Increased blood-brain barrier permeability following paediatric cancer treatments — The Association Specialists
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  3. Increased blood-brain barrier permeability following paediatric cancer treatments

Increased blood-brain barrier permeability following paediatric cancer treatments (21377)

Maya Davies 1 2 , Courtney Cross 1 2 , Long Yu 3 , Paul Trim 4 , Marten Snel 4 , Zarina Greenberg 5 , Cedric Bardy 3 5 , Hannah Rose Wardill 1 2
  1. Precision Medicine Theme, South Australian Medical Research Institute, Adelaide, South Australia, Australia
  2. Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
  3. College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
  4. Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health, and Medical Research Institute, Adelaide, South Australia, Australia
  5. Lifelong Health Theme, South Australian Medical Research Institute, Adelaide, South Australia, Australia

Introduction: 1 in 3 childhood cancer survivors develop severe and persistent cognitive impairment as a direct result of their treatments, impacting academic, vocational, and independent functioning. Unfortunately, there are no effective therapies reflecting a limited understanding of how these systemically administered treatments impact the central nervous system. Hence, we aimed to characterise the impact of anti-cancer treatments on the blood-brain barrier.

Methods: Brain microvasculature endothelial cells (BMECs) derived from human induced pluripotent stem cells were cultured on Transwell inserts and treated with 1.28mM PM (active metabolite of chemotherapeutic cyclophosphamide) for 48-hours. BMECs were fixed and stained with ZO-1 and caspase-3 for immunofluorescent analysis of tight-junction structure and apoptosis, respectively. In parallel, plasma samples from N=47 children undergoing haematopoietic stem cell transplant (HSCT) for haematological malignancies was analysed for markers of blood-brain barrier damage (S100ß), inflammation (interleukin-6), and neurological function (BDNF), pre- and post-transplant. 

Results: PM induced tight-junction malformation staining without inducing significant cell death. In addition, S100ß was significantly elevated in plasma after HSCT compared to baseline levels (78.75mM vs 5.70mM; P<0.0001) suggesting increased blood-brain barrier permeability. Increased plasma interleukin-6 (P=0.02) and decreased BDNF (P=0.0008) were also identified post-transplant.

Significance: These data suggest paediatric cancer treatments impair the integrity of the blood-brain barrier, providing a novel mechanism by which systemically administered anti-cancer treatments can access the brain to impair cognitive function. They also highlight the utility of S100ß in diagnosing blood-brain barrier disruption in the context of childhood cancer. Future work will look to test barrier strengthening compounds in vitro.