Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• The vascular endothelial growth factor-A (VEGF-A)-VEGFR2 pathway is crucial for tumor angiogenesis.
• Endothelial cells (ECs) are key players in tumor vascularization.

Purpose of the Study:

• To investigate the role of sphingosine-1-phosphate receptor 1 (S1PR1) in endothelial cells (ECs) in tumor growth.
• To elucidate the mechanism by which S1PR1 amplifies VEGF-VEGFR2 signaling.

Main Methods:

• Conditional deletion of S1PR1 in ECs (EC-S1pr1-/- mice).
• Investigated the interaction between S1PR1, Gi protein, c-Abl1, and VEGFR2.
• Assessed tumor vascularization and growth in mouse models.

Main Results:

• EC-S1PR1 is essential for tumor vascularization and growth.
• Cancer cells induce S1PR1 activity in ECs.
• S1PR1 amplifies VEGF-VEGFR2 signaling via Gi, c-Abl1, and prolonged VEGFR2 retention, enhancing EC migration.
• S1PR1 or VEGFR2 antagonists inhibit tumor growth.

Conclusions:

• EC-S1PR1 signaling amplifies VEGF-VEGFR2-driven angiogenesis.
• Targeting EC-S1PR1 offers a potential therapeutic strategy to suppress tumor growth by inhibiting proangiogenic signaling.