Evidence of Reelin Signaling in GBM and Its Derived Cancer Stem Cells.

Filippo Biamonte,Alessio D’Alessio,Gigliola Sica,Antonio Filippini

doi:10.3390/brainsci11060745

Abstract

Glioblastoma (GBM) is the most aggressive and malignant form of primary brain cancer, characterized by an overall survival time ranging from 12 to 18 months. Despite the progress in the clinical treatment and the growing number of experimental data aimed at investigating the molecular bases of GBM development, the disease remains characterized by a poor prognosis. Recent studies have proposed the existence of a population of GBM cancer stem cells (CSCs) endowed with self-renewal capability and a high tumorigenic potential that are believed to be responsible for the resistance against common chemotherapy and radiotherapy treatments. Reelin is a large secreted extracellular matrix glycoprotein, which contributes to positioning, migration, and laminar organization of several central nervous system structures during brain development. Mutations of the reelin gene have been linked to disorganization of brain structures during development and behavioral anomalies. In this study, we explored the expression of reelin in GBM and its related peritumoral tissue and performed the same analysis in CSCs isolated from both GBM (GCSCs) and peritumoral tissue (PCSCs) of human patients. Our findings reveal (i) the higher expression of reelin in GBM compared to the peritumoral tissue by immunohistochemical analysis, (ii) the mRNA expression of both reelin and its adaptor molecule Dab1 in either CSC subtypes, although at a different extent; and (iii) the contribution of CSCs-derived reelin in the migration of human primary GBM cell line U87MG. Taken together, our data indicate that the expression of reelin in GBM may represent a potential contribution to the regulation of GBM cancer stem cells behavior, further stimulating the interest on the reelin pathway as a potential target for GBM treatment.

Highlights

GBM is a malignant and a very aggressive form of primary brain cancer whose clinical treatment represents a major challenge based on its great heterogeneity and the high frequency of recurrences
We investigated the expression of both reelin and its adapter molecule Dab1 in cancer stem cells (CSCs) isolated from GBM (GCSCs) and from the peritumoral tissues (PCSCs) derived from GBM patients as previously reported [46] and further characterized by our group [4,5,6,7,9,10,11]
By real time-PCR analysis, the expression of both reelin and its adaptor molecule Dab1 mRNA in both GCSCs and PCSCs isolated from four different GBM patients

Summary

Introduction

GBM is a malignant and a very aggressive form of primary brain cancer whose clinical treatment represents a major challenge based on its great heterogeneity and the high frequency of recurrences. Despite the aggressive treatment of patients with a combination of surgery followed by radio and chemotherapy, GBM remains essentially an incurable disease with a median survival time ranging from 12 to 18 months [1,2,3]. Reelin is a large secreted extracellular glycoprotein of approximately 400 kDa [13,14] that plays a key role in the regulation of neuronal migration during mammalian brain development [15]. Studies performed in the null reeler mouse have suggested that the serine protease activity of reelin is crucial for its function in the developing brain [16]. See [17,18] for a detailed review of the main structural and functional features of the reelin glycoprotein in the nervous system development

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