NK Cell and Sialyl Lewisx in Cancer Metastasis

 The mechanisms of cancer metastasis consist of a complex multi-step cascade. They should be discussed from the viewpoint of both the malignant potential of cancer cells and host immunity. The interaction between tumor-associated carbohydrate antigens such as sialyl Lewisx or sialyl Lewisa expressed on cancer cells and E-selectin on endothelial cells of the target organ is one of the first and crucial steps in the metastasis cascade. On the other hand, natural killer (NK) cells playing important roles in innate immunity can kill cancer cells without antigen stimulation. C-type lectin receptors of NK cells have been studied intensively, but their target structures remain unclear.

In order to determine the roles of sialyl Lewisx in tumor metastasis, mouse melanoma B16-F1 cells were stably transfected with 1, 3-fucosyltransferase III to express sialyl Lewisx structures. The transfected B16-F1 cells, B16-FTIII, were separated by cell sorting into three different groups based on the expression levels of sialyl Lewisx. When these transfected cells were injected into the tail veins of C57BL/6 mice, M cells expressing moderate amounts of sialyl Lewisx produced large numbers of lung tumor nodules. Surprisingly, H cells expressing the highest amount of sialyl Lewisx became apoptotic in lung blood vessels, producing as few lung nodules as N cells which lack sialyl Lewisx. In contrast, H cells formed more tumors in beige mice and NK cell-depleted C57BL/6 mice than did M cells. These results indicate that excessive expression of sialyl Lewisx in tumor cells leads to rejection by NK cells rather than tumor formation facilitated by attachment to endothelial cells.

Furthermore, we confirmed that these observations were also demonstrated in cases using a human melanoma cell line, MeWo. In vitro assays demonstrated that H cells were much more sensitive to NK cell-mediated cytotoxicity than were M cells or N cells, and the susceptibility of H cells to NK cell-mediated cytolysis could be inhibited by the addition of anti- CD94 antibody, anti-sialyl Lewisx anti body or sialyl Lewisx oligosaccharides. These results, combined with structural analysis of carbohydrates, indicate that moderate amounts of sialyl Lewisx lead to tumor metastasis, whereas expression of high levels of sialyl Lewisx leads to an NK cell attack on tumor cells.
Fig.1. Variation in NK cytotoxicity by amount of sialyl Lewisx (sLex) expressed
Chikara Ohyama (Department of Urology, School of Medicine, Hirosaki University)
References (1) Fukuda M: Possible roles of tumor-associated carbohydrate antigens. Cancer Res. 56, 2237-2244, 1996
(2) Nakamori S, Kameyama M, Imaoka S, Furukawa H, Ishikawa O, Sasaki Y, Kabuto T, Iwanaga T, Matsushita Y, Irimura T: Increased expression of sialyl Lewis X antigen correlates with poor survival in patients with colorectal carcinoma: clinicopathological and immunohistochemical study. Cancer Res. 53, 3632-3637, 1993
(3) Ohyama C, Tsuboi S, Fukuda M: Dual roles of sialyl Lewis X oligosaccharides in tumor metastasis and rejection by natural killer cells. EMBO J. 18, 1516-1525, 1999
(4) Ohyama C, Kanto S, Kato K, Nakano O, Arai Y, Kato T, Chen S, Fukuda MN, Fukuda M: Natural killer cells attack tumor cells expressing high levels of sialyl Lewis X oligosaccharides. Proc Natl Acad Sci U S A. 99, 13789-13794, 2002
sialyl Lewisx LE-A05, GP-A03, GT-D03, GG-A00, IS-A02
Sep. 30, 2004

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