Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer

Oncotarget. 2015 May 30;6(15):13803-21. doi: 10.18632/oncotarget.3144.


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.

Keywords: angiogenesis; hypoxia; sphingolipid; vessel normalization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / pharmacology*
  • Cell Hypoxia / drug effects
  • Cell Line, Tumor
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Lysophospholipids / antagonists & inhibitors*
  • Lysophospholipids / immunology*
  • Male
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Prostatic Neoplasms / blood supply
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Random Allocation
  • Signal Transduction
  • Sphingosine / analogs & derivatives*
  • Sphingosine / antagonists & inhibitors
  • Sphingosine / immunology
  • Vascular Remodeling / drug effects


  • Antibodies, Monoclonal
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lysophospholipids
  • sphingosine 1-phosphate
  • Sphingosine