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Introduction of Sd^a Carbohydrate Antigen in Gastrointestinal Cancer Cells Eliminates Selectin Ligands and Inhibits Metastasis

¹ Department of Gastroenterology, Research Institute and ² Department of Surgery, International Medical Center of Japan; and ³ GS platZ Co., Ltd., Tokyo, Japan

Requests for reprints: Taeko Dohi, Department of Gastroenterology, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. Phone: 81-3-3202-7181; Fax: 81-3-3202-7364; E-mail: dohi{at}ri.imcj.go.jp.

The Sd^a blood group carbohydrate structure is expressed in the normal gastrointestinal mucosa. We reported previously that the expression of Sd^a carbohydrate structures and ß1,4-N-acetylgalactosaminyltransferase (ß1,4GalNAcT) activity responsible for Sd^a synthesis were remarkably decreased in cancer lesions of the gastrointestinal tract. In this study, we found that Sd^a antigen was expressed mainly in chief cells of normal stomach but not in cancer tissue by immunohistologic staining. In separated gastric mucosal cells, the Sd^a glycolipids and ß1,4GalNAcT activity were concentrated in a fraction that contained chief cells as a major population. We cloned the cDNA encoding the glycosyltransferase that catalyzes the synthesis of Sd^a (Sd^a-ß1,4GalNAcT). Introduction of this cloned cDNA into KATO III gastric or HT29 colonic cancer cell lines, which originally expressed the E-selectin ligands, sialyl Lewis^x and sialyl Lewis^a, resulted in a marked increase in cell-surface expression of Sd^a along with the concomitant total loss of both sialyl Lewis^x and sialyl Lewis^a. Both KATO III and HT29 cells transfected with the Sd^a-ß1,4GalNAcT gene showed significantly decreased adhesion to activated human umbilical vein endothelial cells when compared with mock-transfected cells. Sd^a determinants showed no direct binding to Siglec-3, -5, -7, and -9. These Sd^a-ß1,4GalNAcT-transfected cells showed strikingly reduced metastatic potential in vivo when compared with mock-transfected cells. In summary, forced expression of Sd^a carbohydrate determinant caused remarkable elimination of carbohydrate ligands for selectin and reduced metastasis of human gastrointestinal tract cancer cells.

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