Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotype.
A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor-associated macrophages (TAMs), which are polarized towards an anti-inflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti-cancer strategies along this line. One potential immune modulating compound, sphingosine-1-phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P-producing enzymes for tumor progression. The growth of SphK2-deficient MCF-7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors was comparable. However, TAMs from SphK2-deficient tumors displayed a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-alpha, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization.
Weigert
Andreas
A
Institute of Biochemistry I/ZAFES, Goethe-University, Theodor-Stern-Kai 7, Frankfurt, Germany.
Schiffmann
Susanne
S
Sekar
Divya
D
Ley
Stephanie
S
Menrad
Heidi
H
Werno
Christian
C
Grosch
Sabine
S
Geisslinger
Gerd
G
Brüne
Bernhard
B
D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016764:Cell Polarity; D002470:Cell Survival; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008246:Lysophospholipids / Q000096:biosynthesis; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D000099157:Sphingosine Kinase
D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate