Histone Deacetylase Inhibitors Impair Vasculogenic Mimicry from Glioblastoma Cells.

Olga Pastorino,Maria Teresa Gentile,Nunzio Del Gaudio,Tullio Florio,Luca Colucci-D’Amato,Alessandro Mancini,Maria Patrizia Stoppelli,Antonella Di Costanzo,Adriana Bajetto,Lucia Altucci,Paola Franco

doi:10.3390/cancers11060747

Abstract

Glioblastoma (GBM), a high-grade glioma (WHO grade IV), is the most aggressive form of brain cancer. Available treatment options for GBM involve a combination of surgery, radiation and chemotherapy but result in a poor survival outcome. GBM is a high-vascularized tumor and antiangiogenic drugs are widely used in GBM therapy as adjuvants to control abnormal vasculature. Vasculogenic mimicry occurs in GBM as an alternative vascularization mechanism, providing a means whereby GBM can escape anti-angiogenic therapies. Here, using an in vitro tube formation assay on Matrigel®, we evaluated the ability of different histone deacetylase inhibitors (HDACis) to interfere with vasculogenic mimicry. We found that vorinostat (SAHA) and MC1568 inhibit tube formation by rat glioma C6 cells. Moreover, at sublethal doses for GBM cells, SAHA, trichostatin A (TSA), entinostat (MS275), and MC1568 significantly decrease tube formation by U87MG and by patient-derived human GBM cancer stem cells (CSCs). The reduced migration and invasion of HDACis-treated U87 cells, at least in part, may account for the inhibition of tube formation. In conclusion, our results indicate that HDACis are promising candidates for blocking vascular mimicry in GBM.

Highlights

Glioblastoma (GBM) is the most common and lethal among nervous system tumors, classified as grade IV glioma by the World Health Organization (WHO) [1,2,3,4]
In order to clarify whether C6 and U87MG glioma cell lines may undergo a vasculogenic switch in three-dimensional cultures and, are suitable models to study vasculogenic mimicry in vitro, we performed tube formation assays on a gelled basement membrane
When cultivated in 3D-Matrigel® (ECM), under serum-free conditions, they form clear-cut tubes developing from elongated cell bodies that connect to each other and form polygonal networks similar to those formed by HUVECs (Figure 1A)

Summary

Introduction

Glioblastoma (GBM) is the most common and lethal among nervous system tumors, classified as grade IV glioma by the World Health Organization (WHO) [1,2,3,4]. It has been suggested that GBM resistance to radio- and chemotherapy and the subsequent tumor recurrence after surgical resection is mainly due to cancer stem cell (CSC) subpopulations, which promote tumor initiation [11,12,13,14], making this cancer one of the most difficult to treat [10,14,15,16,17,18]. Another hallmark of GBM is high vascularization. Vascular endothelial cell growth factor (VEGF), interacting with its receptors (VEGFRs), is a strong stimulator of endothelial cell (ECs) proliferation and mobility during angiogenesis [21] and high levels of VEGF are detected in the tumor microenvironment [22]

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Discussion

Conclusion