Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer
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Isabelle Ader1,2,3, Cécile Gstalder1,2,3,*, Pierre Bouquerel1,2,3,*, Muriel Golzio1,2, Guillaume Andrieu1,2,3, Santiago Zalvidea5, Sylvain Richard5, Roger A. Sabbadini6, Bernard Malavaud1,2,3,4, Olivier Cuvillier1,2,3
1CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France
2Université de Toulouse, UPS, IPBS, Toulouse, France
3Equipe Labellisée Ligue Contre le Cancer, Toulouse, France
4Hôpital Rangueil, Service d’Urologie et de Transplantation Rénale, Toulouse, France
5INSERM U1046, Université Montpellier 1, Université Montpellier 2, CHU Arnaud de Villeneuve, Montpellier, France
6Lpath Inc., San Diego, CA, USA
*These authors have contributed equally to this work
Keywords: angiogenesis, hypoxia, sphingolipid, vessel normalization
Received: December 01, 2014 Accepted: January 12, 2015 Published: January 29, 2015
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.
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