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Carcinoma-associated Expression of Core 2 ß-1,6-N-Acetylglucosaminyltransferase Gene in Human Colorectal Cancer: Role of O-Glycans in Tumor Progression¹

Second Department of Internal Medicine [K. S.] and Department of Laboratory Medicine [K. S., J. N., T. K.], Shinshu University School of Medicine, Matsumoto 390, Japan; Department of Internal Medicine, Nagano Municipal Hospital, Nagano 381, Japan [N. N., O. H.]; and The Glycobiology Program, La Jolla Cancer Research Center, The Burnham Institute, La Jolla, California 92037 [M. F.]

Recently, it was demonstrated that an increased level of NeuNAc2-3Galß1-4(Fuc1-3)GlcNAcß-R (sialyl Le^x) and NeuNAc2-3Galß1-3(Fuc1-4)GlcNAcß-R (sialyl Le^a) expression on the surface of colorectal cancer cells is positively correlated with progression of the disease. It has not been determined, however, which type of glycans, N- or O-glycans, is more closely associated with progression when cancer cells express those oligosaccharides. To address this problem, we have examined expression of sialyl Le^a and sialyl Le^x, those oligosaccharides in O-glycans, and core 2 ß-1,6-N-acetylglucosaminyltransferase (C2GnT) transcripts in colorectal cancer specimens from 46 patients and compared those results with clinicopathological variables. C2GnT is a glycosyltransferase that is responsible for the core 2 branch, which is critical for biosynthesis of sialyl Le^a and sialyl Le^x in O-glycans. Sialyl Le^a and sialyl Le^x were determined by immunohistochemistry, and C2GnT transcripts were detected by reverse transcription-PCR. Sialyl Le^a or sialyl Le^x in O-glycans was assessed by combining immunohistochemistry for sialyl Le^a or sialyl Le^x with reverse transcription-PCR for C2GnT. Sialyl Le^a, detected on cancer cells in 74% of patients, was well correlated with lymph node metastasis, whereas sialyl Le^a and sialyl Le^x in O-glycans, which were specifically detected in cancer tissues of 50 and 61% of patients, respectively, were closely associated with lymphatic and venous invasion. In addition, C2GnT, which was specifically detected in cancer tissues of 63% of patients, was closely correlated with the vessel invasion, as well as depth of tumor invasion. These results strongly suggest that sialyl Le^a and sialyl Le^x in O-glycans and C2GnT, expressed in cancer cells, may play important roles in tumor progression through vessel or direct invasion.

¹ This work was supported by Grant-in-Aid (C) 09670222 for Scientific Research from the Ministry of Education, Science and Culture of Japan (to J. N.), a Grant from EISAI Co., Ltd. (to T. K.), and National Cancer Institute Grants CA 48737 and, in part, CA 33000 (to M. F.).

² To whom requests for reprints should be addressed, at Department of Laboratory Medicine, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390, Japan. Phone: 81-263-37-2801; Fax: 81-263-34-5316.

Received 7/ 9/97. Accepted 10/13/97.

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