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

IF 5.7 2区医学 Q1 Medicine

Cancer Science Pub Date : 2025-02-07 DOI:10.1111/cas.70014

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

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引用次数: 0

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.

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来源期刊

Cancer Science ONCOLOGY-

CiteScore

9.90

自引率

3.50%

发文量

406

审稿时长

17 weeks

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.