Requisite endothelial reactivation and effective siRNA nanoparticle targeting of Etv2/Er71 in tumor angiogenesis

Area of Science:

• Oncology
• Vascular Biology
• Molecular Biology

Background:

• Angiogenesis, the formation of new blood vessels, is crucial for solid tumor growth.
• Current antiangiogenic therapies struggle with selective targeting of tumor-associated vessels, often affecting healthy vasculature.
• Identifying specific molecular targets for tumor angiogenesis is essential for developing effective cancer treatments.

Purpose of the Study:

• To investigate the role of the transcription factor Etv2 in tumor angiogenesis.
• To determine if Etv2 is selectively upregulated in tumor-associated endothelial cells (TAECs).
• To explore Etv2 as a potential target for selective antiangiogenic therapy.

Main Methods:

• Utilized two-photon imaging to observe tumor vasculature in Etv2-deficient models.
• Assessed endothelial cell (EC) function, including proliferation and tube formation, in Etv2-deficient cells.
• Investigated the role of reactive oxygen species (ROS) in Etv2 expression.
• Administered Etv2 siRNA nanoparticles systemically to evaluate tumor growth inhibition.

Main Results:

• Etv2 is selectively upregulated in both human and mouse TAECs and is required for tumor angiogenesis.
• Etv2 deficiency resulted in vasculature resembling steady-state vessels, with reduced Flk1 (Vegfr2) expression and EC proliferation.
• Etv2-deficient ECs showed impaired response to VEGF but not FGF2.
• ROS activated Etv2 expression, and ROS blockade inhibited Etv2 in TAECs.
• Systemic Etv2 siRNA nanoparticle administration effectively inhibited tumor growth and angiogenesis without cardiovascular side effects.

Conclusions:

• Etv2 is a critical regulator of tumor angiogenesis, linking vascular oxidative stress, Etv2 expression, and VEGF response.
• Targeting the Etv2 pathway presents a promising strategy for developing selective antiangiogenic therapies with reduced side effects.