Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting.

Sune Munthe,Bjarne Winther Kristensen,Torben A Kruse,Mark Burton,Justin D Lathia,Mia D Sørensen,Frantz Rom Poulsen,Mads Thomassen

doi:10.1007/s11060-016-2221-y

Abstract

Glioblastoma (GBM) is the most frequent and malignant brain tumor with an overall survival of only 14.6 months. Although these tumors are treated with surgery, radiation and chemotherapy, recurrence is inevitable. A critical population of tumor cells in terms of therapy, the so-called cancer stem cells (CSCs), has been identified in gliomas and many other cancers. These tumor cells have a stem cell-like phenotype and are suggested to be responsible for tumor growth, chemo- and radio-resistance as well as recurrence. However, functional evidence for migrating glioma cells having a stem cell-like phenotype is currently lacking. In the present study, the aim was to characterize the phenotype of migrating tumor cells using a novel migration assay based on serum-free stem cell medium and patient-derived spheroid cultures. The results showed pronounced migration of five different GBM spheroid cultures, but not of the commercial cell line U87MG. An in vitro limiting dilution assay showed preserved but reduced spheroid formation capacity of migrating cells. Orthotopic xenografting in mice showed preserved but reduced tumorigenic capacity. Profiling of mRNAs revealed no significant deregulation of 16 predefined CSC-related genes and the HOX-gene list in migrating cells compared to spheroids. Determination of GBM molecular subtypes revealed that subtypes of spheroids and migrating cells were identical. In conclusion, migrating tumor cells preserve expression of stem cell markers and functional CSC characteristics. Since CSCs are reported to be highly resistant to therapy, these results emphasize that the CSC phenotype should be taken into consideration in future treatment of GBMs.

Highlights

Glioblastoma (GBM) is the most frequent primary malignant central nervous system tumor
We evaluated the migration of the commercial cell line U87MG but without identifying any migrating cells (Fig. 1d)
Spheroids derived from an earlier passage of spheroids versus migrating cells were processed and histological sections stained with CD133 (h, i) and SOX-2 (k, l)

Summary

Introduction

Glioblastoma (GBM) is the most frequent primary malignant central nervous system tumor. Despite multi-modal therapy including surgery, irradiation and chemotherapy, the median survival is only 14.6 months [1, 2]. GBM tumor cells migrate into the normal brain parenchyma along vessels and white matter fiber-tracts [3]. The highly migratory capability is thought to be a major reason for the short overall survival of GBM patients, since it results in tumor cells being left behind after surgery. The phenotype of migrating tumors cells is poorly described thereby preventing development of efficient therapies. A population of tumor cells with stem cell characteristics has been described in GBM and many other cancers [4, 5]

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Discussion

Conclusion