Abstract
Abstract Background: The vast majority of mortalities from cancer, including oral cancer, are due to metastatic disease. Previous studies have shown that sialylated cell surface glycoconjugates mediate the extravasation of circulating tumor cells from several different tumor types. The aim of this study was to investigate whether metastatic oral squamous cell carcinoma (OSCC) cells overexpress and employ sialyl Lewis A/X (sLeA/X) to adhere to E-selectin on endothelial cells. Materials and methods: Twenty-one matched-pairs of primary and nodal metastatic OSCC tissue sections were evaluated immunohistochemically using anti-sLeA (clone KM231) and anti-sLeX (clone KM93) monoclonal antibodies (mAbs). q-PCR was performed to measure relative transcript expression of a panel of glycogens potentially involved in sLeA/X synthesis in OSCC cells. sLeA/X cell surface expression was assessed by flow cytometry and fluorescence immunocytochemistry. sLeA/X involvement in OSCC cell adhesion behavior was evaluated using static and flow adhesion assays employing recombinant E-selectin (rE-selectin) and TNF-α-stimulated human dermal microvascular endothelial cells (HuDMEC) or human lymphatic endothelial cells (HLEC), respectively. Several approaches to prevent OSCC cell binding to rE-selectin or HuDMEC were tested including the use of anti-sLeA/X mAbs, neuraminidase, fucosidase, IELLQAR®, chondroitin sulfate, swainsonine and FUT3 siRNA. Results: Immunohistochemistry analysis showed sLeA/X to be mainly expressed by well- to moderately-differentiated OSCC. sLeA/X expression on primary OSCC correlates with lymph node metastasis but not tumor differentiation status. The metastatic OSCC cells, TR146, displayed higher sLeA/X expression than the non-metastatic OSCC cells, SCC4 and Cal27, and this was at least partially related to up-regulated gene expression of fucosyltransferase III. Knocking down FUT3 expression in TR146 cells reduced sLeX but not sLeA levels. TR146 cells adhered to rE-selectin and TNF-α-stimulated HuDMEC/HLEC in significantly greater numbers than SCC4 cells. Attachment of TR146 cells to rE-selectin was significantly reduced following incubation with anti-sLeA/X mAbs, neuraminidase and FUT3 siRNA. Treatment of TR146 cells with neuraminidase also caused a significant decrease in cell adhesion to HuDMEC under hydrodynamic flow conditions. Conclusions: Elevated levels of sLeX in metastatic OSCC cells results from increased FUT3 expression. Metastatic OSCC cell binding to HuDMEC/HLEC is sLeA/X-mediated and may be a target for anti-metastasis therapy. Citation Format: Ahmed Alkishi, Syed Ali Khurram, Martin Thornhill, Craig Murdoch. Metastatic oral cancer cell adhesion to vascular and lymphatic endothelial cells is sialyl Lewis A/X-dependent. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2091. doi:10.1158/1538-7445.AM2014-2091
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