Effect of circulating tumor cell aggregate configuration on hemodynamic transport and wall contact

Abstract

Selectin-mediated adhesion of circulating tumor cells (CTCs) to the endothelium is a critical step in cancer metastasis, a major factor contributing to the mortality of cancer. The formation of tethers between tumor cells and endothelial selectins initiates cell rolling, which can lead to firm adhesion, extravasation and the formation of secondary metastases. Tumor cells travel through the bloodstream as single cells, or as aggregates known as circulating tumor microemboli (CTM). CTM have increased survivability and metastatic potential relative to CTCs, and the presence of CTM is associated with worse patient prognosis. The motion of cells and cellular aggregates in flow is a function of their size and shape, and these differences influence the frequency and strength of their contact with the endothelium. In this study, a computational model consisting of the hydrodynamic component of the Multiparticle Adhesive Dynamics simulation analyzed the effects of model aggregate conformation and orientation on adhesive binding potential. Model aggregates of the Colo205 colorectal cancer cell line were created, consisting of two, three, and four cells in simple geometrical conformations. Contact time, contact area, and time integral of contact area were measured as a function of fluid shear rate, initial centroid height, and initial orientation for model aggregates that experienced hydrodynamic collisions with the plane wall. It was found that larger CTM conformations with intermediate nonsphericities had the highest adhesion potential. The results of this study shed light on the correlation between environmental conditions and extravasation efficiency, which could inform the development of new anti-metastatic drugs.

Keywords: Cancer metastasis; Circulating tumor cell; Circulating tumor microemboli; Hydrodynamic collision.