Deciphering the relative contribution of vascular inflammation and blood rheology in metastatic spreading

Vascular adhesion of circulating tumor cells (CTCs) is a key step in cancer spreading. If inflammation is recognized to favor the formation of vascular metastatic niches, little is known about the contribution of blood rheology to CTC deposition. Herein, a microfluidic chip, covered by a confluent monolayer of endothelial cells, is used for analyzing the adhesion and rolling of colorectal (HCT 15) and breast (MDA MB 231) cancer cells under different biophysical conditions. These include the analysis of cell transport in a physiological solution and whole blood; over a healthy and a TNF alpha inflamed endothelium; with a flow rate of 50 and 100 nL/min. Upon stimulation of the endothelial monolayer with TNF alpha (25 ng/mL), CTC adhesion increases by 2 to 4 times whilst cell rolling velocity only slightly reduces. Notably, whole blood also enhances cancer cell deposition by 2 to 3 times, but only on the unstimulated vasculature. For all tested conditions, no statistically significant difference is observed between the two cancer cell types. Finally, a computational model for CTC transport demonstrates that a rigid cell approximation reasonably predicts rolling velocities while cell deformability is needed to model adhesion. These results would suggest that, within microvascular networks, blood rheology and inflammation contribute similarly to CTC deposition thereby facilitating the formation of metastatic niches along the entire network, including the healthy endothelium. In microfluidic based assays, neglecting blood rheology would significantly underestimate the metastatic potential of cancer cells.