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.

Analysis of the dielectrophoretic properties of cells using the isomotive AC electric field

“…From the perspective of fluid mechanics, spherical particles forming a line cluster experience greater Stokes drag force than that they experience individually when in an isolated state. 25 This effect becomes more apparent when the length of cluster increases.…”

Fluids and their mechanics in tumour transit: shaping metastasis

“…In addition, a minor proportion of CTCs are known to circulate as clusters in mice and humans 53,94 , and the trajectories of these clusters in the bloodstream have been shown to depend on their size and shape. For example, compact clusters (triangular or square-shaped) will flow in closer proximity to the endothelial barrier than linear clusters 95,96 . Such behaviour might increase their probability of engaging in adhesion with the endothelium, which can be further potentiated by the high density of adhesion proteins on CTCs 97 .…”

“…In addition to providing pro-survival properties, mathematical modelling suggests that travelling in clusters increases the drag force and decreases the speed at which CTC clusters circulate, thereby favouring interactions with endothelial cells and the intravascular arrest of CTCs 95,96 . Clusters are more likely to physically lodge in microvessels at distant sites before seeding metastatic colonies, as inferred from experiments in mice 53 .…”

The Complexities of Metastasis

“…Furthermore, the trajectories traveled by CTC clusters in the circulation are different to the paths of single CTCs, in large part due to size and shape. Compact clusters flow closer to the endothelial barrier than linear clusters or single CTCs and, thus, slowly [166,167], which increases their ability of adhering to the endothelium [168]. Interestingly, the intrinsic differentiation state of a CTC cluster may also influence its flow-dependent adhesive and biomechanical properties.…”