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Updated: Mar 22, 2026
A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference
Sung-Suk Chae1, Ji-Hye Paik, Henry Furneaux
1Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030-3501, USA.
Abstract:
Angiogenesis, or new blood vessel formation, is critical for the growth and spread of tumors. Multiple phases of this process, namely, migration, proliferation, morphogenesis, and vascular stabilization, are needed for optimal tumor growth beyond a diffusion-limited size. The sphingosine 1-phosphate (S1P) receptor-1 (S1P(1)) is required for stabilization of nascent blood vessels during embryonic development. Here we show that S1P(1) expression is strongly induced in tumor vessels. We developed a multiplex RNA interference technique to downregulate S1P(1) in mice. The small interfering RNA (siRNA) for S1P(1) specifically silenced the cognate transcript in endothelial cells and inhibited endothelial cell migration in vitro and the growth of neovessels into subcutaneous implants of Matrigel in vivo. Local injection of S1P(1) siRNA, but not a negative control siRNA, into established tumors inhibited the expression of S1P(1) polypeptide on neovessels while concomitantly suppressing vascular stabilization and angiogenesis, which resulted in dramatic suppression of tumor growth in vivo. These data suggest that S1P(1) is a critical component of the tumor angiogenic response and argue for the utility of siRNA technology in antiangiogenic therapeutics.
Insights
Sphingosine 1-phosphate receptor-1 (S1P(1)) is crucial for stabilizing new blood vessels in tumors. Inhibiting S1P(1) with small interfering RNA (siRNA) suppressed tumor angiogenesis and growth, suggesting a therapeutic target.
Area of Science:
- Oncology
- Vascular Biology
- Molecular Medicine
Background:
- Angiogenesis, the formation of new blood vessels, is essential for tumor growth and metastasis.
- Tumor angiogenesis involves multiple phases, including cell migration, proliferation, morphogenesis, and vascular stabilization.
- Sphingosine 1-phosphate receptor-1 (S1P(1)) plays a key role in stabilizing nascent blood vessels during embryonic development.
Purpose of the Study:
- To investigate the role of S1P(1) in tumor angiogenesis.
- To evaluate the efficacy of S1P(1) downregulation using small interfering RNA (siRNA) as an anti-angiogenic therapeutic strategy.
Main Methods:
- Developed a multiplex RNA interference technique to downregulate S1P(1) in mice.
- Utilized small interfering RNA (siRNA) targeting S1P(1) to silence its expression in endothelial cells.
- Assessed the effects of S1P(1) siRNA on endothelial cell migration in vitro and neovascularization in vivo.
- Administered S1P(1) siRNA locally into established tumors to evaluate its impact on tumor growth.
Main Results:
- S1P(1) expression was significantly upregulated in tumor vasculature.
- S1P(1) siRNA specifically silenced the S1P(1) transcript in endothelial cells, inhibiting their migration in vitro.
- Local injection of S1P(1) siRNA suppressed vascular stabilization and angiogenesis in established tumors.
- Tumor growth was dramatically suppressed following S1P(1) siRNA treatment in vivo.
Conclusions:
- S1P(1) is a critical regulator of tumor angiogenesis and vascular stabilization.
- siRNA technology targeting S1P(1) demonstrates significant anti-tumor efficacy by inhibiting angiogenesis.
- S1P(1) represents a promising therapeutic target for anti-angiogenic cancer treatments.
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02:15Experimental RNAi
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