Regulation of fibrin-mediated tumor cell adhesion to the endothelium using anti-thrombin aptamer.
Molecular intervention during transient stages of various metastatic pathways may lead to development of promising therapeutic technologies. One of such involves soluble fibrin (sFn) that has been implicated as a cross-linker between circulating blood or tumor cells and endothelial cell receptors, promoting cell arrest on the endothelium during circulation. sFn generation is a result of thrombin-mediated fibrinogen (Fg) cleavage due to either vascular injuries or a tumor microenvironment. For cancer therapy, thrombin-mediated conversions of Fg to sFn thus serve as potential intervention points to decrease circulating tumor cell adhesion to the endothelium and subsequent metastatic events. The purpose of this work was to investigate the function of an anti-thrombin oligonucleotide aptamer in reducing tumor cell arrest. Both molecular and cellular interactions were examined to demonstrate the binding and inhibitory effects of anti-thrombin aptamer. The results show that the aptamer is capable of inhibiting thrombin-mediated Fg conversion, thereby reducing sFn-mediated tumor cell adhesion in a concentration-dependent manner. Notably, the aptamer is able to bind thrombin under dynamic flow conditions and reduce tumor cell adhesive events at various physiological shear rates. This study further indicates that oligonucleotide aptamers hold great promise as therapeutic regulators of tumor cell adhesion, and consequently, metastatic activity.
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.
Erin R
ER
Gaddes
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.
Deborah
D
Lee
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.
Gregory
G
Gydush
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.
Yong
Y
Wang
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: cxd23@psu.edu.
Cheng
C
Dong
D052157:Aptamers, Nucleotide / Q000378:metabolism*; D002448:Cell Adhesion; D004591:Electrophoresis, Polyacrylamide Gel; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020349:Surface Plasmon Resonance; D013917:Thrombin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D052157:Aptamers, Nucleotide; C081676:thrombin aptamer; D005337:Fibrin; D013917:Thrombin
Aptamers; Cell–cell interactions; Molecular inhibitor; Molecular recognition; Tumor microenvironment