S1P2 receptor
(S1P2R) negatively regulates
tumor angiogenesis and tumor development
in
vivo
W. Du, N. Takuwa, K. Yoshioka, F. Wang, C.
Nagakura, E. Kaneko and Y. Takuwa
ABSTRACT
Background—
Plasma-derived lipid mediator
sphingosine-1-phosphate (S1P) acts via the G
protein-coupled S1P receptor family to regulate a variety
of physiological and pathological responses.
S1P1
receptor mediates endothelial
cell migration and vascular maturation, promoting vascular
integrity. We have previously shown that
S1P2R
is distinct from S1P1R
in that it negatively regulates cell migration and
endothelial capillary tube formation in vitro. In the present study we investigated
the role of host cell S1P2R
in tumor angiogenesis and development by comparing
S1P2
knock out (KO) and their wild
type (WT) littermate mice.
Methods and
Results—
Lewis lung carcinoma cells
and B16BL6 melanoma cells were subcutaneously injected to
S1P2KO
and WT mice and allowed to grow for 3 weeks. In both types
of tumor cells, tumor development was significantly greater
in S1P2KO
as compared with WT. Tumors in KO mice displayed increased
numbers of blood vessels which were associated with much
higher numbers of desmin-positive mural cells, and marked
upregulation of angiogenic factors including
VEGF, Notch signaling
mediator Delta-like ligand 4 and TGFβ1.
Conclusions—
These results indicate that
S1P2R
negatively regulates tumor angiogenesis in vivo, with inhibition of angiogenic gene
expression and mural cell recruitment, resulting in
inhibition of tumor growth. S1P2R-selective agonist would be a
promising anti-tumor
therapeutic agent.