Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Louisville, KY 40202, USA.
Mol Cancer Res. 2013 Jul;11(7):793-807. doi: 10.1158/1541-7786.MCR-12-0600. Epub 2013 Apr 24.
Evidence suggests that bioactive lipids may regulate pathophysiologic functions such as cancer cell metastasis. Therefore, we determined that the bioactive lipid chemoattractants sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) strongly enhanced the in vitro motility and adhesion of human rhabdomyosarcoma (RMS) cells. Importantly, this effect was observed at physiologic concentrations for both bioactive lipids, which are present in biologic fluids, and were much stronger than the effects observed in response to known RMS prometastatic factors such as stromal derived factors-1 (SDF-1/CXCL12) or hepatocyte growth factor/scatter factor (HGF/SF). We also present novel evidence that the levels of S1P and C1P were increased in several organs after γ-irradiation or chemotherapy, which indicates an unwanted prometastatic environment related to treatment. Critically, we found that the metastasis of RMS cells in response to S1P can be effectively inhibited in vivo with the S1P-specific binder NOX-S93 that is based on a high-affinity Spiegelmer. These data indicate that bioactive lipids play a vital role in dissemination of RMS and contribute to the unwanted side effects of radio/chemotherapy by creating a prometastatic microenvironment.
有证据表明，生物活性脂质可能调节生理病理功能，如癌细胞转移。因此，我们确定生物活性脂质化学引诱物鞘氨醇-1-磷酸（S1P）和神经酰胺-1-磷酸（C1P）强烈增强了人横纹肌肉瘤（RMS）细胞的体外迁移和黏附。重要的是，这种作用在两种生物活性脂质的生理浓度下观察到，这两种脂质存在于生物体液中，比观察到的对已知的 RMS 促转移因子如基质衍生因子-1（SDF-1/CXCL12）或肝细胞生长因子/分散因子（HGF/SF）的反应要强得多。我们还提供了新的证据表明，γ辐射或化疗后几种器官中 S1P 和 C1P 的水平增加，这表明与治疗相关的不良促转移环境。关键的是，我们发现，NOX-S93 可以有效地抑制 RMS 细胞对 S1P 的转移，NOX-S93 是一种基于高亲和力 Spiegelmer 的 S1P 特异性结合物。这些数据表明，生物活性脂质在 RMS 的传播中起着至关重要的作用，并通过创造促转移的微环境，导致放射/化学疗法的不良副作用。
