J. Tsuchida1, M. Nagahashi1, K. Moro1, M. Ikarashi1, Y. Koyama1, H. Ichikawa1, Y. Shimada1, J. Sakata1, T. Kobayashi1, H. Kameyama1, K. Takabe2,3, T. Wakai1 3University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York,Department Of Surgery,Buffalo, NEW YORK, USA 1Niigata University Graduate School of Medical and Dental Sciences,Division Of Digestive And General Surgery,Niigata, NIIGATA, Japan 2Roswell Park Comprehensive Cancer Center,Breast Surgery, Department Of Surgical Oncology,Buffalo, NEW YORK, USA
Introduction: A bioactive lipid mediator, sphingosine-1-phosphate (S1P) has emerged as a key regulatory molecule in cancer progression. S1P exerts its regulatory functions after it is secreted out of cancer and stromal cells and regulates various cellular functions, such as cell proliferation, migration, and angiogenesis. We previously demonstrated that S1P is a crucial mediator of breast cancer-induced angiogenesis and lymphangiogenesis and promotes metastasis to the lymph nodes and to the lung (Cancer Res 2012, Cancer Res 2018). We have also reported that high S1P levels in the tumor are associated with lymph node metastasis in breast cancer patients (J Surg Res 2016), however, the role of S1P in plasma has not been fully investigated in breast cancer patients. In this study, we studied the levels of sphingolipids including S1P in plasma from breast cancer patients to reveal their clinical significance.
Methods: A retrospective analysis was conducted on 88 breast cancer patients, who received curative surgery in our institute. Among them, 18 patients received neoadjuvant chemotherapy. The plasma from the patients were obtained immediately prior to the operation. Sphingolipids, including sphingosine, dihydro-sphingosine, S1P and dihydro-S1P, were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The levels of sphingolipids were analyzed with patients’ clinical demographics, and statistical analysis was performed with the Mann- Whitney U-test.
Results: The levels of sphingolipids including sphingosine, dihydro-sphingosine, S1P, dihydro-S1P were detected successfully in the plasma from all the breast cancer patients. Levels of S1P in patients with neoadjuvant chemotherapy (N=18, median 1144, range 657–1555 pmol/ml) was significantly higher than that in patients without neoadjuvant chemotherapy (N=70, median 797, range 448–1827 pmol/ml) (P<0.0001). Levels of sphingosine in patients with neoadjuvant chemotherapy (median 25, range 17–61 pmol/ml) was significantly higher than that in patients without neoadjuvant chemotherapy (median 20, range 9–76 pmol/ml) (P=0.0143). Among the 70 patients without neoadjuvant chemotherapy, S1P levels in patients with pathologically proven lymph node metastasis (N=17, median 884, range 698–1275 pmol/ml) was significantly higher than that in patients without lymph node metastasis (N=53, median 758, range 448–1827 pmol/ml) (P=0.0091). Sphingosine levels in the patients with pathologically proven lymph node metastasis (median 22, range 12–76 pmol/ml) was also significantly higher than that in the patients without lymph node metastasis (median 19, range 9–63 pmol/ml) (P=0.0340).
Conclusion: Our results suggest that S1P in plasma plays an important role during the process of lymph node metastasis in breast cancer patients. It also implicates a possibility of plasma S1P as a biomarker for lymph node metastasis.