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.

[1]  R. Ji Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis , 2011, Cellular and Molecular Life Sciences.

[2]  A. Jemal,et al.  Cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[3]  Jinghang Zhang,et al.  CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis , 2011, Nature.

[4]  S. Milstien,et al.  The outs and the ins of sphingosine-1-phosphate in immunity , 2011, Nature Reviews Immunology.

[5]  Xian Zhou,et al.  RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[7]  Michael Detmar,et al.  In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno-positron emission tomography. , 2010, Cancer research.

[8]  K. Takabe,et al.  Lymphangiogenesis: a new player in cancer progression. , 2010, World journal of gastroenterology.

[9]  L. Obeid,et al.  Role of sphingosine kinase‐1 in paracrine/transcellular angiogenesis and lymphangiogenesis in vitro , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  Jay W. Shin,et al.  Tumor lymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin. , 2010, The American journal of pathology.

[11]  Arlene Chan,et al.  Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  S. Pyne,et al.  Sphingosine 1-phosphate and cancer , 2010, Nature Reviews Cancer.

[13]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[14]  K. Alitalo,et al.  Lymphangiogenesis: Molecular Mechanisms and Future Promise , 2010, Cell.

[15]  Sarah Spiegel,et al.  Estradiol Induces Export of Sphingosine 1-Phosphate from Breast Cancer Cells via ABCC1 and ABCG2* , 2010, The Journal of Biological Chemistry.

[16]  K. Hatakeyama,et al.  Depth of invasion determines the postresectional prognosis for patients with T1 extrahepatic cholangiocarcinoma , 2010, Cancer.

[17]  Ying Xu,et al.  Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning , 2009, The Journal of experimental medicine.

[18]  York Springer,et al.  Ajcc Cancer Staging Manual. 7th Ed. New , 2010 .

[19]  Cheng Luo,et al.  Regulation of Histone Acetylation in the Nucleus by Sphingosine-1-Phosphate , 2009, Science.

[20]  S. Milstien,et al.  Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. , 2009, Cancer research.

[21]  S. Milstien,et al.  Export and functions of sphingosine-1-phosphate. , 2009, Biochimica et biophysica acta.

[22]  Y. Hannun,et al.  Role for sphingosine kinase 1 in colon carcinogenesis , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  Yong Song Gho,et al.  Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways. , 2008, Blood.

[24]  Barbara S. Paugh,et al.  A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. , 2008, Blood.

[25]  S. Milstien,et al.  Targeting SphK1 as a new strategy against cancer. , 2008, Current drug targets.

[26]  S. Milstien,et al.  “Inside-Out” Signaling of Sphingosine-1-Phosphate: Therapeutic Targets , 2008, Pharmacological Reviews.

[27]  A. Griffioen,et al.  Isolation of endothelial cells from fresh tissues , 2008, Nature Protocols.

[28]  T. Karn,et al.  Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer , 2008, Breast Cancer Research and Treatment.

[29]  E. Perez,et al.  Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. , 2007, The New England journal of medicine.

[30]  T. Zou,et al.  HIV protease inhibitors increase TNF-α and IL-6 expression in macrophages: Involvement of the RNA-binding protein HuR , 2007 .

[31]  K. Hatakeyama,et al.  Perimuscular connective tissue contains more and larger lymphatic vessels than the shallower layers in human gallbladders. , 2007, World journal of gastroenterology.

[32]  S. Milstien,et al.  Targeting sphingosine-1-phosphate: a novel avenue for cancer therapeutics. , 2006, Cancer cell.

[33]  W. Stetler-Stevenson,et al.  Quantitative assessment of angiogenic responses by the directed in vivo angiogenesis assay. , 2003, The American journal of pathology.

[34]  P. Sismondi,et al.  Angiopoietin‐2 expression in breast cancer correlates with lymph node invasion and short survival , 2003, International journal of cancer.

[35]  C. Compton,et al.  AJCC Cancer Staging Manual , 2002, Springer New York.

[36]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[37]  J. P. Hobson,et al.  Sphingosine 1-Phosphate Stimulates Cell Migration through a Gi-coupled Cell Surface Receptor , 1999, The Journal of Biological Chemistry.

[38]  K. Claffey,et al.  Vascular Endothelial Cell Adherens Junction Assembly and Morphogenesis Induced by Sphingosine-1-Phosphate , 1999, Cell.

[39]  Lars Holmgren,et al.  Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression , 1995, Nature Medicine.

[40]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[41]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.