Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients

Lin-Fang Wang,Emmanouil Fokas,Frank Rose,Rita Engenhart-Cabillic,Han-Xiang An,An You,Axel Pagenstecher,Janko Juricko

doi:10.1186/1471-2407-8-79

Abstract

BackgroundMalignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM). Ephs and ephrins have many well-defined functions during embryonic development of central nervous system such as axon mapping, neural crest cell migration, hindbrain segmentation and synapse formation as well as physiological and abnormal angiogenesis. Accumulating evidence indicates that Eph and ephrins are frequently overexpressed in different tumor types including GBM. However, their role in tumorigenesis remains controversial, as both tumor growth promoter and suppressor potential have been ascribed to Eph and ephrins while the function of EphA7 in GBM pathogenesis remains largely unknown.MethodsIn this study, we investigated the immunohistochemical expression of EphA7 in a series of 32 primary and recurrent GBM and correlated it with clinical pathological parameters and patient outcome. In addition, intratumor microvascular density (MVD) was quantified by immunostaining for endothelial cell marker von Willebrand factor (vWF).ResultsOverexpression of EphA7 protein was predictive of the adverse outcome in GBM patients, independent of MVD expression (p = 0.02). Moreover, high density of MVD as well as higher EphA7 expression predicted the disease outcome more accurately than EphA7 variable alone (p = 0.01). There was no correlation between MVD and overall survival or recurrence-free survival (p > 0.05). However, a statistically significant correlation between lower MVD and tumor recurrence was observed (p = 0.003).ConclusionThe immunohistochemical assessment of tissue EphA7 provides important prognostic information in GBM and would justify its use as surrogate marker to screen patients for tyrosine kinase inhibitor therapy.

Highlights

Malignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM)
The Eph receptors and their ligands, ephrins, represent the largest known family of Receptor tyrosine kinases (RTKs). Their role has been largely studied during the development of nervous system. They are involved in the development of central nervous system, including axon guidance, axon fasciculation, neural crest cell migration, hindbrain segmentation, vasculogenesis and neuronal cell survival during embryonic development [6,7,8,9,10,11,12,13]
Whereas several studies in recent years have clearly indicated that altered expression of Eph receptors and ephrin ligands is associated with increased potential for tumor growth, angiogenesis, metastasis and adverse outcome [34,35,36,37,38,39,40,41,42], few studies have addressed the role of EphA7 in tumor pathogenicity

Summary

Introduction

Malignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM). Ephs and ephrins have many well-defined functions during embryonic development of central nervous system such as axon mapping, neural crest cell migration, hindbrain segmentation and synapse formation as well as physiological and abnormal angiogenesis. Accumulating evidence indicates that Eph and ephrins are frequently overexpressed in different tumor types including GBM. Their role in tumorigenesis remains controversial, as both tumor growth promoter and suppressor potential have been ascribed to Eph and ephrins while the function of EphA7 in GBM pathogenesis remains largely unknown. EphA receptors bind the glycosylphosphatidylinositol (GPI)-anchored ephrin-A ligands, whereas EphB receptors bind the transmembrane ephrin-B ligands, whose cytoplasmic domain is capable to engage in various signaling activities; an exception is the EphA4 receptor that binds ephrin-B2 and ephrin-B3 as well as ephrin-A ligands [1416] These RTKs have the ability to induce both forward and reverse (bi-directional) signaling between adjacent interacting cells

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Conclusion