-beta receptor (R) II were quantified in surgicalspecimens comprising normal human colon, pre-malignant dysplastic tissue, in situ,and invasive colon cancer specimens, at mRNA and protein levels, respectively byreal-time PCR and immunohistochemistry. Serum concentrations of solubleEndoglin and TGF-beta1 were evaluated. mRNA and CD105+-microvessel density(MVD) increased significantly in dysplastic colon and carcinoma versus normaltissues; values correlated respectively with dysplasia degree and Dukes' stages.TGF-beta1 expression was significantly upregulated in most severe dysplasticadenoma specimens, while TGF-beta1 transcript and protein signals were intense incarcinoma, positively-correlated with tumor progression. TGF-beta1 RII wasoverexpressed in adenoma and carcinoma versus normal samples, but unrelated

with dysplasia or Dukes' stage. Soluble Endoglin serum levels were equivalent inadenoma and normal tissues; in carcinoma the highest levels were in invasivetumor. Circulating TGF-beta1 levels were increased in severe dysplasia andprogressed with tumor progression. Correlations between adenoma dysplasiadegree and TGF-beta RII and CD105+-MVD, and between tumor Dukes' stagingand TGF-beta1 and CD105+-MVD, were significant. TGF-beta1 and Endoglin andTGF-beta1 serum levels, TGF-beta1 staining and CD105+-MVD were significantlyand inversely associated with disease-free survival. TGF-beta1 levels were anindependent and significant prognostic factor of disease-free survival. Thesefindings suggest active angiogenesis occurs in many pre-malignant colon cases andsupports more careful evaluation of different chemopreventive agents.


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Increased plasma soluble endoglin levels as anindicator of cardiovascular alterations inhypertensive and diabetic patients

Year: 2010

Author: A. M. Blazquez-Medela, L. Garcia-Ortiz, M. A. Gomez-Marcos, J. I.Recio-Rodriguez, A. Sanchez-Rodriguez, J. M. Lopez-Novoa and C.Martinez-Salgado

Journal: BMC MedVolume: 8Pages: 86

BACKGROUND: Endoglin is involved in the regulation of endothelial function, butthere are no studies concerning its relation with hypertension- anddiabetes-associated pathologies. Thus, we studied the relationship between plasmalevels of soluble endoglin and cardiovascular alterations associated withhypertension and diabetes. METHODS: We analyzed 288 patients: 64 with type 2diabetes, 159 with hypertension and 65 healthy patients. We assessed therelationship of soluble endoglin plasma levels measured by enzyme-linkedimmunosorbent assay with basal glycemia, glycosylated hemoglobin, bloodpressure, endothelial dysfunction (assessed by pressure wave velocity),hypertensive retinopathy (by Keith-Wagener classification), left ventricularhypertrophy (by Cornell and Sokolow indexes), cardiovascular risk and target organ(heart, vascular, kidney) damage. RESULTS: There are significant correlationsbetween endoglin and glycemia, systolic blood pressure, pulse pressure, pressurewave velocity and electrocardiographically assessed left ventricular hypertrophy.Endoglin levels were significantly higher in patients with diabetes who hadnondipper and extreme dipper circadian blood pressure patterns than in dippercircadian patterns, in patients with hypertension and diabetes who had riser pattern

than in the other patients, and in patients with diabetes but not hypertension whohad extreme dipper pattern than in dipper, nondipper and riser groups. There wasalso a significant correlation between plasma-soluble endoglin and lower levels ofsystolic night-day ratio. Higher endoglin levels were found in patients with diabeteswho had retinopathy, in patients with diabetes who had a high probability of 10-yearcardiovascular risk, and in patients with diabetes and hypertension who had three ormore damaged target organs (heart, vessels, kidney) than in those with no organsaffected. CONCLUSIONS: This study shows that endoglin is an indicator ofhypertension- and diabetes-associated vascular pathologies as endothelialdysfunction and cardiovascular damage.


