Abstract
Endothelial (E-) and platelet (P-) selectin mediated adhesion of tumor cells to vascular endothelium is a pivotal step of hematogenous metastasis formation. Recent studies have demonstrated that selectin deficiency significantly reduces metastasis formation in vivo. We selected an E- and P-Selectin specific DNA Aptamer (SDA) via SELEX (Systematic Evolution of Ligands by EXponential enrichment) with a K d value of approximately 100 nM and the capability of inhibiting the interaction between selectin and its ligands. Employing human colorectal cancer (HT29) and leukemia (EOL-1) cell lines we could demonstrate an anti-adhesive effect for SDA in vitro. Under physiological shear stress conditions in a laminar flow adhesion assay, SDA inhibited dynamic tumor cell adhesion to immobilized E- or P-selectin. The stability of SDA for more than two hours allowed its application in cell-cell adhesion assays in cell culture medium. When adhesion of HT29 cells to TNFα-stimulated E-selectin presenting human pulmonary microvascular endothelial cells was analyzed, inhibition via SDA could be demonstrated as well. In conclusion, SDA is a potential new therapeutic agent that antagonizes selectin-mediated adhesion during metastasis formation in human malignancies.
Highlights
Despite all advances in molecular medicine, the treatment of metastatic disease is still an unresolved problem, the mortality of cancer is still high
With the aim to select DNA aptamers that inhibit the interaction between human E-selectins and their ligands presented on cancer cells, we performed Systematic Evolution of Ligands by EXponential Enrichment (SELEX) using recombinantly produced human E-selectin fusion protein as target molecule
Due to sequence similarities between E- and P-selectins [6,22,23,24], we tested the affinity of specific DNA Aptamer (SDA) for recombinant human Eselectin/IgG-Fc-chimeras
Summary
Despite all advances in molecular medicine, the treatment of metastatic disease is still an unresolved problem, the mortality of cancer is still high. In 2013, about 1,600,000 incidences of cancer and 580,000 cancer deaths were registered alone in the United States [1] This high mortality rate is mostly due to the fact that metastasized cancer cannot be treated curatively. During haematogeneous metastasis formation tumor cells have to adhere to and transmigrate the endothelium at the target site of the future metastasis. In doing so, they mimic the behavior of normal leukocytes as they use the selectin-mediated migratory pathway of leucocytes in inflammation [3,4]. Cancer cells adhere on the endothelium by interacting with endothelial (E-) and platelet (P-) selectins [3,4] following transmigration into the underlying tissue and subsequent proliferation (Figure 1). Monoclonal antibodies, glycomimetic antagonists [9], and different modified aptamers [10,11,12] have been tested as selectin inhibitors in pre-clinical trials
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