H. Ichikawa1, M. Nagahashi1, M. Nemoto1, T. Hanyu1, T. Ishikawa1, Y. Kano1, Y. Muneoka1, Y. Hirose1, Y. Shimada1, J. Sakata1, T. Kobayashi1, H. Kameyama1, T. Kazuaki2,3, 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: Lymphatic invasion and lymph node metastasis are main mode of spread in esophageal squamous cell carcinoma (ESCC). Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, is one of the important molecule in cancer progression. Sphingosine kinase 1 (SphK1) is activated by phosphorylation and produce S1P. Phospho-SphK1 (pSphK1) were also elucidated to confer to the lymphatic spread of cancer in previous studies. However, the significance of pSphK1 in the progression of ESCC have not been fully investigated to date.
Methods: We retrospectively analyzed the cases of 96 patients who underwent esophagectomy without preoperative therapy for ESCC from 2000 to 2008. Immunohistochemistry of the surgically resected specimens was conducted using the primary polyclonal antibody against pSphK1. Sixty-one of the 96 patients (63.5%) had tumors with high pSphK1 expression (pSphK1-high group), and the others had ones with low pSphK1 expression (pSphK1-low group). We compared clinicopathological factors and overall survival after esophagectomy between the two groups.
Results: Pathological N category according to TNM classification of UICC 7th edition was significantly higher in pSphK1-high group (P < 0.01). Median number of lymph node metastasis (pSphK1-high: 2 vs. pSphK1-low: 0; P < 0.01), the proportion of tumor with lymphatic invasion (67.2% vs. 17.1%; P < 0.01) and that with intramural metastasis (26.2% vs. 2.9%; P < 0.01) were significantly higher in pSphK1-high group than in pSphK1-low group. Multivariate analysis revealed that the presence of lymphatic invasion was independently associated with high expression of pSphK1 (Odds ratio = 8.45; P < 0.01). The 5-year overall survival rate after esophagectomy in the pSphK1-high group was significantly lower compared to the pSphK1-low group (50.8% vs. 67.3%; P = 0.01).
Conclusions: We provide the first evidence of the association between high expression of pSphK1 and lymphatic spread in ESCC. Our study demonstrated that S1P signaling pathway is worth investigating to further understand the molecular mechanism of lymphatic spread in ESCC.