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The role of urinary soluble endoglin in the

diagnosis of pre-eclampsia: comparison withsoluble fms-like tyrosine kinase 1 to placentalgrowth factor ratio

Year: 2010

Author: C. S. Buhimschi, M. A. Baumbusch, A. T. Dulay, S. Lee, M. Wehrum, G.Zhao, M. O. Bahtiyar, C. M. Pettker, U. A. Ali, E. F. Funai and I. A. Buhimschi

Journal: BJOGVolume: 117Issue: 3Pages: 321-30

OBJECTIVE: Endoglin, an anti-angiogenic glycoprotein expressed on endothelialcells, has been proposed recently as a biomarker of pre-eclampsia (PE). Given thatPE is characterised by an imbalance of angiogenic factors, we sought to determinethe clinical utility of urinary soluble endoglin, relative to the soluble fms-like tyrosinekinase 1 to placental growth factor (PlGF) ratio, in the diagnosis of PE duringgestation. DESIGN: Prospective observational cohort. SETTING: Tertiary referral

university hospital. POPULATION: Two hundred and thirty-four pregnant womenwere enrolled prospectively in the following groups: healthy controls, n = 63;gestational age (GA), median (interquartile range), 33 weeks (27-39 weeks); chronichypertension, n = 27; GA, 33 weeks (30-36 weeks); mild PE, n = 38; GA, 37 weeks(34-40 weeks); severe PE, n = 106; GA, 32 weeks (29-37 weeks). METHODS: Freeurinary levels of soluble endoglin, soluble fms-like tyrosine kinase 1 and PlGF weremeasured by sensitive and specific immunoassay. Levels for all urinary analyteswere normalised to creatinine. MAIN OUTCOME MEASURES: Urinary solubleendoglin, and the soluble fms-like tyrosine kinase 1 to PlGF ratio. RESULTS: Inhealthy controls, urinary soluble endoglin levels were increased significantly at termrelative to those earlier in gestation. Severe PE was characterised by an increased

urinary level of soluble endoglin, soluble fms-like tyrosine kinase 1, protein tocreatinine ratio and soluble fms-like tyrosine kinase 1 to PlGF ratio compared withall other groups. There was a direct correlation between urinary soluble endoglinand proteinuria that remained after GA correction (R = 0.382, P < 0.001). Urinarysoluble endoglin could not differentiate mild PE from severe preterm PE. Overall,soluble endoglin had the ability to discriminate PE from chronic hypertension andhealthy controls only in women who were evaluated at


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Plasma soluble endoglin concentration inpre-eclampsia is associated with an increasedimpedance to flow in the maternal and fetalcirculations

Year: 2010

Author: T. Chaiworapongsa, R. Romero, J. P. Kusanovic, P. Mittal, S. K. Kim, F.Gotsch, N. G. Than, S. Mazaki-Tovi, E. Vaisbuch, O. Erez, L. Yeo, S. S. Hassanand Y. Sorokin

Journal: Ultrasound Obstet GynecolVolume: 35Issue: 2Pages: 155-62

OBJECTIVES: To examine the relationship between abnormalities in uterine (UtA)and/or umbilical artery (UA) Doppler velocimetry and maternal plasmaconcentrations of soluble endoglin (sEng) in patients with pre-eclampsia (PE).

