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Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition.

ABSTRACT: Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular stabilization. We used in vivo and in vitro angiogenesis models including a postnatal retinal angiogenesis model and a renal cell carcinoma murine tumor model to test whether simultaneous inhibition of S1P1 and VEGF leads to improved angiogenic inhibition. Here, we show that inhibition of S1P signaling reduces the endothelial cell barrier and leads to excessive angiogenic sprouting. Simultaneous inhibition of S1P and VEGF signaling further disrupts the tumor vascular beds, decreases tumor volume, and increases tumor cell death compared with monotherapies. These studies suggest that inhibition of angiogenesis at two stages of the multistep process may maximize the effects of antiangiogenic therapy. Together, these data suggest that combination of S1P1 and VEGFR-targeted therapy may be a useful therapeutic strategy for the treatment of renal cell carcinoma and other tumor types.

SUBMITTER: Fischl AS

PROVIDER: S-EPMC6992361 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition.

Fischl Anthony S AS Wang Xiaoen X Falcon Beverly L BL Almonte-Baldonado Rowena R Bodenmiller Diane D Evans Glenn G Stewart Julie J Wilson Takako T Hipskind Philip P Manro Jason J Uhlik Mark T MT Chintharlapalli Sudhakar S Gerald Damien D Alsop David C DC Benjamin Laura E LE Bhatt Rupal S RS

Molecular cancer therapeutics 20190220 4

Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular s ...[more]

PMID: 30787172

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Project description:Hyperglycemia aggravates hepatic ischemia/reperfusion injury (IRI), but the underlying mechanism for the aggravation remains elusive. Sphingosine-1-phosphate (S1P) and sphingosine-1-phosphate receptors (S1PRs) have been implicated in metabolic and inflammatory diseases. Here, we discuss whether and how S1P/S1PRs are involved in hyperglycemia-related liver IRI. For our in vivo experiment, we enrolled diabetic patients with benign hepatic disease who had liver resection, and we used streptozotocin (STZ)-induced hyperglycemic mice or normal mice to establish a liver IRI model. In vitro bone marrow-derived macrophages (BMDMs) were differentiated in high-glucose (HG; 30 mM) or low-glucose (LG; 5 mM) conditions for 7 days. The expression of S1P/S1PRs was analyzed in the liver and BMDMs. We investigated the functional and molecular mechanisms by which S1P/S1PRs may influence hyperglycemia-related liver IRI. S1P levels were higher in liver tissues from patients with diabetes mellitus and mice with STZ-induced diabetes. S1PR3, but not S1PR1 or S1PR2, was activated in liver tissues and Kupffer cells under hyperglycemic conditions. The S1PR3 antagonist CAY10444 attenuated hyperglycemia-related liver IRI based on hepatic biochemistry, histology, and inflammatory responses. Diabetic livers expressed higher levels of M1 markers but lower levels of M2 markers at baseline and after ischemia/reperfusion. Dual-immunofluorescence staining showed that hyperglycemia promoted M1 (CD68/CD86) differentiation and inhibited M2 (CD68/CD206) differentiation. Importantly, CAY10444 reversed hyperglycemia-modulated M1/M2 polarization. HG concentrations in vitro also triggered S1P/S1PR3 signaling, promoted M1 polarization, inhibited M2 polarization, and enhanced inflammatory responses compared with LG concentrations in BMDMs. In contrast, S1PR3 knockdown significantly retrieved hyperglycemia-modulated M1/M2 polarization and attenuated inflammation. In conclusion, our study reveals that hyperglycemia specifically triggers S1P/S1PR3 signaling and exacerbates liver IRI by facilitating M1 polarization and inhibiting M2 polarization, which may represent an effective therapeutic strategy for liver IRI in diabetes.

Project description:Background and purposeCollateral growth after acute occlusion of an intracranial artery is triggered by increasing shear stress in preexisting collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1) on endothelial cells was reported to be essential in sensing fluid shear stress. Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral growth and subsequent ischemic damage after focal ischemia.MethodsIn C57Bl/6 mice (n = 133) subjected to unilateral common carotid occlusion (CCAO) and sham surgery. The first series examined the time course of collateral growth, cell proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO. The second series examined the relationship between pharmacological regulation of S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly assigned to one of the following groups: LtCCAO and daily intraperitoneal (i.p.) injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day); sham surgery and daily i.p. injection for 7 days of SEW2871 after surgery; LtCCAO and daily i.p. injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg); LtCCAO and daily i.p. injection of DMSO for 7 days after surgery; and sham surgery and daily i.p. injection of DMSO for 7 days. Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex perfusion method, and a set of animals underwent subsequent permanent middle cerebral artery occlusion (pMCAO) 7 days after the treatment termination. Neurological functions 1 hour, 1, 4, and 7 days and infarction volume 7 days after pMCAO were evaluated.ResultsIn parallel with the increase in S1PR1 mRNA levels, S1PR1 expression colocalized with endothelial cell markers in the leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7 days after CCAO. Mitotic cell numbers in the leptomeningeal arteries increased after CCAO. Administration of the S1PR1 selective agonist significantly increased cerebral blood flow (CBF) and the diameter of leptomeningeal collateral vessels (42.9 ± 2.6 ?m) compared with the controls (27.6 ± 5.7 ?m; P < 0.01). S1PR1 inverse agonist administration diminished the effect of the S1PR1 agonist (P < 0.001). After pMCAO, S1PR1 agonist pretreated animals showed significantly smaller infarct volume (17.5% ± 4.0% vs. 7.7% ± 4.0%, P < 0.01) and better functional recovery than vehicle-treated controls.ConclusionsThese results suggest that S1PR1 is one of the principal regulators of leptomeningeal collateral recruitment at the site of increased shear stress and provide evidence that an S1PR1 selective agonist has a role in promoting collateral growth and preventing of ischemic damage and neurological dysfunction after subsequent stroke in patients with intracranial major artery stenosis or occlusion.

Dataset Information

Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition.

Publications

Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition.

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