Abstract
Simple SummaryHypoxia has been recognized as a hallmark of solid tumors and a negative prognostic factor for response to therapeutics and survival of patients. Studies have demonstrated that the Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway regulates the expression of the HIF-1 transcription factor in a number of solid tumor models, but no data are available in osteosarcoma characterized by hypoxia. The objectives of the present study were (i) to assess the contribution of SphK1/S1P signaling in regulating HIF-1α expression under hypoxia in various osteosarcoma cell models, (ii) quantify SphK1 enzymatic activity in biopsies of osteosarcoma, and (iii) examine the relationship between SphK1, S1P receptor 1 (S1P1) and hypoxia (GLUT-1) in 130 cases of osteosarcoma by immunohistochemistry. Our data suggest that the SphK1/S1P signaling might represent a potential target to investigate in osteosarcoma patients, considering that fingolimod, which inhibits SphK1 and the S1P1 receptor, is now reconsidered for repurposing in cancer.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 S1P1 receptor are involved in HIF-1α accumulation in hypoxic osteosarcoma cells. FTY720 (Fingolimod), which targets SphK1 and S1P1, 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 S1P1 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 S1P1 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 S1P1 were associated with an increased risk of death in long bones.
Highlights
Rare, osteosarcoma is the most common malignancy of bone predominantly affecting children and young adults [1,2]
In agreement with work conducted by others [47–52], hypoxia was associated with increased hypoxia-inducible factors (HIFs)-1α accumulation in U-2 OS, MG-63 and SaOS-2 cell lines, peaking at
Pathway is a regulator of both HIF-1α and HIF-2α during hypoxia in multiple cancer cell lineages [25–27,38], we evaluated its relevance with regard to HIF-1α expression in osteosarcoma cells. ln line with our previous findings in renal cell carcinoma models [27], we found an increase in Sphingosine kinase-1 (SphK1) and S1P receptor 1 (S1P1 ) mRNA expression after 60 min of hypoxia in the U-2 OS cell model (Figure 1B)
Summary
Osteosarcoma is the most common malignancy of bone predominantly affecting children and young adults [1,2]. It often occurs in the metaphyses of long bones such as the femur or tibia, and is pathologically characterized by cells with high-grade atypia and aberrant osteoid formation [1]. Jaw osteosarcoma accounts for only 6% of all osteosarcomas and develops mainly in the mandible. It is diagnosed approximately two decades later than long bone osteosarcoma and entails a lower risk of lung metastases reported to be 20–25% versus 44–49% for long bone osteosarcomas [3]. Conventional osteosarcoma is highly heterogeneous with cells that produce varying amounts of osteoid/chondroid matrix [2]
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