METHODS: A cross-sectional study was conducted in 135 normal pregnant womenand 69 patients with PE. Patients with PE were subclassified into four groups: thosewho had Doppler abnormalities in both the UtA and UA, patients who had Dopplerabnormalities in the UtA alone, those who had Doppler abnormalities in the UAalone, and patients without Doppler abnormalities in either vessel. Plasmaconcentrations of sEng were determined by enzyme-linked immunosorbent assay.RESULTS: Among patients with PE, those with abnormal UtA and UA Dopplervelocimetry had the highest median plasma concentration of sEng compared withany other group (P < 0.001, Kruskal-Wallis test). Women with PE with normalDoppler velocimetry in both vessels had the lowest median plasma concentration ofsEng. There was a significant relationship between plasma concentrations of sEng

and mean UtA resistance index (Spearman Rho = 0.5, P < 0.001) as well as UApulsatility index (Spearman Rho = 0.4, P = 0.002). Multiple regression analysissuggested that Doppler abnormalities in the UtA and UA as well as gestational ageat blood sampling contributed to plasma sEng concentrations (P < 0.001).CONCLUSIONS: Abnormalities of impedance to blood flow in the UtA and UA areassociated with an excess of sEng in the circulation of mothers with PE. Thesefindings suggest that the 'antiangiogenic state' in PE is partially reflected inabnormalities of Doppler velocimetry.



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Serum endoglin levels in patients suffering fromsystemic sclerosis and elevated systolic pulmonary

arterial pressureYear: 2010

Author: P. X. Coral-Alvarado, M. F. Garces, J. E. Caminos, A. Iglesias-Gamarra, J.F. Restrepo and G. Quintana

Journal: Int J RheumatolVolume: 2010

Background. Pulmonary arterial hypertension (PAH) is the main cause of

morbimortality in systemic sclerosis (SSc). Increased Eng expression has beendemonstrated in SSc patients. Objective. Ascertaining serum levels of Eng in SScpatients with and without elevated systolic pulmonary arterial pressure (sPAP) andcomparing them with that of healthy volunteers. Methods. A cross-sectional studywas carried out. A commercial ELISA kit was used for measuring serumconcentrations of Eng in 60 subjects: 40 patients with SSc with and without elevatedsPAP, compared to 20 healthy control subjects. Elevated sPAP was detected byechocardiogram. Results. No association between positive Eng and elevated sPAPwas found when compared to the SSc without elevated sPAP group (OR = 2.85;0.65-12.88 95% CI; P = .11); however, an association was found between positiveEng and elevated sPAP compared to healthy controls (OR = 23.22; 2.46-1050.33

95% CI; P = .001), and weak association was found between the positive Eng withSSc without elevated sPAP group compared to healthy controls (OR = 8.14,0.8-393.74 95% CI; P = .046). Conclusion. Raised serum levels of Eng in SScpatients compared to healthy controls were found, suggesting a role for Eng in SScvasculopathy and not just in elevated sPAP. However, prospective studies areneeded to verify such observations.

Reference Type: Journal Article

Record Number: 48

Vascular endothelial growth factor and endoglinexpression in colorectal cancer

Year: 2010

Author: K. Dassoulas, M. Gazouli, G. Theodoropoulos, Z. Christoni, S. Rizos, A.Zisi-Serbetzoglou, C. Glava, T. Karantanos, C. Klonaris and P. Karakitsos

Journal: J Cancer Res Clin OncolVolume: 136


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PURPOSE AND METHODS: Vascular endothelial growth factor (VEGF)overexpression has been associated with advanced stage and poor survival in

several cancers. Additionally, endoglin was proposed as a marker ofneovascularization in solid malignancies. The aim of this study was to evaluate theassociation between the VEGF and endoglin expression in colorectal carcinomapatients, as well as to correlate the VEGF and endoglin expression with standardparameters, to define their potential prognostic role. VEGF and endoglin expressionwere evaluated in 99 unrelated patients with colorectal cancer usingimmunohistochemistry. RESULTS: Vascular endothelial growth factor andendoglobin expression were positively interrelated. No significant correlation ofVEGF and endoglin expression with clinicopathological parameters was observed inour cases. The Kaplan-Meier survival curves have demonstrated a clear associationof cancer-specific overall survival with high VEGF, as well as high endoglin

expression. CONCLUSION: Our results support that VEGF and endoglin act as twovaluable indicators of prognosis.


