K. Yuza1, M. Nagahashi1, Y. Hirose1, M. Nakajima1, K. Miura1, H. Ichikawa1, Y. Shimada1, J. Sakata1, H. Kameyama1, T. Kobayashi1, K. Takabe2,3, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata City, 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:
Pancreatic cancer is one of the most lethal diseases and it often spreads quickly before it causes any symptoms. Elucidation of the underlying mechanisms how pancreatic cancer progresses and metastasizes is the key to improve outcome. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator plays critical roles in cancer progression. S1P is involved in numerous cellular functions such as cell proliferation, migration, survival, angiogenesis and lymph angiogenesis, all of which are related to cancer progression and metastasis. Although it is expected that S1P plays an important role in pancreatic cancer progression based on the previous findings of experimental models, its role in human pancreatic cancer has never been revealed. We hypothesized that sphingolipids including S1P are produced higher in pancreatic cancer compared with normal pancreas tissue.
Methods:
Tumor and non-cancerous pancreas tissue were obtained from 10 patients with pancreatic cancer. Both tumor and non-cancerous pancreas tissue were collected from the same resected specimen, and non-cancerous tissue was collected from normal pancreas as far away as possible from the cancer site. Sphingolipids including S1P and their metabolites were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The levels of each sphingolipid were compared between tumor and non-cancerous pancreas tissue by using the Wilcoxon matched-pairs signed rank test. All of the tests were two-sided and P values < 0.05 were considered to be statistically significant.
Results:
Levels of sphingosine, dihydro-sphingosine, S1P, and dihydro-S1P in the pancreatic cancer and normal pancreas tissue were all successfully determined. The levels of all these sphingolipids were universally higher in the cancer tissue than in the normal pancreas tissue (P<0.001 for sphingosine, dihydro-sphingosine, and S1P; P<0.05 for dihydro-S1P). We also determined the levels of each species of ceramide (C14:0, C16:0, C18:1, C18:0, C20:0, C22:0, C24:1, C24:0, C26:1 and C26:0) in the pancreatic cancer and normal pancreas tissue. We found that C14:0 alone was significantly higher in the cancer tissue than in the normal pancreas tissue.
Conclusion:
Levels of sphingolipids in cancer tissue are generally higher than normal pancreas tissue in patients with pancreatic cancer. The high levels of S1P and its metabolites in cancerous tissues implicate the important role of S1P in pancreatic cancer.