Author(s): Masayuki Nagahashi, Subramaniam Ramachandran, Omar M Rashid, Akimitsu Yamada, Kazuaki Takabe
Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that promotes breast cancer pro- gression by diverse mechanisms that remain somewhat unclear. Here we report pharmacologic evidence of a critical role for sphingosine kinase 1 (SphK1) in producing S1P and mediating tumor-induced hemangiogenesis and lymphangiogenesis in a murine model of breast cancer metastasis. S1P levels increased both in the tumor and the circulation. In agreement, serum S1P levels were signi fi cantly elevated in stage IIIA human breast cancer patients, compared with age/ethnicity-matched healthy volunteers. However, treatment with the speci fi c SphK1 inhibitor SK1-I suppressed S1P levels, reduced metastases to lymph nodes and lungs, and decreased overall tumor burden of our murine model. Both S1P and angiopoietin 2 (Ang2) stimulated hemangiogenesis and lymphan- giogenesis in vitro , whereas SK1-I inhibited each process. We quanti fi ed both processes in vivo from the same specimen by combining directed in vivo angiogenesis assays with fl uorescence-activated cell sorting, thereby con fi rming the results obtained in vitro . Notably, SK1-I decreased both processes not only at the primary tumor but also in lymph nodes, with peritumoral lymphatic vessel density reduced in SK1-I – treated animals. Taken together, our fi ndings show that SphK1-produced S1P is a crucial mediator of breast cancer – induced heman- giogenesis and lymphangiogenesis. Our results implicate SphK1 along with S1P as therapeutic targets in breast cancer.