CD105 (Endoglin) expression in breast carcinoma

effusions is a marker of poor survivalYear: 2010

Author: B. Davidson, H. T. Stavnes, M. Forsund, A. Berner and A. C. Staff

Journal: BreastVolume: 19Issue: 6Pages: 493-8

We analyzed the expression and clinical role of endoglin (CD105) in breastcarcinoma effusions. Endoglin levels were measured in 36 effusion supernatants byELISA and studied for association with the cancer-associated markers calprotectin,VEGF, and the VEGF receptor sFlt1. Endoglin expression was further studied in 46effusions and 22 primary carcinomas using immunohistochemistry. The foursecreted molecules were detected in all specimens and their levels significantlycorrelated (p < 0.001). In effusions, endoglin was localized to carcinoma cells andreactive mesothelium using immunohistochemistry. Tumor cell expression washigher in effusions compared to primary carcinomas (p = 0.025), and inpost-chemotherapy compared to pre-chemotherapy effusions (p = 0.017). Highertumor endoglin expression was associated with poor overall (p = 0.021) anddisease-free (p = 0.032) survival in univariate analysis, and was an independentpredictor in Cox multivariate analysis (p = 0.001 and p = 0.038, respectively). Our


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data suggest that endoglin may be an important therapeutic target in metastaticbreast cancer.


Endoglin as a marker in cervical paragangliomas

Year: 2010

Author: N. Eleno, A. Duwel, A. Munoz, J. Paz-Bouza, J. M. Lopez-Novoa and F.Lozano

Journal: Head NeckVolume: 32Issue: 6Pages: 737-43

BACKGROUND: Endoglin is expressed on endothelium and is implicated in thecontrol of angiogenesis. This study compares the expression of endoglin withvascular endothelial growth factor (VEGF), commonly used as a marker forneoangiogenesis in cervical paragangliomas (CPG). METHODS: The CPG weresurgically obtained from 5 patients and compared with nontumoral lung obtainedfrom patients subjected to pulmonary resection. Detection with specific antibodieswas used to determine the expression of the proteins VEGF and endoglin. Theexpressions of hypoxia-inducible factor (HIF) and vascular cell adhesion molecule-1(VCAM-1) were used to determine the degree of hypoxia and capillarization,respectively. RESULTS: Endoglin is located at the plasma membrane of endothelialcells. The relative expression of endoglin is significantly higher in CPG respect tolung (p < .02), whereas that of VEGF is similar. CONCLUSION: Endoglin expressionin CPG is significantly superior to that of VEGF and correlates with tumorvascularization.


Alterations of serum and placental endoglin inpre-eclampsia

Year: 2010

Author: M. Fang, Y. He, H. Li, M. Wu, X. Shi and H. Du

Journal: J Int Med Res


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Volume: 38Issue: 1Pages: 43-51

Serum levels of endoglin were measured in pre-eclamptic women in their third

trimester and in women in their second trimester who later developedpre-eclampsia. Placental levels of endoglin at birth were also determined inpre-eclamptic women and healthy controls. Serum endoglin was significantly higherin pre-eclamptic women in the third trimester than in controls (median 35.15 versus10.35 ng/ml, respectively) and in women with severe compared with mildpre-eclampsia (median 51.68 versus 20.99 ng/ml, respectively). Placental endoglinwas also significantly higher in pre-eclamptic women than controls (median 26.24versus 9.21 ng/mg, respectively) and in women with severe compared with mildpre-eclampsia (median 28.77 versus 13.38 ng/mg, respectively). Pregnant womenin the second trimester who eventually developed pre-eclampsia had significantlyhigher serum endoglin than age- and gestational age-matched controls (median

5.90 versus 5.20 ng/ml, respectively). These findings suggest that endoglin plays animportant role in the pathogenesis of pre-eclampsia.


