D-2-hydroxyglutarate regulates human brain vascular endothelial cell proliferation and barrier function

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Gain-of-function mutations in isocitrate dehydrogenase (IDH) genes lead to excessive (D)-2-hydroxyglutarate (D-2HG) production.
• D-2HG influences tumor cell epigenetics and surrounding non-cancerous cells, but its paracrine effect on endothelial cells in the tumor microenvironment is unclear.

Purpose of the Study:

• To investigate the paracrine effect of D-2HG on endothelial cells within the tumor microenvironment.
• To determine if D-2HG influences microvessel density and endothelial barrier function in astrocytoma.

Main Methods:

• Quantified microvessel density in high-grade astrocytic gliomas using immunohistochemistry.
• Conducted ex vivo experiments with D-2HG on endothelial cells to assess migration, wound healing, and tube formation.
• Evaluated D-2HG's impact on endothelial barrier function, including permeability and T-cell transendothelial migration.

Main Results:

• Microvessel density was reduced in IDH-mutated gliomas.
• D-2HG inhibited endothelial cell proliferation, migration, wound healing, and tube formation, potentially via the mTOR/STAT3 pathway.
• D-2HG enhanced endothelial barrier function by increasing junctional protein expression, reducing permeability and T-cell extravasation.

Conclusions:

• D-2HG reduces intratumoral vasculature density and impairs endothelial barrier function in astrocytoma.
• These findings suggest D-2HG influences the tumor vascular microenvironment and may contribute to resistance to antiangiogenic therapies.
• Combining IDH inhibition with antiangiogenic or immunologic approaches may be a promising therapeutic strategy.