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Identification of two glioblastoma-associated stromal cell subtypes with different carcinogenic properties in histologically normal surgical margins

Journal of Neuro-Oncology volume 122, pages 1–10 (2015)Cite this article

Abstract

Glioblastoma (GB) is a highly infiltrative tumor recurring within a few centimeters of the resection cavity in 85 % of cases, even in cases of complete tumor resection and adjuvant chemo/radiotherapy. We recently isolated GB-associated stromal cells (GASCs) from the GB peritumoral zone, with phenotypic and functional properties similar to those of the cancer-associated fibroblasts present in the stroma of carcinomas. In particular, GASCs promote blood vessel development and have tumor-promoting effects on glioma cells in vitro and in vivo. In this study, we characterized these cells further, by analyzing the transcriptome and methylome of 14 GASC and five control stromal cell preparations derived from non-GB peripheral brain tissues. We identified two subtypes of GASCs in surgical margins in GB patients: GASC-A and GASC-B. GASC-B promoted the development of tumors and endothelium, whereas GASC-A did not. A difference in DNA methylation may underlie these two subtypes. We identified various proteins as being produced in the procarcinogenic GASC-B. Some of these proteins may serve as prognostic factors for GB and/or targets for anti-glioma treatment. In conclusion, in this era of personalized therapy, the status of GASCs in GB-free surgical margins should be taken into account, to improve treatment and the prevention of recurrence.

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Abbreviations

CAFs:

Cancer-associated fibroblasts

CM:

Conditioned medium

DMEM-HG:

Dulbecco’s modified Eagles’ medium—high glucose

EBM-2:

Endothelial basal medium-2

EGM-2:

Endothelial cell growth medium-2

FCA:

Absolute fold-change

FCS:

Foetal calf serum

GASCs:

Glioblastoma-associated stromal cells

GB:

Glioblastoma

HABS:

Human AB serum

HUVECs:

Human umbilical vein endothelial cells

PDGFRβ:

Platelet derived growth factor receptor-beta

αSMA:

Alpha smooth muscle actin

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Acknowledgments

We thank Abderrahmane Hamlat and Véronique Quillien (CHU, Rennes) for providing control and tumor samples. We also thank Pierre Legras and Jérôme Roux (Service Commun d’Animalerie Hospitalo-Universitaire, Angers), Catherine Guillet (Paltform PACeM, Angers), and the Cancéropole Grand Ouest for allowing us to use their facilities. We thank Alex Edelman and Associates for correcting the English language of the manuscript.

Conflict of interest

We have no potential conflicts of interest to declare.

Funding

This work was supported by the Pays de la Loire and Bretagne regions and Ligue contre le cancer-49-Comité de Maine-et-Loire.

Author information

Affiliations

  1. LUNAM, Université d’Angers, 49035, Angers, France

    Anne Clavreul, Clément Tétaud, Audrey Rousseau & Philippe Menei

  2. INSERM U1066, Micro et Nanomédecines Biomimétiques (MINT), 49933, Angers, France

    Anne Clavreul, Clément Tétaud, Audrey Rousseau & Philippe Menei

  3. Département de Neurochirurgie, CHU, 49933, Angers, France

    Anne Clavreul & Philippe Menei

  4. INSERM U1066, 49100, Angers, France

    Anne Clavreul

  5. CNRS, UMR 6290, Institut de Génétique et Développement de Rennes (IGdR), 35043, Rennes, France

    Amandine Etcheverry & Jean Mosser

  6. Université Rennes1, UEB, UMS 3480 Biosit, Faculté de Médecine, 35043, Rennes, France

    Amandine Etcheverry & Jean Mosser

  7. Service de Génétique Moléculaire et Génomique, CHU Rennes, 35033, Rennes, France

    Amandine Etcheverry & Jean Mosser

  8. Laboratoire Pathologie Cellulaire et Tissulaire, CHU, 49933, Angers, France

    Audrey Rousseau

  9. Centre Régional de Lutte Contre le Cancer Eugène Marquis, 35000, Rennes, France

    Tony Avril

  10. Centre Régional de Lutte Contre le Cancer Paul Papin, INSERM U892, 49000, Angers, France

    Cécile Henry

  11. Plate-forme Génomique Santé Biosit, Université Rennes1, 35043, Rennes, France

    Jean Mosser

Authors
  1. Anne Clavreul
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  2. Amandine Etcheverry
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  6. Cécile Henry
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  7. Jean Mosser
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  8. Philippe Menei
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Correspondence to Anne Clavreul.

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Clavreul, A., Etcheverry, A., Tétaud, C. et al. Identification of two glioblastoma-associated stromal cell subtypes with different carcinogenic properties in histologically normal surgical margins. J Neurooncol 122, 1–10 (2015). https://doi.org/10.1007/s11060-014-1683-z

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  • DOI: https://doi.org/10.1007/s11060-014-1683-z

Keywords

  • Translational study
  • Glioblastoma
  • Peritumoral brain zone
  • Cancer-associated fibroblasts