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G. M. Seigel, S. H. Hayes, K. Rana, C. Hackett, B. Ksander, P. Kolovou, Y. Geng, M. R. King; Tumor Initiation and Cell Adhesion of ABCG2+/ICAM-1+ Cells in Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1574.
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Tumor-initiating stem-like cells have the potential to evade standard chemotherapies and metastasize via the bloodstream. Many circulating tumor cells bind directly to the endothelium via transient adhesive events mediated by selectins. Our previous studies have shown that retinoblastoma cells do not express selectin ligands or beta-2 integrins, suggesting an alternate method of adhesion. In this study, we sought to determine a potential mechanism for tumor progression in retinoblastoma based on cell adhesive properties.
RB143 human retinoblastoma cells were screened for immunoreactivity to cell adhesive molecules [NCAM, Thy1 and ICAM-1] by flow cytometry. Co-immunoreactivity was visualized by fluorescence microscopy. Interactions between RB cells and human leukocytes were measured using a parallel plate flow chamber apparatus.
We found that 23.6% of RB143 cells were immunoreactive for ICAM-1 (CD54), including all of the ABCG2+ cells that preferentially form invasive xenograft tumors in NOD-SCID mice. Since ICAM-1 could potentially mediate RB-leukocyte binding in the bloodstream as a ferrying mechanism, we next combined RB cells with human leukocytes in an adhesion molecule coated microtube apparatus. When RB cells were perfused alone, only 3-4 cells per 10 random regions were captured on the E-selectin surface. However, when RB cells were mixed with human mononuclear cells (MNCs), a significantly higher number of RB cells were captured on the E-selectin surface (10-13 cells per 10 random regions). Approximately 60% of these attached cells were adherent to MNCs. In vivo, we observed ICAM-1+ cells adjacent to leukocytes in both human RB tissue, as well as RB143 xenograft tumors.
We have identified ABCG2+/ICAM-1+cells in retinoblastoma. These cells preferentially form invasive tumors in NOD-SCID mice. Under hemodynamic flow conditions, RB cells adhere to leukocytes, which preferentially leads to capture on an E-selectin surface. These results suggest a role for leukocyte:retinoblastoma adhesive interactions as a means of promoting retinoblastoma arrest on the endothelium during tumor progression. Further studies with ICAM-1 blocking antibodies will determine the specificity of this interaction.
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