J. Tsuchida1, M. Nagahashi1, K. Moro1, T. Niwano1, K. Tatsuda1, C. Toshikawa1, M. Hasegawa1, Y. Koyama1, T. Kobayashi1, S. Kosugi3, H. Kameyama1, H. Aoki2, K. Takabe2, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata, NIIGATA, Japan 2Virginia Commonwealth University School Of Medicine And The Massey Cancer Center,Division Of Surgical Oncology,Niigata, NIIGATA, Japan 3Uonuma Kikan Hospital,General Surgery,Minami Uonuma, NIIGATA, Japan
Introduction: The 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 cells and by binding to specific G protein-coupled receptors. We previously demonstrated that S1P is a crucial mediator of breast cancer-induced angiogenesis and lymphangiogenesis, generation of new blood and lymphatic vessels, and promote metastasis to the lymph nodes and to the lung. Although important roles of S1P in breast cancer progression has been repeatedly reported in experimental models, the research field suffers from very few data on human patients due to the difficulty in accurate measurements of S1P levels in the clinical samples. In this study, we measure the levels of sphingolipids including S1P in serum from the patients with breast cancer utilizing state-of-the-art mass spectrometry.
Methods: A retrospective analysis was conducted on 49 patients who were pathologically diagnosed with stage I or II breast cancer. The serum from the patients were obtained at the time of diagnosis, prior to any treatment. Sphingolipids were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The levels of sphingolipids including S1P were analyzed with patients’ clinical demographics.
Results: The levels of sphingolipids including sphingosine, dihydro-sphingosine, S1P, dihydro-S1P were detected successfully in the serum from 49 breast cancer patients. Despite our expectation, no significant differences in serum S1P levels were identified by age, hormone receptors (ER, PgR) and HER2 status, Ki-67 index, nuclear grade, lymphatic and vascular invasion of the tumor, pT, and pStage. Interestingly, however, S1P levels in patients with pathologically proven lymph node metastasis (median 2198, range 1575–3462 pmol/ml) was significantly higher than that in patients without lymph node metastasis (median 1977, range 1309–2746 pmol/ml) (P = 0.029). In contrast, levels of sphingosine in patients with lymph node metastasis showed trend to be lower compared to patients without lymph node metastasis (P = 0.073).
Conclusion: Our results indicate an important role of S1P during the process of lymph node metastasis of breast cancer patients. It may also implicate that serum S1P level may have a role as a biomarker for lymph node metastasis. Further study is required to investigate the mechanisms how S1P promotes the lymph node metastasis in human patients and whether S1P levels correlate with lymph node metastasis. This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research Grant Number 15H05676 and 15K15471 for M.N and 15H04927 for W.T. M.N. is supported by the Uehara Memorial Foundation, Nakayama Cancer Research Institute, Takeda Science Foundation, and Tsukada Memorial Foundation.