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Abstract
Cell adhesion mediated by selectins (expressed by activated endothelium, activated platelets, and leukocytes) binding to their resepective selectin ligands (expressed by cancer cells) may be involved in metastasis. Therefore, methods of characterizing selectin ligands expressed on human tissue may serve as valuable assays. Presented herein is an innovative method for detecting functional selectin ligands expressed on human tissue that uses a dynamic approach, which allows for control over the force applied to the bonds between the probe and target molecules. This new method of tissue interrogation, known as dynamic biochemical tissue analysis (DBTA), involves the perfusion of molecular probe-coated microspheres over tissues. DBTA using selectin-coated probes is able to detect functional selectin ligands expressed on tissue from multiple cancer types at both primary and metastatic sites.
Highlights
Accruing evidence suggests metastasis is facilitated by adhesive interactions between E, P, and L-selectin and their respective ligands[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]
We have developed a flow-based assay, termed dynamic biochemical tissue analysis (DBTA), to characterize the expression of functional selectin ligands expressed on tissue[45]
Specificity of P-selectin DBTA probe interaction with purported selectin ligands expressed by the tissue was validated using 10 mM EDTA and human IgG DBTA probes as controls
Summary
Accruing evidence suggests metastasis is facilitated by adhesive interactions between E-, P-, and L-selectin (expressed by activated vascular endothelium, activated vascular endothelium and activated platelets, and leukocytes, respectively) and their respective ligands (expressed by cancer cells)[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. E-selectin-mediated interactions have been shown to be involved in the homing of circulating breast cancer cells expressing E-selectin ligands to bone marrow expressing E-selectin[7] Despite these findings, characterization of functional selectin ligands on human tissue remains elusive, perhaps due to the nature of the bonds formed by selectins with their ligands (i.e., selectin/selectin-ligand bonds). Marshall et al used bond lifetime distribution analysis from atomic force microscopy experiments coupled with flow chamber experiments to show that the bond lifetime of the P-selectin/PSGL-1 complex initially increases, reaches a maximum, and decreases with increasing amounts of applied force[27] This phenomenon is known as the ‘catch to slip’ bond transition and helped provide an explanation for the shear threshold effect[26,29]. The relevance of functional selectin ligand expression by human cancerous tissue, distinct from circulating tumor cells, as a biomarker is not well understood
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