Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits Angiogenesis and Tumor Vascularization

Abstract

FTY720, a potent immunomodulator, becomes phosphorylated in vivo (FTY-P) and interacts with sphingosine-1-phosphate (S1P) receptors. Recent studies showed that FTY-P affects vascular endothelial growth factor (VEGF)-induced vascular permeability, an important aspect of angiogenesis. We show here that FTY720 has antiangiogenic activity, potently abrogating VEGF-and S1P-induced angiogenesis in vivo in growth factor implant and corneal models. FTY720 administration tended to inhibit primary and significantly inhibited metastatic tumor growth in a mouse model of melanoma growth. In combination with a VEGFR tyrosine kinase inhibitor PTK787/ ZK222584, FTY720 showed some additional benefit. FTY720 markedly inhibited tumor-associated angiogenesis, and this was accompanied by decreased tumor cell proliferation and increased apoptosis. In transfected HEK293 cells, FTY-P internalized S1P 1 receptors, inhibited their recycling to the cell surface, and desensitized S1P receptor function. Both FTY720 and FTY-P apparently failed to impede VEGF-produced increases in mitogen-activated protein kinase activity in human umbilical vascular endothelial cells (HUVEC), and unlike its activity in causing S1PR internalization, FTY-P did not result in a decrease of surface VEGFR2 levels in HUVEC cells. Pretreatment with FTY720 or FTY-P prevented S1P-induced Ca 2+ mobilization and migration in vascular endothelial cells. These data show that functional antagonism of vascular S1P receptors by FTY720 potently inhibits angiogenesis; therefore, this may provide a novel therapeutic approach for pathologic conditions with dysregulated angiogenesis.

Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade

“…FTY-720 has been shown to have direct antitumor effects (32,33). We initially confirmed that treatment with low doses of FTY-720 had no effect on tumor growth whilst retaining the capacity to reduce both circulating and tumor-infiltrating T-cell populations (Supplemental Fig.…”

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

“…3,27 In contrast, other studies have reported that FTY720 actually inhibits vascular endothelial growth factor-induced vascular permeability and angiogenesis. [28][29][30] The antiangiogenic effects of FTY720, though surprising based on its potent agonist activity, are proposed to occur as a result of functional antagonism. Although both S1P and FTY720 have been shown to internalize the S1P 1 receptor into the endosomal pathway, FTY720 induces ubiquitinylation and proteosomal degradation of the receptor.…”

Roles of sphingosine-1-phosphate signaling in angiogenesis

“…The S1P signaling system is involved in tumor neovascularization [50,51] . A recent report [52] has shown that repeated administration of monoclonal anti-S1P antibody inhibits tumor growth in several tumor models, including orthotopic injections of MDA MB-231 and MDA MB-468 breast carcinoma cells and SKOV3 ovarian cancer cells, and subcutaneous injection of A549 lung adenocarcinoma cells.…”