Endoglin differentially regulates TGF-beta-induced

Smad2/3 and Smad1/5 signalling and its expressioncorrelates with extracellular matrix production andcellular differentiation state in human chondrocytes

Year: 2010

Author: K. W. Finnson, W. L. Parker, Y. Chi, C. D. Hoemann, M. B. Goldring, J.Antoniou and A. Philip

Journal: Osteoarthritis Cartilage

Volume: 18Issue: 11Pages: 1518-27

OBJECTIVE: Transforming growth factor-beta (TGF-beta) plays a critical role incartilage homeostasis and deregulation of its signalling is implicated in osteoarthritis(OA). TGF-beta isoforms signal through a pair of transmembrane serine/threoninekinases known as the type I and type II TGF-beta receptors. Endoglin is a TGF-betaco-receptor that binds TGF-beta with high affinity in the presence of the type IITGF-beta receptor. We have previously shown that endoglin is expressed in humanchondrocytes and that it forms a complex with the TGF-beta signalling receptors.However, the functional significance of endoglin expression in chondrocytes isunknown. Our objective was to determine whether endoglin regulates TGF-beta


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Smad signalling and extracellular matrix (ECM) production in human chondrocytesand whether its expression varies with chondrocyte differentiation state. METHOD:Endoglin function was determined by overexpression or antisense morpholinosiRNA knockdown of endoglin in human chondrocytes and measuringTGF-beta-induced Smad phosphorylation, transcriptional activity and ECM

production. Alterations in endoglin expression levels were determined duringsubculture-induced dedifferentiation of human chondrocytes and in normal vs OAcartilage samples. RESULTS: Endoglin enhances TGF-beta1-induced Smad1/5phosphorylation and inhibits TGF-beta1-induced Smad2 phosphorylation,Smad3-driven transcriptional activity and ECM production in human chondrocytes.In addition, the enhancing effect of endoglin siRNA knockdown onTGF-beta1-induced Smad3-driven transcription is reversed by ALK1overexpression. Furthermore, endoglin levels are increased in chondrocytesfollowing subculture-induced dedifferentiation and in OA cartilage as compared tonormal cartilage. CONCLUSION: Together, our results suggest that endoglinregulates the balance between TGF-beta/ALK1/Smad1/5 and ALK5/Smad2/3

signalling and ECM production in human chondrocytes and that endoglin mayrepresent a marker for chondrocyte phenotype.


Maternal plasma soluble endoglin at 11-13 weeks'

gestation in pre-eclampsiaYear: 2010

Author: J. M. Foidart, C. Munaut, F. Chantraine, R. Akolekar and K. H. Nicolaides

Journal: Ultrasound Obstet GynecolVolume: 35Issue: 6Pages: 680-7

OBJECTIVES: To examine the performance of screening for pre-eclampsia (PE) bya combination of maternal factors, soluble endoglin (sEng), pregnancy associatedplasma protein-A (PAPP-A), placental growth factor (PlGF) and uterine artery lowestpulsatility index (L-PI) at 11-13 weeks' gestation. METHODS: Uterine artery L-PI,sEng, PAPP-A and PlGF were measured at 11-13 weeks in 90 singletonpregnancies that subsequently developed PE, including 30 that required deliverybefore 34 weeks (early PE) and 60 with late PE, and 180 unaffected controls.Screening performance for PE by maternal factors, sEng, PAPP-A, PlGF anduterine artery L-PI and their combinations was determined. RESULTS: In early PE,compared to controls, plasma sEng and uterine L-PI were significantly increasedand serum PAPP-A and PlGF were decreased. In late PE, compared to controls,serum PlGF was decreased and uterine L-PI was increased but plasma sEng andserum PAPP-A were not significantly different. In screening for early PE, the


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detection rate for a 10% false-positive rate was 46.7% for sEng alone and 96.3% fora combination of maternal factors, sEng, PlGF and uterine artery L-PI.CONCLUSIONS: Effective screening for early PE can be provided by a combinationof maternal factors, sEng, PlGF and uterine artery L-PI at 11-13 weeks' gestation.


