Gomez-Brouchet Anne, Illac Claire, Ledoux Adeline, Fortin Pierre-Yves, de Barros Sandra, Vabre Clémentine, Despas Fabien, Peries Sophie, Casaroli Christelle, Bouvier Corinne, Aubert Sébastien, de Pinieux Gonzague, Larousserie Frédérique, Galmiche Louise, Talmont Franck, Pitson Stuart, Maddelein Marie-Lise, Cuvillier Olivier
CNRS, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
Université de Toulouse, UPS, 31400 Toulouse, France.
Cancers (Basel). 2022 Jan 19;14(3):499. doi: 10.3390/cancers14030499.
The Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway is overexpressed in various cancers, and is instrumental for the adaptation to hypoxia in a number of solid tumor models, but no data are available in osteosarcoma. Here we report that SphK1 and the S1P receptor are involved in HIF-1α accumulation in hypoxic osteosarcoma cells. FTY720 (Fingolimod), which targets SphK1 and S1P prevented HIF-1α accumulation, and also inhibited cell proliferation in both normoxia and hypoxia unlike conventional chemotherapy. In human biopsies, a significant increase of SphK1 activity was observed in cancer compared with normal bones. In all sets of TMA samples (130 cases of osteosarcoma), immunohistochemical analysis showed the hypoxic marker GLUT-1, SphK1 and S1P were expressed in tumors. SphK1 correlated with the GLUT-1 suggesting that SphK1 is overexpressed and correlates with intratumoral hypoxia. No correlation was found between GLUT-1 or SphK1 and response to chemotherapy, but a statistical difference was found with increased S1P expression in patients with poor response in long bone osteosarcomas. Importantly, multivariate analyses showed that GLUT-1 was associated with an increased risk of death in flat bone, whereas SphK1 and S1P were associated with an increased risk of death in long bones.
鞘氨醇激酶-1/1-磷酸鞘氨醇（SphK1/S1P）信号通路在多种癌症中过度表达，在一些实体瘤模型中对缺氧适应起重要作用，但骨肉瘤方面尚无相关数据。在此我们报告，SphK1和S1P受体参与缺氧骨肉瘤细胞中HIF-1α的积累。靶向SphK1和S1P的FTY720（芬戈莫德）可阻止HIF-1α积累，并且与传统化疗不同，在常氧和缺氧条件下均能抑制细胞增殖。在人体活检中，与正常骨相比，癌症中SphK1活性显著增加。在所有TMA样本集（130例骨肉瘤）中，免疫组化分析显示缺氧标志物GLUT-1、SphK1和S1P在肿瘤中表达。SphK1与GLUT-1相关，提示SphK1过度表达且与肿瘤内缺氧相关。未发现GLUT-1或SphK1与化疗反应之间存在相关性，但在长骨骨肉瘤中，反应较差的患者S1P表达增加存在统计学差异。重要的是，多因素分析显示，GLUT-1与扁骨死亡风险增加相关，而SphK1和S1P与长骨死亡风险增加相关。
