Title | Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | LaMontagne K, Littlewood-Evans A, Schnell C, O'Reilly T, Wyder L, Sanchez T, Probst B, Butler J, Wood A, Liau G, Billy E, Theuer A, Hla T, Wood J |
Journal | Cancer Res |
Volume | 66 |
Issue | 1 |
Pagination | 221-31 |
Date Published | 2006 Jan 01 |
ISSN | 0008-5472 |
Keywords | Animals, Calcium, Cell Growth Processes, Cell Movement, Cornea, Endothelial Cells, Female, Fingolimod Hydrochloride, Humans, Melanoma, Experimental, Mice, Mitogen-Activated Protein Kinases, Neovascularization, Pathologic, Neovascularization, Physiologic, Phosphorylation, Phthalazines, Propylene Glycols, Pyridines, Receptors, Lysosphingolipid, Sphingosine, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2 |
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 S1P1 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 Ca2+ 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. |
DOI | 10.1158/0008-5472.CAN-05-2001 |
Alternate Journal | Cancer Res |
PubMed ID | 16397235 |
Related Faculty:
Teresa Sanchez, Ph.D.