Elsevier

Human Pathology

Volume 36, Issue 6, June 2005, Pages 665-669
Human Pathology

Original contribution
αvβ3 Integrin in central nervous system tumors

https://doi.org/10.1016/j.humpath.2005.03.014Get rights and content

Summary

αvβ3 is an integrin specifically expressed in endothelial cells of newly forming blood vessels. Integrin-mediated angiogenesis is hypothesized to play a central role in the development and the progression of central nervous system neoplasms. Accordingly, it is considered a potential target for antiangiogenic therapy. In the current study, we compare the expression of αvβ3 in ependymomas, oligodendrogliomas, pilocytic astrocytomas, medulloblastomas, and vestibular schwannomas (acoustic neuromas). Samples of 5 tumors of each of the 5 tumor types were harvested surgically and frozen. After the pathological diagnosis was confirmed, immunohistochemistry was performed using an anti-αvβ3 monoclonal antibody (LM609). The expression of αvβ3 was assessed using a 4-tiered (0-3) grading scheme reflecting the percentage of positively staining vessels. All vestibular schwannomas demonstrated strong (grade 3) αvβ3 expression. The expression was uniformly prominent in Antoni B regions of the tumors. Of 5 ependymomas, 4 demonstrated uniformly strong αvβ3 expression. Oligodendrogliomas, medulloblastomas, and pilocytic astrocytomas demonstrated more variable αvβ3 expression. αvβ3 may contribute significantly to angiogenesis in vestibular schwannomas and ependymomas. Despite the high vascular density of oligodendrogliomas, pilocytic astrocytomas, and medulloblastomas, these tumors had variable moderate αvβ3 expression. This discrepancy suggests temporal and/or regional variability in the angiogenesis in these types of tumor. This study provides the first demonstration of αvβ3 expression in vestibular schwannomas, medulloblastomas, and pilocytic astrocytomas.

Introduction

Tumor growth is dependent on newly formed vessels to provide oxygen and nutrients and to remove toxic metabolites [1]. Few tumors grow larger than 2 to 3 mm in diameter without developing new vessels [2]. The acquisition of an angiogenic phenotype determines, to some degree, the ability of a tumor to reach a clinically significant size [2]. In the normal adult brain, angiogenesis is tightly down-regulated. However, brain tumors can increase the proportion of endothelial cells involved in angiogenesis [3], [4].

Vessel sprouting is one proposed mechanism of angiogenesis. Sprouting is divided into 2 stages: growth and stabilization. The growth stage begins with nitric oxide–induced vasodilation mediated by a vascular endothelial growth factor pathway. Vasodilation and the resulting increase in permeability allow extravasation of plasma proteins that support endothelial cell proliferation. Concomitantly, the basement membrane and the surrounding interstitial matrix of the parent vessel are dissolved by matrix metalloproteinases. The newly formed space is soon filled by endothelial cells and pericytes that form an endothelial sprout. Lumina form within the sprouts, and fusion of individual sprouts produces new conduits. In the stabilization stage, the basement membrane reforms, cell replication ceases, and vascular permeability decreases. In the absence of vessel stabilization, the cells of the immature vessels undergo apoptosis [5], [6].

Integrins are thought to play an important role in sprouting. Integrins are cell surface receptors that mediate adhesion of endothelial cells to the extracellular matrix and the adjacent cells. Integrins also play a central role in angiogenesis by affecting local protease activity and migration of tumor cells. Last, they mediate the anchorage-dependent proliferation, adhesion, and migration of endothelial cells [7].

The presence of a particular integrin, αvβ3, on vessels of glioblastoma multiforme, anaplastic astrocytomas, and oligodendrogliomas (albeit weakly) has already been established. The expression of αvβ3 in medulloblastomas has been implied through the use of direct antagonists, but it has not been directly demonstrated. Previous studies have indicated a lack of αvβ3 expression in ependymomas [8]. The expression of αvβ3 has never been examined in vestibular schwannomas [2], [9]. In this study, we determined the immunohistochemical patterns of αvβ3 expression in oligodendrogliomas, medulloblastomas, pilocytic astrocytomas, ependymomas, and vestibular schwannomas.

Section snippets

Materials and methods

Since June 2001, tumors of all histological grades of astrocytoma, oligodendroglioma, ependymoma, meningioma, and vestibular schwannomas have been collected, snap frozen, and stored in the Stanford Tumor Bank under an institutional review board–approved protocol. A spectrum of tumors, including World Health Organization (WHO) grade 2 oligodendrogliomas, WHO grades 2 and 3 ependymomas, pilocytic astrocytomas, medulloblastomas, and vestibular schwannomas, was selected for use in this study. The

Results

All 5 vestibular schwannomas demonstrated strong (3+) αvβ3 expression. Expression was predominantly, but not exclusively, in the less cellular areas of Antoni B architectural regions (Fig. 1). Of 5 ependymomas (all WHO grades 2 and 3), 4 demonstrated strong (3+) αvβ3 expression (Fig. 2). No αvβ3 expression was identified in the fifth ependymoma specimen. Oligodendrogliomas (Fig. 3), medulloblastomas (Fig. 4), and pilocytic astrocytomas (Fig. 5) demonstrated heterogeneous staining within each

Discussion

Integrins are composed of 2 subunits, α˙ and β˙ [10], [11]. The α˙ subunit has an extracellular domain that binds matrix molecules, and the β˙ subunit has a cytoplasmic domain that interacts with the actin cytoskeleton, microfilament-associated proteins, and several signaling mediators. Stimulation of the integrin activates a signaling cascade that promotes the transcription of genes involved in cell-cell contacts and endothelial cell migration [11]. In addition, integrins help convey stimuli

Conclusion

We found that the integrin αvβ3 is expressed at varying levels of intensity in oligodendrogliomas, pilocytic astrocytomas, ependymomas, medulloblastomas, and vestibular schwannomas. The pattern of staining intensity was relatively uniform in vestibular schwannomas and ependymomas. The range of expression within the other tumor groups may reflect either temporal and/or regional variability in the course of angiogenesis among a group of tumors or within an individual tumor. To clarify the

Acknowledgments

This research was supported by the Giannini Family Foundation grant, National Institutes of Health grant 1F32NS049794-01A, and Stanford Brain Tumor Research Fund.

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