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<p>Blood-brain barrier (BBB) disruption is a well-known phenomenon in glioblastoma (GBM). However, the mechanism driving BBB dysfunction in previously established vasculature at the invasive edge of GBM is still unknown. In this study, we aimed to determine if GBM paracrine signaling is sufficient to induce BBB dysfunction and identify changes in the tight junctions of the BBB. An in vivo U-87 MG xenograft model and an in vitro primary brain endothelial cell BBB model were established for barrier dysfunction monitoring. Immunofluorescent staining revealed significantly higher claudin-1 expression and significantly lower claudin-5 expression in the tumor vs. normal brain tissue of our in vivo model (<i>p</i> &lt; 0.01). Additionally, claudin-1 expression co-localized with brain cell type markers for endothelium, pericytes, and microglia. In vitro exposure of brain microvascular endothelial cells to GBM conditioned media resulted in a significant decrease in transendothelial electrical resistance as well as delocalization of claudin-5 from the tight junctions. These results suggest GBM cells secrete factors capable of inducing changes in the tight junction proteins of the BBB and decreasing barrier integrity. Future studies will aim to identify the mechanism in which these changes occur.</p>

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Glioblastoma induced blood-brain barrier dysfunction via a paracrine mechanism that increases claudin-1 expression

  • 期刊论文

  • 发表日期：

    2025年2月17日

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  • Brittany Schweiger,
  • Forrest M. Kievit

摘要

Blood-brain barrier (BBB) disruption is a well-known phenomenon in glioblastoma (GBM). However, the mechanism driving BBB dysfunction in previously established vasculature at the invasive edge of GBM is still unknown. In this study, we aimed to determine if GBM paracrine signaling is sufficient to induce BBB dysfunction and identify changes in the tight junctions of the BBB. An in vivo U-87 MG xenograft model and an in vitro primary brain endothelial cell BBB model were established for barrier dysfunction monitoring. Immunofluorescent staining revealed significantly higher claudin-1 expression and significantly lower claudin-5 expression in the tumor vs. normal brain tissue of our in vivo model (p < 0.01). Additionally, claudin-1 expression co-localized with brain cell type markers for endothelium, pericytes, and microglia. In vitro exposure of brain microvascular endothelial cells to GBM conditioned media resulted in a significant decrease in transendothelial electrical resistance as well as delocalization of claudin-5 from the tight junctions. These results suggest GBM cells secrete factors capable of inducing changes in the tight junction proteins of the BBB and decreasing barrier integrity. Future studies will aim to identify the mechanism in which these changes occur.