Involvement of carbohydrate antigen sialyl Lewis(x) in colorectal cancer metastasis

PURPOSE: Recognition of metastatic tumor cells with distinct biochemical phenotypes predominant in the primary tumors should be useful not only for establishment of new therapeutic approaches but also for identification of high-risk patients for relapse. We examined whether carbohydrate antigens, sialyl Lewis(x) (sLe(x)) and sialyl Lewisa (sLe(a)) are involved in colorectal cancer metastasis. METHODS: Metastic abilities of human colon cancer cell variants that were selected for their high or low cell surface levels of sLe(x) (DM12-HX and KM12-LX, respectively) were analyzed. Also, immunohistochemical expressions of sLe(x) and sLe(a) in 159 primary colorectal cancers were examined to determine the clinical significance of increased expression of these antigens. RESULTS: KM12-HX cells adhered more readily to tumor necrosis factor-alpha activated endothelial cells than did KM12-LX cells. Increased adhesion of KM12-HX cells to activated endothelial cells were inhibited by antibodies against E-selectin and sLe(x) and by modification of cell surface carbohydrates. KM12-HX cells showed more invasive ability in vitro and more metastatic potential in the liver of nude mice than KM12-LX cells. Although no difference was seen in the expression of six messenger ribonucleic acids corresponding to progression or metastasis of colorectal cancer, expression of fucosyltransferase was found to be responsible for the higher expression of sLe(x) in KM12-HX cells. Clinical records of patients showed that disease-free survival rate of patients with sLe(x)-positive tumors was significantly poorer than that of those with sLe(x)-negative tumors. Cox's multivariate analysis revealed that the sLe(x) status was an independent predictive factor for disease recurrence (P = 0.004), depth of invasion (P = 0.0005), and histologic type (P = 0.037), but sLe(a) status, age, gender, tumor location , N stage, and vessel invasion were not. CONCLUSION: Increased expression of sLe(x) could be involved in establishment of colorectal cancer metastasis. It appears that examining sLe(x) expression may serve as a potent marker of the recurrence in patients with colorectal cancer.