Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis.
Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that promotes breast cancer progression 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 significantly elevated in stage IIIA human breast cancer patients, compared with age/ethnicity-matched healthy volunteers. However, treatment with the specific 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 lymphangiogenesis in vitro, whereas SK1-I inhibited each process. We quantified both processes in vivo from the same specimen by combining directed in vivo angiogenesis assays with fluorescence-activated cell sorting, thereby confirming 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 findings show that SphK1-produced S1P is a crucial mediator of breast cancer-induced hemangiogenesis and lymphangiogenesis. Our results implicate SphK1 along with S1P as therapeutic targets in breast cancer.
Division of Surgical Oncology, Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.
Masayuki
M
Nagahashi
Subramaniam
S
Ramachandran
Eugene Y
EY
Kim
Jeremy C
JC
Allegood
Omar M
OM
Rashid
Akimitsu
A
Yamada
Renping
R
Zhao
Sheldon
S
Milstien
Huiping
H
Zhou
Sarah
S
Spiegel
Kazuaki
K
Takabe
D000605:Amino Alcohols / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
D000605:Amino Alcohols; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D042461:Vascular Endothelial Growth Factor A; D000099157:Sphingosine Kinase; C544832:N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol; C060506:sphingosine 1-phosphate