Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer.
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.
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Université de Toulouse, UPS, IPBS, Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, Toulouse, France.
Isabelle
I
Ader
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Université de Toulouse, UPS, IPBS, Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, Toulouse, France.
Cécile
C
Gstalder
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Université de Toulouse, UPS, IPBS, Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, Toulouse, France.
Pierre
P
Bouquerel
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Université de Toulouse, UPS, IPBS, Toulouse, France.
Muriel
M
Golzio
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Université de Toulouse, UPS, IPBS, Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, Toulouse, France.
Guillaume
G
Andrieu
INSERM U1046, Université Montpellier 1, Université Montpellier 2, CHU Arnaud de Villeneuve, Montpellier, France.
Santiago
S
Zalvidea
INSERM U1046, Université Montpellier 1, Université Montpellier 2, CHU Arnaud de Villeneuve, Montpellier, France.
Sylvain
S
Richard
Lpath Inc., San Diego, CA, USA.
Roger A
RA
Sabbadini
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Université de Toulouse, UPS, IPBS, Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, Toulouse, France.|Hôpital Rangueil, Service d'Urologie et de Transplantation Rénale, Toulouse, France.
Bernard
B
Malavaud
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Université de Toulouse, UPS, IPBS, Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, Toulouse, France.
Olivier
O
Cuvillier
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000276:immunology; D066253:Vascular Remodeling / Q000187:drug effects
D000911:Antibodies, Monoclonal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
angiogenesis; hypoxia; sphingolipid; vessel normalization