Abnormal Vessels Potentially Accelerate Glioblastoma Proliferation by Inducing the Protumor Activation of Macrophages.

in Cancer science by Hiroaki Matsuzaki, Keitaro Kai, Yoshihiro Komohara, Hiromu Yano, Cheng Pan, Yukio Fujiwara, Rin Yamada, Ai Iwauchi, Nei Fukasawa, Toshihide Tanaka, Masayuki Shimoda, Hiroshi Watanabe, Toru Maruyama, Toru Takeo, Yoshiki Mikami, Akitake Mukasa

TLDR

  • The study investigated the relationship between BBB disruption and GAM activation in GBM, finding PLVAP as a key marker of BBB disruption and AGP as a key contributor to GAM activation and tumor progression.
  • The study suggests that targeting PLVAP and AGP may improve treatment outcomes for GBM patients.

Abstract

Glioblastoma (GBM) involves disruptions in the blood-brain barrier (BBB) and alterations in the immune microenvironment, including the activation of glioma-associated macrophages (GAMs). Vascular endothelial growth factor inhibitors, commonly used in recurrent GBM treatment, can influence these processes. This study investigates the relationship between BBB disruption and GAM activation, focusing on plasmalemma vesicle-associated protein (PLVAP), a marker of BBB disruption, and α1-acid glycoprotein (AGP), an inflammatory protein implicated in tumor progression. PLVAP expression was analyzed by immunohistochemistry (IHC) in human GBM samples to determine correlations with tumor grade, proliferation, and GAM activation. Pre- and post-bevacizumab treatment GBM samples were compared to assess changes in BBB integrity and macrophage activity. AGP's role in GAM activation was studied through in vitro assays and glioma implantation in AGP knockout mice, with assessments of tumor growth and angiogenesis. Results showed elevated PLVAP expression in higher-grade gliomas, correlating with increased tumor proliferation and GAM activation, particularly around PLVAP-positive vessels. Bevacizumab treatment reduced PLVAP expression and macrophage activity. AGP localized to regions of BBB disruption, promoting macrophage-mediated tumor growth in vitro. AGP knockout mice demonstrated reduced angiogenesis and prolonged survival. Spatial analysis revealed increased expression of macrophage-inducing molecules near PLVAP-positive vessels. These findings suggest PLVAP as a marker of BBB disruption and glioma malignancy. AGP, associated with BBB leakage, contributes to GAM activation and tumor progression, highlighting its potential as a therapeutic target for GBM.

Overview

  • The study investigates the relationship between blood-brain barrier (BBB) disruption and glioma-associated macrophages (GAM) activation in glioblastoma (GBM).
  • The study focuses on plasmalemma vesicle-associated protein (PLVAP) as a marker of BBB disruption and α1-acid glycoprotein (AGP) as an inflammatory protein implicated in tumor progression.
  • The study aims to understand the role of PLVAP and AGP in GBM and to identify potential therapeutic targets to improve treatment outcomes.

Comparative Analysis & Findings

  • The study found elevated PLVAP expression in higher-grade gliomas, correlating with increased tumor proliferation and GAM activation.
  • Bevacizumab treatment reduced PLVAP expression and macrophage activity, suggesting that VEGF inhibitors can influence BBB integrity and macrophage activity.
  • AGP localized to regions of BBB disruption, promoting macrophage-mediated tumor growth in vitro, and AGP knockout mice demonstrated reduced angiogenesis and prolonged survival.

Implications and Future Directions

  • The study suggests that PLVAP can serve as a marker of BBB disruption and glioma malignancy.
  • AGP, associated with BBB leakage, contributes to GAM activation and tumor progression, highlighting its potential as a therapeutic target for GBM.
  • Future studies should investigate the potential of PLVAP and AGP as therapeutic targets for GBM treatment, and explore the use of VEGF inhibitors to improve treatment outcomes.
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