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Development of a transplantable glioma tumour model from genetically engineered mice: MRI/MRS/MRSI characterisation

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Abstract

The initial aim of this study was to generate a transplantable glial tumour model of low-intermediate grade by disaggregation of a spontaneous tumour mass from genetically engineered models (GEM). This should result in an increased tumour incidence in comparison to GEM animals. An anaplastic oligoastrocytoma (OA) tumour of World Health Organization (WHO) grade III was obtained from a female GEM mouse with the S100β-v-erbB/inK4a-Arf (+/−) genotype maintained in the C57BL/6 background. The tumour tissue was disaggregated; tumour cells from it were grown in aggregates and stereotactically injected into C57BL/6 mice. Tumour development was followed using Magnetic Resonance Imaging (MRI), while changes in the metabolomics pattern of the masses were evaluated by Magnetic Resonance Spectroscopy/Spectroscopic Imaging (MRS/MRSI). Final tumour grade was evaluated by histopathological analysis. The total number of tumours generated from GEM cells from disaggregated tumour (CDT) was 67 with up to 100 % penetrance, as compared to 16 % in the local GEM model, with an average survival time of 66 ± 55 days, up to 4.3-fold significantly higher than the standard GL261 glioblastoma (GBM) tumour model. Tumours produced by transplantation of cells freshly obtained from disaggregated GEM tumour were diagnosed as WHO grade III anaplastic oligodendroglioma (ODG) and OA, while tumours produced from a previously frozen sample were diagnosed as WHO grade IV GBM. We successfully grew CDT and generated tumours from a grade III GEM glial tumour. Freezing and cell culture protocols produced progression to grade IV GBM, which makes the developed transplantable model qualify as potential secondary GBM model in mice.

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Abbreviations

BBB:

Blood–brain barrier

CDT:

Cells from disaggregated tumour

CE:

Contrast-enhanced

Cho:

Choline

Cr:

Creatine

DCE:

Dynamic contrast enhancement

DMSO:

Dimethyl sulfoxide

FASTMAP:

Fast automatic shimming technique by mapping along projections

GABRMN:

Grup d’aplicacions Biomèdiques de la Ressonància Magnètica Nuclear

GBM:

Glioblastoma

GEM:

Genetically engineered models

GFAP:

Glial fibrillary acidic protein

Glc:

d-glucose

ip:

Intraperitoneal

IST:

Inter-slice thickness

KO:

Knocked out

Lac:

Lactate

LET:

Long echo time

ML:

Mobile lipids

MR:

Magnetic Resonance

MRI,:

Magnetic Resonance Imaging

MRS:

Magnetic Resonance Spectroscopy

MRSI:

Magnetic Resonance Spectroscopic Imaging

NA:

Number of averages

NAA:

N-Acetylaspartate

OA:

Oligoastrocytoma

ODG:

Oligodendroglioma

Olig2:

Oligodendrocyte transcription factor 2

PBS:

Phosphate buffered saline

PCR:

Polymerase chain reaction

PE-MRSI:

Perturbation enhanced MRSI

p.i.:

Post-implantation

PR:

Pattern recognition

PRESS:

Point-resolved spectroscopy

RARE:

Rapid acquisition with relaxation enhancement

SD:

Standard deviation

SET:

Short echo time

spv:

Spectral vector

ST:

Slice thickness

SV:

Single voxel

TAT:

Total acquisition time

Tau:

Taurine

TE:

Echo time

TR:

Recycling time

UL:

Unit length

VAPOR:

Variable pulse power and optimized relaxation delays

VOI:

Volume of interest

WHO:

World Health Organization

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Acknowledgments

This work was funded by the Ministerio de Economía y Competitividad (MINECO) grants MARESCAN (SAF 2011–23870), MOLIMAGLIO (SAF2014-52332-R) and SAF2012-37417. Also funded by the ISCiii-Subdirección General de Evaluación and European Regional Development Fund (ERDF) [RETICS to JMC (RD12/0019/0002; Red de Terapia Celular)], Spain, and by Centro de Investigación Biomédica en Red—Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN, http://www.ciber-bbn.es/en), an initiative of the Instituto de Salud Carlos III (Spain) co-funded by EU Fondo Europeo de Desarrollo Regional (FEDER). M. Ciezka held an FI-DGR predoctoral fellowship (FI-DGR 2012) from the Generalitat de Catalunya.

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    Authors and Affiliations

    1. Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici Cs, Universitat Autònoma de Barcelona, 08193, Cerdanyola del Vallès, Spain

      Magdalena Ciezka, Milena Acosta, Ana Paula Candiota & Carles Arús

    2. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès, Spain

      Magdalena Ciezka, Milena Acosta, Martí Pumarola, Ana Paula Candiota & Carles Arús

    3. Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain

      Cristina Herranz & Josep M. Canals

    4. Research and Development Unit, Cell Therapy Program, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain

      Cristina Herranz & Josep M. Canals

    5. Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

      Cristina Herranz & Josep M. Canals

    6. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

      Cristina Herranz & Josep M. Canals

    7. Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193, Cerdanyola del Vallès, Spain

      Ana Paula Candiota & Carles Arús

    8. Departament de Medicina i Cirurgia Animals, Facultat de Veterinària, Edifici V, Universitat Autònoma de Barcelona, 08193, Cerdanyola del Vallès, Spain

      Martí Pumarola

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    1. Magdalena Ciezka
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    2. Milena Acosta
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    3. Cristina Herranz
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    Corresponding author

    Correspondence to Ana Paula Candiota.

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    M. Ciezka and M. Acosta have contributed equally to data acquisition.

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    Ciezka, M., Acosta, M., Herranz, C. et al. Development of a transplantable glioma tumour model from genetically engineered mice: MRI/MRS/MRSI characterisation. J Neurooncol 129, 67–76 (2016). https://doi.org/10.1007/s11060-016-2164-3

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