Targeting cancer vasculature via endoglin/CD105: anovel antibody-based diagnostic and therapeuticstrategy in solid tumours

Year: 2010

Author: E. Fonsatti, H. J. Nicolay, M. Altomonte, A. Covre and M. Maio

Journal: Cardiovasc ResVolume: 86Issue: 1Pages: 12-9

Endoglin/CD105 is well acknowledged as being the most reliable marker ofproliferation of endothelial cells, and it is overexpressed on tumour neovasculature.Our current knowledge of its structure, physiological role, and tissue distributionsuggests that targeting of endoglin/CD105 is a novel and powerful diagnostic andtherapeutic strategy in human malignancies, through the imaging oftumour-associated angiogenesis and the inhibition of endothelial cell functionsrelated to tumour angiogenesis. Among biotherapeutic agents, monoclonalantibodies have shown a major impact on the clinical course of human malignanciesof different histotypes. Along this line, the potential efficacy of anti-endoglin/CD105antibodies and their derivatives for clinical purposes in cancer is supported by alarge body of available pre-clinical in vitro and in vivo data. In this review, the mainfindings supporting the translation of antibody-based endoglin/CD105 targeting from

pre-clinical studies to clinical applications in human cancer are summarized anddiscussed.


VEGF Induces More Severe CerebrovascularDysplasia in Endoglin than in Alk1 Mice

Year: 2010


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Author: Q. Hao, Y. Zhu, H. Su, F. Shen, G. Y. Yang, H. Kim and W. L. Young

Journal: Transl Stroke ResVolume: 1


Brain arteriovenous malformations (BAVMs) are an important cause of intracranialhemorrhage (ICH) in young adults. A small percent of BAVMs is due to hereditaryhemorrhagic telangiectasia 1 and 2 (HHT1 and 2), which are caused by mutations intwo genes involved in TGF-beta signaling: endoglin (ENG) and activin-like kinase 1(ALK1). The BAVM phenotype is an incomplete penetrant in HHT patients, and themechanism is unknown. We tested the hypothesis that a "response-to-injury"triggers abnormal vascular (dysplasia) development, using Eng and Alk1haploinsufficient mice. Adeno-associated virus (AAV) expressing vascularendothelial growth factor (VEGF) was used to mimic the injury conditions. VEGFoverexpression caused a similar degree of angiogenesis in the brain of all groups,except that the cortex of Alk1(+/-) mice had a 33% higher capillary density thanother groups. There were different levels of cerebrovascular dysplasia inhaploinsufficient mice (Eng(+/)>Alk1(+/-)), which simulates the relative penetranceof BAVM in HHT patients (HHT1>HHT2). Few dysplastic capillaries were observedin AAV-LacZ-injected mice. Our data indicate that both angiogenic stimulation andgenetic alteration are necessary for the development of dysplasia, suggesting thatanti-angiogenic therapies might be adapted to slow the progression of the diseaseand decrease the risk of spontaneous ICH.


Matrix metalloproteinase-14 (MT1-MMP)-mediatedendoglin shedding inhibits tumor angiogenesis

Year: 2010

Author: L. J. Hawinkels, P. Kuiper, E. Wiercinska, H. W. Verspaget, Z. Liu, E.Pardali, C. F. Sier and P. ten Dijke

Journal: Cancer ResVolume: 70Issue: 10Pages: 4141-50

Endoglin is a transforming growth factor-beta coreceptor with a crucial role inangiogenesis. A soluble form of endoglin is present in the circulation, but the role ofsoluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding


