Expression of sialyl Lewis(a) relates to poor prognosis in cholangiocarcinoma.

AIM High levels of serum sialyl Lewis(a) (sLea) are frequently found in cholangiocarcinoma (CCA) patients and have been suggested to be a serum marker for CCA. However, the significance of this antigen in CCA is unknown. In this study, the clinical significance of sLea expression in CCA tissues and the possible role of sLea in vascular invasion in vitro were elucidated. METHODS Expression of sLea in tumor tissues of 77 patients with mass-forming CCA and 33 with periductal infiltrating CCA was determined using immunohistochemistry. The in vitro assays on adhesion and transmigration of CCA cells to human umbilical vein endothelial cells were compared between CCA cell lines with and without sLea expression. RESULTS sLea was aberrantly expressed in 60% of CCA tumor tissues. A significant relationship was found between the frequency of sLea expression and the mass-forming type CCA (P = 0.041), well differentiated histological grading (P = 0.029), and vascular invasion (P = 0.030). Patients with positive sLea expression had a significantly poorer prognosis (21.28 wk, 95% CI = 16.75-25.81 wk) than those negative for sLea (37.30 wk, 95% CI = 27.03-47.57 wk) (P<0.001). Multivariate analysis with adjustment for all covariates showed that patients positive for sLea possessed a 2.3-fold higher risk of death than patients negative for sLea (P<0.001). The role of sLea in vascular invasion was demonstrated using in vitro adhesion and transmigration assays. KKU-M213, a human CCA cell-line with a high expression of sLea, adhered and transmigrated to IL-1beta-activated endothelial cells of the human umbilical vein more than KKU-100, the line without sLea expression (P<0.001). These processes were significantly diminished when the antibodies specific to either sLea or E-selectin were added to the assays (P<0.001). CONCLUSION This study demonstrates the clinical significance of sLea expression in vascular invasion, and an unfavorable outcome in CCA. The role of sLea in vascular invasion which may lead to poor prognosis is supported by the in vitro adhesion and transmigration studies.

[1]  Min Lu,et al.  Utility of serum CA19-9 in diagnosis of cholangiocarcinoma: in comparison with CEA. , 2004, World journal of gastroenterology.

[2]  H. Ozkan,et al.  Comparison of tumor marker CA 242 with CA 19-9 and carcinoembryonic antigen (CEA) in pancreatic cancer. , 2003, Hepato-gastroenterology.

[3]  A. Bergquist,et al.  Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography, with special reference to patients with primary sclerosing cholangitis. , 2002, Endoscopy.

[4]  W. Silverman,et al.  Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. , 2002, Gastrointestinal endoscopy.

[5]  M. Makuuchi,et al.  Accuracy of the preoperative determination of tumor markers in the differentiation of liver mass lesions in surgical patients. , 2002, Hepato-gastroenterology.

[6]  Y. Yasukochi,et al.  Differentiation‐Induced Transmigration of HL60 Cells across Activated HUVEC Monolayer Involves E‐selectin‐Dependent Mechanism a , 2000, Annals of the New York Academy of Sciences.

[7]  M. Aubert,et al.  Restoration of alpha(1,2) fucosyltransferase activity decreases adhesive and metastatic properties of human pancreatic cancer cells. , 2000, Cancer research.

[8]  N. Chalasani,et al.  Cholangiocarcinoma in patients with primary sclerosing cholangitis: A multicenter case‐control study , 2000, Hepatology.

[9]  G. Gores,et al.  The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis , 2000, American Journal of Gastroenterology.

[10]  J. L. Goodman,et al.  A cloned CD15s‐negative variant of HL60 cells is deficient in expression of FUT7 and does not adhere to cytokine‐stimulated endothelial cells , 1999, European journal of haematology.

[11]  Å. Danielsson,et al.  A 3-year prospective study on serum tumor markers used for detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. , 1999, Journal of hepatology.

[12]  H. Mori,et al.  An immunohistochemical study of hepatic atypical adenomatous hyperplasia, hepatocellular carcinoma, and cholangiocarcinoma with α‐fetoprotein, carcinoembryonic antigen, CA19‐9, epithelial membrane antigen, and cytokeratins 18 and 19 , 1999, Pathology international.

[13]  K. Lillemoe,et al.  Diagnosis and management of cholangiocarcinoma in primary sclerosing cholangitis , 1998, Journal of Gastrointestinal Surgery.

[14]  D L Morton,et al.  Endothelial‐selectin ligands sialyl Lewisx and sialyl Lewisa are differentiation antigens immunogenic in human melanoma , 1997, Cancer.

[15]  W. Yoon,et al.  Effect of O-glycosylated mucin on invasion and metastasis of HM7 human colon cancer cells. , 1996, Biochemical and biophysical research communications.

[16]  T. Terada,et al.  Expression of blood group‐related antigens in cholangiocarcinoma in relation to non‐neoplastic bile ducts , 1996, Histopathology.

[17]  R. Kannagi,et al.  Contribution of carbohydrate antigens sialyl Lewis A and sialyl Lewis X to adhesion of human cancer cells to vascular endothelium. , 1993, Cancer research.

[18]  I. Fidler,et al.  Regulation of tumor cell growth at organ-specific metastases. , 1992, In vivo.

[19]  M. Kiso,et al.  Structural requirements for the carbohydrate ligand of E-selectin. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Kannagi,et al.  Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A. , 1991, Biochemical and biophysical research communications.

[21]  F. Gaeta,et al.  ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex. , 1990, Science.

[22]  J. Lowe,et al.  ELAM-1-dependent cell adhesion to vascular endothelium determined by a transfected human fucosyltransferase cDNA , 1990, Cell.

[23]  V. Titapant,et al.  A high incidence of liver cancer in Khon Kaen Province, Thailand. , 1990, The Southeast Asian journal of tropical medicine and public health.

[24]  S. Hakomori,et al.  Quantitative and qualitative characterization of human cancer-associated serum glycoprotein antigens expressing epitopes consisting of sialyl or sialyl-fucosyl type 1 chain. , 1988, Cancer research.

[25]  R. Kannagi,et al.  Fucosylated type‐2 chain polylactosamine antigens in human lung cancer , 1988, International journal of cancer.

[26]  H. Koprowski,et al.  Identification of the gastrointestinal and pancreatic cancer-associated antigen detected by monoclonal antibody 19-9 in the sera of patients as a mucin. , 1983, Cancer research.

[27]  V. Zurawski,et al.  Radioimmunometric assay for a monoclonal antibody-defined tumor marker, CA 19-9. , 1983, Clinical chemistry.

[28]  M. Herlyn,et al.  Colorectal carcinoma antigens detected by hybridoma antibodies , 1979, Somatic cell genetics.