Sphingosine-1-Phosphate Produced by Sphingosine Kinase 1 Promotes Breast Cancer Progression by Stimulating Angiogenesis and Lymphangiogenesis

Abstract

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 pharmacological 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 to 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 (DIVAA) with Fluorescence Activated Cell Sorting (DIVAA/FACS), 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 demonstrate 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.

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…This result is contradictory with those of previous studies 6, 19, 23, 24. We discuss this inconsistency in the following.…”

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

“…35,36 The increased expression of SphK1 in PAH is consistent with literature suggesting that it is upregulated in many types of cancer and that the S1P-generating enzyme has many features of an oncogene. [37][38][39][40] SphK1 can be activated by several mediators, and S1P produced and released into the extracellular milieu promotes cell proliferation and survival by acting on its G protein-coupled receptors and by transactivating a spectrum of receptor tyrosine kinases, including those of plateletderived growth factor (PDGF), transforming growth factor β, epidermal growth factor, hepatocyte growth factor, and VEGF. 41 Importantly, constitutive activation of SphK1 in endothelial cells induces a proinflammatory and proangiogenic phenotype, 42 and SphK inhibitors block pathologic neovascularization in animal models.…”

A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

“…SPHK1 Activity Is Necessary for Angiogenic Signaling-S1P has for some time been recognized as a potent angiogenic factor, and a role in tumor angiogenesis has been established using both genetic and pharmacological approaches (41)(42)(43). Angiogenesis was examined in a three-dimensional coculture model in which HMEC-1 cells were grown on microcarrier beads embedded in a fibrin gel and formed sprouts in response to angiogenic factors secreted by U87MG cells grown on top of the fibrin gel (Fig.…”