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mechanism is not known. Therefore, we examined the role of sEndoglin in tumorangiogenesis and the mechanism by which the extracellular domain of endoglin isreleased from the membrane.In colorectal cancer specimens, we observed highendothelial endoglin protein expression, accompanied with slightly lower sEndoglinlevels in the circulation, compared with healthy controls. In vitro analysis using

endothelial sprouting assays revealed that sEndoglin reduced spontaneous andvascular endothelial growth factor-induced endothelial sprouting. Human umbilicalvascular endothelial cells were found to secrete high levels of sEndoglin. Endoglinshedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease.Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase insEndoglin levels. Endoglin shedding required a direct interaction between endoglinand membrane-localized MMP-14. Using cleavage site mutants, we determined thatMMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain.Taken together, this study shows that MMP-14 mediates endoglin shedding, whichmay regulate the angiogenic potential of endothelial cells in the (colorectal) tumor

microenvironment.


Transforming growth factor-beta co-receptorendoglin suppresses breast cancer invasion and

metastasisYear: 2010

Author: L. Henry, D. Johnson, S. Lee, P. Quinlan, T. Crook, A. Thompson, J.Reis-Filho and C. Isacke

Journal: Breast Cancer ResVolume: 12 Suppl 1Pages: O6


Endoglin expression in breast tumor cellssuppresses invasion and metastasis and correlates

with improved clinical outcome


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Year: 2010

Author: L. A. Henry, D. A. Johnson, D. Sarrio, S. Lee, P. R. Quinlan, T. Crook, A.M. Thompson, J. S. Reis-Filho and C. M. Isacke

Journal: Oncogene

Tumor growth factor-beta (TGF-beta) signaling in cancer has been implicated ingrowth suppression of early lesions and enhancing tumor cell invasion andmetastasis. However, the cellular mechanisms that determine this signaling outputin individual tumors are still largely unknown. In endothelial cells, TGF-beta signalingis modulated by the TGF-beta co-receptor endoglin (CD105). Here we demonstratethat endoglin is expressed in a subset of invasive breast cancers and cell lines andis subject to epigenetic silencing by gene methylation. Endoglin downregulation innon-tumorigenic MCF10A breast cells leads to the formation of abnormal acini in 3Dculture, but does not promote cell migration or transformation. In contrast, in the

presence of activated ErbB2, endoglin downregulation in MCF10A cells leads toenhanced invasion into a 3D matrix. Consistent with these data, ectopic expressionof endoglin in MDA-MB-231 cells blocks TGF-beta-enhanced cell motility andinvasion and reduces lung colonization in an in vivo metastasis model. Unlikeendothelial cells, endoglin does not modulate Smad-mediated TGF-beta signaling inbreast cells but attenuates the cytoskeletal remodeling to impair cell migration andinvasion. Importantly, in a large cohort of invasive breast cancers, lack of endoglinexpression in the tumor cell compartment correlates with ENG gene methylation andpoor clinical outcome.Oncogene advance online publication, 1 November 2010;doi:10.1038/onc.2010.488.


Soluble endoglin in preeclamptic patients with orwithout HELLP syndrome

Year: 2010

Author: A. Hertig, J. Fort, G. Lefevre, N. Chabbert-Buffet, M. Uzan, E. Rondeauand P. Rozenberg

Journal: Am J Obstet GynecolVolume: 202Issue: 6Pages: 594 e1-4

OBJECTIVE: The pathogenesis of the HELLP (hemolysis, enzyme liver, lowplatelets) syndrome is unknown. Recently soluble endoglin (sEng) was identified asa cause of the appearance of schistocytes and liver pathology in an animal model ofpreeclampsia (PE). STUDY DESIGN: We explored the value of sEng in 82 women


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who delivered in a context of normal pregnancy (NP, n = 10), PE (n = 49), or HELLP(n = 23). RESULTS: sEng was elevated in pathological pregnancies (66.7 +/- 62and 75.7 +/- 48 pg/mL in PE and HELLP, respectively, vs 5.29 +/- 1.25 in NP, P

abstrak penelitian tentang endoglin di tahun 2010

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