Abstract
Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1α (HIF-1α), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α under hypoxia. Taking advantage of a monoclonal antibody neutralizing extracellular S1P (sphingomab), we report that inhibition of S1P extracellular signaling blocks HIF-1α accumulation and activity in several cancer cell models exposed to hypoxia. In an orthotopic xenograft model of prostate cancer, we show that sphingomab reduces hypoxia and modifies vessel architecture within 5 days of treatment, leading to increased intratumoral blood perfusion. Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling. These findings validate sphingomab as a potential new normalization agent that could contribute to successful sensitization of hypoxic tumors to chemotherapy.
Highlights
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite regulating pleiotropic activities such as proliferation, survival, migration, inflammation or angiogenesis [1,2,3,4]
Taking advantage of a monoclonal antibody neutralizing extracellular S1P, we report that inhibition of S1P extracellular signaling blocks hypoxia-inducible factor 1α (HIF-1α) accumulation and activity in several cancer cell models exposed to hypoxia
Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling
Summary
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite regulating pleiotropic activities such as proliferation, survival, migration, inflammation or angiogenesis [1,2,3,4]. The S1P content in cells is low and is kept under control through a delicately regulated balance between its synthesis and its degradation. The balance between the intracellular levels of S1P and its metabolic precursors, ceramide and sphingosine, has been suggested to be a switch determining whether a cell proliferates or dies [5]. The predominant regulator of this ceramide/S1P balance is the sphingosine kinase-1 (SphK1). S1P is exported by specific transporters such as spinster 2 (Spns2) [7,8,9], to exert paracrine or autocrine effects as a ligand for five high-affinity G protein-coupled receptors (S1P1–5), with specific effects dictated by the predominance of S1P receptor subtypes expressed [10]. Alternative GPCR-independent signaling of S1P exist [11] with recent findings demonstrating direct modulation of several intracellular proteins [12, 13]
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