Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer.
Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer.
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DOI：
10.18632/oncotarget.3144
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发表时间：
2015-05-30
期刊：
影响因子：
--
通讯作者：
Cuvillier O
中科院分区：
文献类型：
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作者：
Ader I;Gstalder C;Bouquerel P;Golzio M;Andrieu G;Zalvidea S;Richard S;Sabbadini RA;Malavaud B;Cuvillier O
缺氧促进新血管形成，增加肿瘤生长和治疗抗性。低氧诱导因子1α（hypoxia-inducible factor 1α，HIF-1α）是低氧适应的主要调控因子。我们以前发现鞘氨醇激酶1/鞘氨醇1-磷酸（SphK 1/S1 P）途径是缺氧条件下HIF-1α的一种新的调节剂。利用中和细胞外S1 P（sphingomab）的单克隆抗体，我们报告了在暴露于缺氧的几种癌细胞模型中，抑制S1 P细胞外信号传导可阻断HIF-1α的积累和活性。在前列腺癌原位异种移植模型中，我们发现鞘氨醇单抗在治疗5天内减少缺氧并改变血管结构，导致肿瘤内血液灌注增加。支持肿瘤血管的短暂血管正常化是鞘氨醇单抗发挥作用的机制这一观点，我们证明化疗前5天给予抗体比任何其他治疗方案在局部肿瘤控制和转移性播散方面更有效。这些发现验证了鞘氨醇单抗作为一种潜在的新的正常化剂，可能有助于低氧肿瘤对化疗的成功敏感化。
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.