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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Tumour-associated glial host cells display a stem-like phenotype with a distinct gene expression profile and promote growth of GBM xenografts

Authors: Lina Leiss, Ercan Mutlu, Anne Øyan, Tao Yan, Oleg Tsinkalovsky, Linda Sleire, Kjell Petersen, Mohummad Aminur Rahman, Mireille Johannessen, Sidhartha S. Mitra, Hege K. Jacobsen, Krishna M. Talasila, Hrvoje Miletic, Inge Jonassen, Xingang Li, Nicolaas H. Brons, Karl-Henning Kalland, Jian Wang, Per Øyvind Enger

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

Little is known about the role of glial host cells in brain tumours. However, supporting stromal cells have been shown to foster tumour growth in other cancers.

Methods

We isolated stromal cells from patient-derived glioblastoma (GBM) xenografts established in GFP-NOD/scid mice. With simultaneous removal of CD11b+ immune and CD31+ endothelial cells by fluorescence activated cell sorting (FACS), we obtained a population of tumour-associated glial cells, TAGs, expressing markers of terminally differentiaed glial cell types or glial progenitors. This cell population was subsequently characterised using gene expression analyses and immunocytochemistry. Furthermore, sphere formation was assessed in vitro and their glioma growth-promoting ability was examined in vivo. Finally, the expression of TAG related markers was validated in human GBMs.

Results

TAGs were highly enriched for the expression of glial cell proteins including GFAP and myelin basic protein (MBP), and immature markers such as Nestin and O4. A fraction of TAGs displayed sphere formation in stem cell medium. Moreover, TAGs promoted brain tumour growth in vivo when co-implanted with glioma cells, compared to implanting only glioma cells, or glioma cells and unconditioned glial cells from mice without tumours. Genome-wide microarray analysis of TAGs showed an expression profile distinct from glial cells from healthy mice brains. Notably, TAGs upregulated genes associated with immature cell types and self-renewal, including Pou3f2 and Sox2. In addition, TAGs from highly angiogenic tumours showed upregulation of angiogenic factors, including Vegf and Angiopoietin 2. Immunohistochemistry of three GBMs, two patient biopsies and one GBM xenograft, confirmed that the expression of these genes was mainly confined to TAGs in the tumour bed. Furthermore, their expression profiles displayed a significant overlap with gene clusters defining prognostic subclasses of human GBMs.

Conclusions

Our data demonstrate that glial host cells in brain tumours are functionally distinct from glial cells of healthy mice brains. Furthermore, TAGs display a gene expression profile with enrichment for genes related to stem cells, immature cell types and developmental processes. Future studies are needed to delineate the biological mechanisms regulating the brain tumour-host interplay.
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Metadata
Title
Tumour-associated glial host cells display a stem-like phenotype with a distinct gene expression profile and promote growth of GBM xenografts
Authors
Lina Leiss
Ercan Mutlu
Anne Øyan
Tao Yan
Oleg Tsinkalovsky
Linda Sleire
Kjell Petersen
Mohummad Aminur Rahman
Mireille Johannessen
Sidhartha S. Mitra
Hege K. Jacobsen
Krishna M. Talasila
Hrvoje Miletic
Inge Jonassen
Xingang Li
Nicolaas H. Brons
Karl-Henning Kalland
Jian Wang
Per Øyvind Enger
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3109-8

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