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1.
Br J Cancer ; 118(9): 1179-1188, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29563634

RESUMEN

BACKGROUND: Vascular endothelial (VE)-cadherin is an endothelial cell-specific protein responsible for endothelium integrity. Its adhesive properties are regulated by post-translational processing, such as tyrosine phosphorylation at site Y685 in its cytoplasmic domain, and cleavage of its extracellular domain (sVE). In hormone-refractory metastatic breast cancer, we recently demonstrated that sVE levels correlate to poor survival. In the present study, we determine whether kidney cancer therapies had an effect on VE-cadherin structural modifications and their clinical interest to monitor patient outcome. METHODS: The effects of kidney cancer biotherapies were tested on an endothelial monolayer model mimicking the endothelium lining blood vessels and on a homotypic and heterotypic 3D cell model mimicking tumour growth. sVE was quantified by ELISA in renal cell carcinoma patients initiating sunitinib (48 patients) or bevacizumab (83 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). RESULTS: Human VE-cadherin is a direct target for sunitinib which inhibits its VEGF-induced phosphorylation and cleavage on endothelial monolayer and endothelial cell migration in the 3D model. The tumour cell environment modulates VE-cadherin functions through MMPs and VEGF. We demonstrate the presence of soluble VE-cadherin in the sera of mRCC patients (n = 131) which level at baseline, is higher than in a healthy donor group (n = 96). Analysis of sVE level after 4 weeks of treatment showed that a decrease in sVE level discriminates the responders vs. non-responders to sunitinib, but not bevacizumab. CONCLUSIONS: These data highlight the interest for the sVE bioassay in future follow-up of cancer patients treated with targeted therapies such as tyrosine-kinase inhibitors.


Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores Farmacológicos , Cadherinas/metabolismo , Carcinoma de Células Renales/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéutico , Biomarcadores Farmacológicos/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Células Cultivadas , Ensayos Clínicos como Asunto , Endotelio Vascular/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Terapia Molecular Dirigida/métodos , Metástasis de la Neoplasia , Estudios Retrospectivos , Resultado del Tratamiento
2.
Br J Cancer ; 116(3): 356-361, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28056463

RESUMEN

BACKGROUND: Patients with metastatic breast cancer (MBC) represent a heterogeneous group, with large differences in outcomes from individual patients. VE-cadherin, an endothelial-specific cadherin, was shown to promote tumour proliferation and angiogenesis. Soluble VE-cadherin has been recently associated to breast cancer progression. This study was designed to investigate the prognosis significance of soluble VE-cadherin in hormone-refractory MBC. METHODS: Between 2004 and 2007, 150 patients with a fully documented history of hormone-refractory MBC were included in the prospective SEMTOF study. Serum concentrations of VE-cadherin were measured at inclusion for 141 patients and 6 weeks after the beginning of chemotherapy, using a sandwich enzyme immunoassay. RESULTS: The presence of high levels of serum VE-cadherin was significantly correlated to a shorter progression-free (PFS) and overall survival (OS). In a multivariate analysis along with clinical and biologic prognostic parameters, high serum VE-cadherin level was an independent adverse prognostic variable for PFS (median PFS 9.7 (IC95: 8; 11.9) vs 5.8 (IC95: 4.1; 8) months P=0.0008) and OS (median OS 34 (IC95: 26.6; 47.1) vs 14.8 (IC95: 9.3; 21.4) months P=0.0007). Moreover, VE-cadherin decrease during chemotherapy was also associated with good prognosis. CONCLUSIONS: Serum VE-cadherin levels correlate to poorer survival in patients with hormone-refractory MBC. As sVE-cadherin reflects tumour angiogenesis, this could have therapeutic implications for antiangiogenic treatment.


Asunto(s)
Antígenos CD/sangre , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/diagnóstico , Cadherinas/sangre , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Análisis de Supervivencia
3.
Int Arch Allergy Immunol ; 170(2): 108-14, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27475458

