A potential role for 6-sulfo sialyl Lewis X in metastasis of bladder urothelial carcinoma

OBJECTIVE - It is widely accepted that sialyl Lewis X (sLeX) and sialyl Lewis A (sLeA, also known as CA 19-9) glycans expressed on cancer cells function in E-selectin-mediated metastasis. Recently, it was reported that 6-sulfo sLeX glycans detected by the MECA-79 monoclonal antibody are expressed in roughly a quarter of gastric adenocarcinoma cases, and that these cases show a poorer prognosis than MECA-79-negative cases do. The present study was undertaken to assess expression of 6-sulfo sLeX glycans in bladder urothelial carcinoma and evaluate potential clinical implications.

METHODS - We analyzed 78 specimens representing bladder urothelial carcinoma, as well as 4 bladder urothelial carcinoma cell lines, by immunostaining with a battery of anticarbohydrate antibodies. We also undertook an E-selectin•IgM chimera binding assay to assess E-selectin binding to 6-sulfo sLeX expressed on bladder urothelial carcinoma cells and performed reverse transcription polymerase chain reaction and complementary DNA transfection to determine which N-acetylglucosamine-6-O-sulfotransferases function in 6-sulfo sLeX biosynthesis in those cells. Finally, we performed double-immunofluorescence staining for MECA-79 and either CD3 or CD8 to evaluate potential association between high endothelial venule (HEV)-like vessels and tumor-infiltrating T lymphocytes.

RESULTS - 6-Sulfo sLeX glycans were expressed in ~20% of bladder urothelial carcinoma cases, particularly in plasmacytoid and micropapillary variants. Positive cells were also bound by E-selectin•IgM chimeras in a calcium-dependent manner. Transcripts encoding N-acetylglucosamine-6-O-sulfotransferase-2 were detected preferentially in HT-1197 bladder urothelial carcinoma cells expressing 6-sulfo sLeX, and transfection of the enzyme complementary DNA into HT-1376 cells, which do not express 6-sulfo sLeX glycans, resulted in cell surface expression of 6-sulfo sLeX. Furthermore, 6-sulfo sLeX glycans were expressed in HEV-like vessels induced in and around lymphocyte aggregates formed near carcinoma cell nests. These HEV-like vessel-associated tumor-infiltrating lymphocytes were composed primarily of CD3(+) T cells, with a fraction of CD8(+) cytotoxic T cells.

CONCLUSIONS - Our findings indicate that 6-sulfo sLeX glycans likely play 2 roles in bladder urothelial carcinoma progression: one in lymphocyte recruitment to enhance antitumor immune responses, and the other in E-selectin-mediated tumor cell adhesion to vascular endothelial cells, which is potentially associated with metastasis.

Urol Oncol. 2015 Jun 29. pii: S1078-1439(15)00270-7. doi: 10.1016/j.urolonc.2015.05.026. [Epub ahead of print]

Taga M1, Hoshino H2, Low S2, Imamura Y3, Ito H4, Yokoyama O4, Kobayashi M5.

1 Division of Tumor Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; Division of Urology, Department of Surgery, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.
2 Division of Tumor Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.
3 Division of Surgical Pathology, University of Fukui Hospital, Eiheiji, Japan.
4 Division of Urology, Department of Surgery, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.
5 Division of Tumor Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.

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