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Human pontine glioma cells can induce murine tumors

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Abstract

Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9 months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy (1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or (2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprising human cells. Of note, direct injection of cells obtained postmortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.

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Acknowledgments

We would like to thank the patients and families who so generously donated tissue for this research. We sincerely thank the architect and artist Alessandra Luoni for drawing Fig. 1a. We gracefully acknowledge Alyssa Noll (Departments of Neurology and Pediatrics) for support with animal experiments, and Patty Lovelace (FACS Core) for her expertise with flow cytometry experiments; all from Stanford, USA. The flow cytometer used was purchased using an NIH S10 Shared Instrumentation Grant (1S10RR02933801). We are thankful to Jacqueline Cloos (Department of Pediatric Oncology, VU University Medical Center, The Netherlands) and Dana Bangs (Cytogenetics Laboratory, Stanford, USA) for their mastery in analyzing metaphase spreads. We are also thankful to Sridevi Yadavilli for processing postmortem specimens and assisting in murine injections, Research Center for Genetic Medicine, Children’s National Medical Center, Washington, USA. This work was supported by the Semmy Foundation, KiKa Children Cancer Free, Child Health Research Institute, Lucile Packard Foundation for Children’s Health, as well as the Stanford CTSA—award number UL1 TR000093—(V.C.), Stanford University School of Medicine Dean’s Fellowship (V.C.), National Institutes of Neurological Disease and Stroke (NINDS grant K08NS070926), Alex’s Lemonade Stand Foundation, McKenna Claire Foundation, The Cure Starts Now, Lyla Nsouli Foundation, Connor Johnson Memorial Fund, Dylan Jewett Memorial Fund, Dylan Frick Memorial Fund, Abigail Jensen Memorial Fund, Zoey Ganesh Memorial Fund, Wayland Villars Memorial Fund and Musella Foundation.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Departments of Neurology, Neurosurgery and Pediatrics, Stanford University School of Medicine, Stanford, USA

    Viola Caretti & Michelle Monje

  2. Department of Pathology, Stanford University School of Medicine, Stanford, USA

    Hannes Vogel

  3. Research Center for Genetic Medicine, Children’s National Medical Center, Washington, USA

    Javad Nazarian

  4. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Thomas Wurdinger

  5. Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands

    Viola Caretti, A. Charlotte P. Sewing, Tonny Lagerweij, Pepijn Schellen, Marc H. A. Jansen, Dannis G. van Vuurden, Gertjan J. L. Kaspers & Esther Hulleman

  6. Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands

    Viola Caretti, A. Charlotte P. Sewing, Tonny Lagerweij, Pepijn Schellen, W. Peter Vandertop, David P. Noske, Esther Hulleman & Thomas Wurdinger

  7. Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands

    Viola Caretti, A. Charlotte P. Sewing, Tonny Lagerweij, Pepijn Schellen, Marc H. A. Jansen, Dannis G. van Vuurden, David P. Noske, Pieter Wesseling, Esther Hulleman & Thomas Wurdinger

  8. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    Marianna Bugiani & Pieter Wesseling

  9. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands

    Ilona Horsman

  10. Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands

    Anna C. Navis & Pieter Wesseling

  11. Stanford University School of Medicine, 265 Campus Drive, Room G3077, Stanford, CA, 94305, USA

    Viola Caretti & Michelle Monje

  12. VU University Medical Center, CCA Room 3.34, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Esther Hulleman & Thomas Wurdinger

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  1. Viola Caretti
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Corresponding authors

Correspondence to Viola Caretti, Esther Hulleman, Michelle Monje or Thomas Wurdinger.

Additional information

E. Hulleman, M. Monje and T. Wurdinger contributed equally.

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Supplementary material 1 Supplementary Fig. 1 Histopathological characterization of human and murine VU-DIPG-3 and -5. H&E images of a, b h-VU-DIPG-3, c, d h-VU-DIPG-5, e–h m-VU-DIPG-3 (transplant generations 3–10, except h = transplant generation 1) and i–l m-VU-DIPG-5 (transplant generations 3–10, except k = transplant generation 1). High magnification image of small cell phenotype in (a, d) h-VU-DIPG-3 and -5 and in (e, j) the correspondent m-VU-DIPG-3 and -5. b, f Numerous tumor cells surrounding the tunica adventitia in h-VU-DIPG-3 and m-VU-DIPG-3. The arrow in figure b indicates a fibrin aggregate. c, f and i Leptomeningeal spread in h-VU-DIPG-5 and in m-VU-DIPG-3 and -5. The arrow in figure c points at a leptomeningeal artery presenting thick walls. Note the tumor front invading the surrounding brain parenchyma in figure i. d, g, l Tumor cells clustered around vessels in h-VU-DIPG-3 and m-VU-DIPG-3 and -5. Arrows indicate perivascular growth. g Murine intraparencymal tumors presented areas of more compact growth (asterisk) along with diffuse growth after the first two transplant generation. h Perineuronal satellistosis, the arrow points at the neuronal cell body. k m-VU-DIPG-5 invading the skull bone. Scale bars a, c, d, e, g, h, I and j 10 μm; b 100 μm; f, k and l 20 μm. Supplementary Fig. 2 Metaphase spreads in murine pontine tumors and h-SU-DIPG-VI. a Murine VU-DIPG-3 abnormal metaphase with 41 chromosomes including an apparent dicentric chromosome (arrow). b Murine VU-DIPG-5 polyploid metaphase with 80 chromosomes including two centric fusion chromosomes (arrows). c Murine CNMC-D1 diploid metaphase and d grossly abnormal metaphase. e Human SU-DIPG-VI (in vitro passage 10) tetraploid metaphase spread with arrows indicating some of the abnormal chromosomes present. Murine VU-DIPG-3 and -5 cells were obtained from subcutaneous tumors at transplant generation 3–10; m-CNMC-D1 cells were obtained form pontine xenograft (transplant generation 1) and cultured in vitro for eight passages. Supplementary Fig. 3 Murine array-comparative genomic hybridization raw data. Fluorescent image of m-VU-DIPG-3 hybridized with m-DNA CTRL on (a) a human platform and on (b) a murine platform. Supplementary Table 1 Clinical characteristics of subjects whose DIPG tumors were evaluated for microglia/macrophage markers. WHO refers to World Health Organization and GBM refers to glioblastoma multiforme (grade IV). The clinical characteristics for SU-DIPG-VI are reported in Table 1. Supplementary Table 2 Primer sequences. The following primer was used for sequencing the murine H3F3A region of interest: AGATACATGTGTTCACAAAC. Supplementary Table 3 Human SU-DIPG-VI Control Cortex DNA Short Tandem Repeat (STR) fingerprint (PPTX 7102 kb)

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Caretti, V., Sewing, A.C.P., Lagerweij, T. et al. Human pontine glioma cells can induce murine tumors. Acta Neuropathol 127, 897–909 (2014). https://doi.org/10.1007/s00401-014-1272-4

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