The neurovascular unit in diffuse intrinsic pontine gliomas

  • Fatma E. El-Khouly Emma Children’s Hospital, Amsterdam UMC – location VUmc, Department of Pediatric Oncology, Cancer Center Amsterdam, de Boelelaan 1117, Amsterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands https://orcid.org/0000-0003-1451-8516
  • Rianne Haumann Emma Children’s Hospital, Amsterdam UMC – location VUmc, Department of Pediatric Oncology, Cancer Center Amsterdam, de Boelelaan 1117, Amsterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  • Marjolein Breur Amsterdam UMC – location VUmc, Department of Pathology, de Boelelaan 1117, Amsterdam, The Netherlands
  • Sophie E.M. Veldhuijzen van Zanten Emma Children’s Hospital, Amsterdam UMC – location VUmc, Department of Pediatric Oncology, Cancer Center Amsterdam, de Boelelaan 1117, Amsterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  • Gertjan J.L. Kaspers Emma Children’s Hospital, Amsterdam UMC – location VUmc, Department of Pediatric Oncology, Cancer Center Amsterdam, de Boelelaan 1117, Amsterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  • N. Harry Hendrikse Amsterdam UMC – location VUmc, Department of Clinical Pharmacology & Pharmacy, de Boelelaan 1117, Amsterdam, The Netherlands; Amsterdam UMC – location VUmc, Department of Radiology & Nuclear Medicine, de Boelelaan 1117, Amsterdam, The Netherlands
  • Esther Hulleman Emma Children’s Hospital, Amsterdam UMC – location VUmc, Department of Pediatric Oncology, Cancer Center Amsterdam, de Boelelaan 1117, Amsterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  • Dannis G. van Vuurden Emma Children’s Hospital, Amsterdam UMC – location VUmc, Department of Pediatric Oncology, Cancer Center Amsterdam, de Boelelaan 1117, Amsterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  • Marianna Bugiani Amsterdam UMC – location VUmc, Department of Pathology, de Boelelaan 1117, Amsterdam, The Netherlands
Keywords: Diffuse intrinsic pontine glioma (DIPG), Neurovascular unit (NVU), Blood-brain barrier (BBB), Tight junctions, Brainstem, Pons

Abstract

Aims: Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a median overall survival of eleven months. Lack of chemotherapy efficacy may be related to an intact blood-brain barrier (BBB). In this study we aim to investigate the neurovascular unit (NVU) in DIPG patients.

Methods: DIPG biopsy (n = 4) and autopsy samples (n = 6) and age-matched healthy pons samples (n = 20) were immunohistochemically investigated for plasma protein extravasation, and the expression of tight junction proteins claudin-5 and zonula occludens-1 (ZO-1), basement membrane component laminin, pericyte marker PDGFR-β, and efflux transporters P-gp and BCRP. The mean vascular density and diameter were also assessed.

Results: DIPGs show a heterogeneity in cell morphology and evidence of BBB leakage. Both in tumor biopsy and autopsy samples, expression of claudin-5, ZO-1, laminin, PDGFR-β and P-gp was reduced compared to healthy pontine tissues. In DIPG autopsy samples, vascular density was lower compared to healthy pons. The density of small vessels (<10 µm) was significantly lower (P<0.001), whereas the density of large vessels (≥10 µm) did not differ between groups (P = 0.404). The median vascular diameter was not significantly different: 6.21 µm in DIPG autopsy samples (range 2.25-94.85 µm), and 6.26 µm in controls (range 1.17-264.77 µm).

Conclusion: Our study demonstrates evidence of structural changes in the NVU in DIPG patients, both in biopsy and autopsy samples, as well as a reduced vascular density in end-stage disease. Adding such a biological perspective may help to better direct future treatment choices for DIPG patients.

Published
2021-07-05
How to Cite
El-Khouly, F., Haumann, R., Breur, M., Veldhuijzen van Zanten, S., Kaspers, G., Hendrikse, N., Hulleman, E., van Vuurden, D., & Bugiani, M. (2021). The neurovascular unit in diffuse intrinsic pontine gliomas. Free Neuropathology, 2, 17. https://doi.org/10.17879/freeneuropathology-2021-3341
Section
Original Papers