RESUMEN

BACKGROUND: The aetiology of angio-oedema (AE) is difficult to determine; however, it is essential in emergency situations when two major contexts may be present: mast cell-mediated AE and bradykinin-mediated AE. Different forms of AE are currently distinguished based on clinical criteria (spontaneous duration of the attack, presence of concomitant or late-appearing superficial urticaria, history of atopy, and others), but specific biomarkers could improve patient management. OBJECTIVE: In this prospective study, potential biomarkers have been identified, and their statistical characteristics were examined. METHODS: Samples were taken on day 0 (D0) and D7 for 3 patient groups (n = 11 each): bradykinin-mediated AE [peripheral site of attack, ear, nose, throat (ENT), and abdominal involvement], mast cell-mediated AE, and non-bradykinin-mediated abdominal pain. RESULTS: Assay of the potential biomarkers revealed no significant differences in C1 inhibitor and C4 levels. In contrast, D-dimer levels peaked during bradykinin-mediated AE attacks (median 2.2 mg/l at D0 vs. 0.52 mg/l at D7; p < 10-3) as well as during mast cell-mediated AE attacks (1.97 vs. 0.65 mg/l; p = 0.04) and were high in bradykinin-mediated AE compared to the control group (0.69 mg/l; p = 0.01). A threshold value of 0.62 mg/l was found to have a negative predictive value of 100% for bradykinin-mediated AE compared to other causes of abdominal pain (group 3). Circulating VE-cadherin levels were also increased during an attack (1,990 at D0 vs. 1,566 ng/ml at D7; p = 0.01), but could not distinguish between bradykinin-mediated and mast cell-mediated AE, like D-dimers. CONCLUSIONS: Exploration of changes in fibrinolysis-related markers (particularly D-dimers) is thus promising for the diagnosis of AE attacks in difficult-to-diagnose abdominal forms, although it was not able to differentiate between bradykinin and mast cell-mediated AE.


Asunto(s)
Angioedema/diagnóstico , Angioedema/etiología , Biomarcadores , Bradiquinina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/sangre , Cadherinas/sangre , Proteína Inhibidora del Complemento C1 , Proteínas del Sistema Complemento , Femenino , Productos de Degradación de Fibrina-Fibrinógeno , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Adulto Joven
4.
Biotechnol J ; 13(12): e1800463, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30457706

RESUMEN

A major problem for the detection of cancer biomarkers in plasma or serum is that common clinical practice does not require the patient to be in a fasting state. Considering that lipoproteins are the main population affected by food intake, the authors hypothesized that biomarkers could be embedded in lipid particles and thereby opens a new avenue for detection. Using the recently published biomarker, soluble VE-cadherin (sVE), the authors tested our hypothesis using techniques of biophysics, biochemistry and the tools of nanobiotechnology on serum samples from kidney cancer patients (n = 106). Optical density as well as contact angle measurements of serum revealed heterogeneity in the particle content of the serum samples. Isolation of the lipidic moieties by ultracentrifugation showed that sVE was detected in this compartment. Further, isolation of lipoprotein subclasses by precipitation with sodium phosphotungstate and MgCl2 , showed that HDL carried the majority of sVE. Immunoprecipitation of sVE confirmed that it was associated with Apolipoprotein A1, a major compound of HDL. Using a biomimetic lipid bilayer membrane coupled with impedance spectroscopy the authors quantified, in real-time, that the sVE adsorbed to the lipid bilayer membrane without altering its structure. Taken together, these results show for the first time a direct interaction of a cancer biomarker with lipids. The authors anticipate these results to prompt fasting for future blood tests for large-scale studies in the biomarkers research field.


Asunto(s)
Biomarcadores de Tumor/sangre , Materiales Biomiméticos , Colesterol/sangre , Antígenos CD/sangre , Apolipoproteína A-I/sangre , Biotecnología , Cadherinas/sangre , Células HEK293 , Humanos , Inmunoprecipitación , Neoplasias Renales/sangre , Lipoproteínas/sangre , Modelos Teóricos , Nanotecnología
5.
Joint Bone Spine ; 84(6): 685-691, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28011155

RESUMEN

OBJECTIVES: The aim of this study was to investigate the clinical value of sVE and anti-vascular endothelial-cadherin antibodies (AAVE) in RA treated with etanercept or adalimumab combined with methotrexate. METHODS: This was an 18-month prospective multicenter study in which patients had active RA, requiring TNF antagonist. sVE rates and AAVE titers were measured respectively by dot blot and ELISA. The relationship of these biomarkers with parameters reflecting articular or systemic disease activity, progression of structural damage, and response or remission to treatment was analyzed. RESULTS: Forty-eight patients received TNF blocking agents. Variation of sVE rates were significantly correlated with that of C-reactive protein (CRP) levels at weeks 6, 12, 26 and 52. A significant decrease in sVE levels was observed in the group of patients exhibiting a decrease in CRP levels as compared to the patient group with unmodified CRP. AAVE at baseline were correlated with rheumatoid factor. Kinetics analysis of sVE levels and AAVE titers showed that their level were not associated with disease activity score and to methotrexate/adalimumab or etanercept response. CONCLUSIONS: sVE is a biomarker associated with systemic RA activity under anti-TNF. AAVE are related to autoantibodies usually associated to RA.


Asunto(s)
Adalimumab/uso terapéutico , Antígenos CD/análisis , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Autoanticuerpos/análisis , Cadherinas/análisis , Etanercept/uso terapéutico , Adulto , Anciano , Antígenos CD/inmunología , Artritis Reumatoide/diagnóstico , Autoanticuerpos/inmunología , Biomarcadores/análisis , Cadherinas/inmunología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Francia , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Solubilidad , Resultado del Tratamiento
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