Y. Hirose1, M. Nagahashi1, K. Yuza1, K. Miura1, J. Sakata1, T. Kobayashi1, H. Ichikawa1, Y. Shimada1, H. Kameyama1, K. Takabe2,3, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata, NIIGATA, Japan 2Roswell Park Cancer Institute,Breast Surgery, Department Of Surgical Oncology,Buffalo, NY, USA 3University At Buffalo Jacobs School Of Medicine And Biomedical Sciences, The State University Of New York,Department Of Surgery,Buffalo, NY, USA
Introduction: Biliary tract cancer, including gallbladder cancer, intra- and extrahepatic bile duct cancer, is one of the most lethal diseases among gastrointestinal cancer. Previous studies have suggested that chronic inflammation is involved in the disease process of biliary tract cancer. Sphingosine-1-phosphate (S1P) has emerged as a pleiotropic sphingolipid mediator that regulates many cellular functions associated with inflammation and cancer. Indeed, it has been previously suggested that S1P plays important roles in bile duct cancer progression in experimental model. However, the roles of S1P in human biliary tract cancer has yet to be clarified. The aim of this study is to determine the levels of sphingolipids including S1P and their metabolites in biliary tract cancer tissues and normal biliary tract tissues, and to clarify the difference in the levels of each sphingolipid between the two tissues.
Methods: We examined biliary tract cancer tissues (gallbladder cancer, N=5; intrahepatic bile duct cancer, N=2; and extrahepatic bile duct cancer, N=8) and normal biliary tract tissues (normal gallbladder mucosa, N=5; normal extrahepatic bile duct mucosa, N=12) in patients with biliary tract cancer. Sphingolipids including S1P and their metabolites of dihydro-S1P (DHS1P), sphingosine (Sph), and dihydro-Sph (DHSph) were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The levels of each sphingolipid were compared between cancer tissues and normal tissues using the Mann-Whitney U test. All tests were two-sided and P<0.05 were considered statistically significant.
Results:In the comparison between all biliary tract cancer tissues (N=15) and all normal biliary tract tissues (N=17), the levels of S1P, DHS1P, Sph, and DHSph were significantly higher in cancer tissues than normal tissues (S1P, P=0.004; DHS1P, P=0.030; Sph, P=0.011; DHSph, P<0.001). In the comparison between intra- and extrahepatic bile duct cancer tissues (N=10) and normal bile duct mucosa (N=12), the levels of S1P, DHS1P, Sph, and DHSph were significantly higher in cancer tissues than normal tissues (S1P, P=0.004; DHS1P, P=0.030; Sph, P=0.011; DHSph, P<0.001). In the comparison between gallbladder cancer tissues (N=5) and normal gallbladder mucosa (N=5), the levels of DHSph were significantly higher in cancer tissues than normal tissues (P=0.016), but there were no significant difference in the levels of S1P, DHS1P and Sph.
Conclusion:To our knowledge, this is the first study to reveal the levels of sphingolipids including S1P in human biliary tract cancer patients by mass spectrometry. The high levels of sphingolipids in the cancer tissue may indicate the important roles of S1P in disease process of biliary tract cancer in human patients.