EphB4 mediates resistance to antiangiogenic therapy in experimental glioma.

Abstract:

INTRODUCTION:Alterations in vascular morphogenesis are hallmarks of antiangiogenesis-resistant tumor vessels. Vascular morphogenesis is regulated by ephrinB2-EphB4 system which may induce different biological effects depending on the oncological and molecular contexts. It was the aim of the current study to characterize the influence of EphB4 on tumor microcirculation after antiangiogenic treatment using different SF126 glioma models. MATERIALS AND METHODS:Using an ecotropic transfection system, empty vector (pLXSN) or EphB4 (EphB4OE) overexpressing Phoenix-ECO cells were coimplanted with SF126 glioma cells subcutaneously (dorsal skinfold chamber, DSC) and orthotopically (cranial window, CW). Tumor volume was assessed by MRI. Intravital microscopy (IVM) allowed microcirculatory analysis (total {TVD} and functional vessel density {FVD}, diameter {D}, and permeability index {PI}) before and after antiangiogenic treatment (Sunitinib: DSC: 40 mg/kg BW, 6 days; CW: 80 mg/kg BW, 4 days). Immunohistochemistry included Pecam-Desmin, Ki67, TUNEL, and Caspase 3 stainings. RESULTS:EphB4OE induced large and treatment-resistant tumor vessels (FVD: Control/Su: 110 ± 23 cm/cm2 vs. EphB4OE/Su: 103 ± 42 cm/cm2). Maintenance of pericyte-endothelial cell interactions (Control: 80 ± 12 vs. Control/Su: 47 ± 26%; EphB4OE: 88 ± 9 vs. EphB4OE/Su: 74 ± 25%) and reduced antiproliferative (Control: 637 ± 80 vs. Control/Su: 110 ± 22; EphB4OE: 298 ± 108 vs. EphB4OE/Su: 213 ± 80) and proapoptotic responses (Control: 196 ± 25 vs. Control / Su: 404 ± 60; EphB4OE: 183 ± 20 vs. EphB4OE/Su: 270 ± 66) were observed under EphB4 overexpression. CONCLUSION:EphB4 overexpression leads to vascular resistance by altering vascular morphogenesis, pericyte coverage, and cellular proliferation/apoptosis in experimental SF126 glioma models.

journal_name

Angiogenesis

journal_title

Angiogenesis

authors

Uhl C,Markel M,Broggini T,Nieminen M,Kremenetskaia I,Vajkoczy P,Czabanka M

doi

10.1007/s10456-018-9633-6

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

873-881

issue

4

eissn

0969-6970

issn

1573-7209

pii

10.1007/s10456-018-9633-6

journal_volume

21

pub_type

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