Sphingosine-1-phosphate (S1P) can regulate several physiological and
pathological processes. S1P signaling via its
cell surface receptor S1PR1 has been shown to enhance
tumorigenesis and stimulate growth, expansion, angiogenesis,
metastasis, and survival of
cancer cells. S1PR1-mediated
tumorigenesis is supported and amplified by activation of downstream effectors including STAT3,
interleukin-6, and NF-κB networks. S1PR1 signaling can also trigger various other signaling pathways involved in
carcinogenesis including activation of PI3K/AKT, MAPK/ERK1/2, Rac, and PKC/Ca, as well as suppression of cyclic
adenosine monophosphate (cAMP). It also induces immunological tolerance in the tumor microenvironment, while the immunosuppressive function of S1PR1 can also lead to the generation of pre-metastatic niches. Some
tumor cells upregulate S1PR1 signaling pathways, which leads to drug resistant
cancer cells, mainly through activation of STAT3. This signaling pathway is also implicated in some inflammatory conditions leading to the instigation of
inflammation-driven
cancers. Furthermore, it can also increase survival via induction of anti-apoptotic pathways, for instance, in
breast cancer cells. Therefore, S1PR1 and its signaling pathways can be considered as potential anti-
tumor therapeutic targets, alone or in combination
therapies. Given the oncogenic nature of S1PR1 and its distribution in a variety of
cancer cell types along with its targeting advantages over other molecules of this family, S1PR1 should be considered a favorable target in therapeutic approaches to cancer. This review describes the role of S1PR1 in
cancer development and progression, specifically addressing
breast cancer,
glioma, and
hematopoietic malignancies. We also discuss the potential use of S1P signaling modulators as therapeutic targets in
cancer therapy.