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Oncotarget. 2015 May 30;6(15):13803-21.

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

Author information

1
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
2
Université de Toulouse, UPS, IPBS, Toulouse, France.
3
Equipe Labellisée Ligue Contre le Cancer, Toulouse, France.
4
INSERM U1046, Université Montpellier 1, Université Montpellier 2, CHU Arnaud de Villeneuve, Montpellier, France.
5
Lpath Inc., San Diego, CA, USA.
6
Hôpital Rangueil, Service d'Urologie et de Transplantation Rénale, Toulouse, France.

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.

KEYWORDS:

angiogenesis; hypoxia; sphingolipid; vessel normalization

PMID:
25915662
PMCID:
PMC4537051
DOI:
10.18632/oncotarget.3144
[Indexed for MEDLINE]
Free PMC Article

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