Localization of Rolling and Firm-Adhesive Interactions Between Circulating Tumor Cells and the Microvasculature Wall

Introduction: The adhesion of tumor cells to vessel wall is a critical stage in cancer metastasis. Firm adhesion of cancer cells is usually followed by their extravasation through the endothelium. Despite previous studies identifying the influential parameters in the adhesive behavior of the cancer cell to a planer substrate, less is known about the interactions between the cancer cell and microvasculature wall and whether these interactions exhibit organ specificity. The objective of our study is to characterize sizes of microvasculature where a deformable circulating cell (DCC) would firmly adhere or roll over the wall, as well as to identify parameters that facilitate such firm adherence and underlying mechanisms driving adhesive interactions. Methods: A three-dimensional model of DCCs is applied to simulate the fluid-structure interaction between the DCC and surrounding fluid. A dynamic adhesion model, where an adhesion molecule is modeled as a spring, is employed to represent the stochastic receptor-ligand interactions using kinetic rate expressions. Results: Our results reveal that both the cell deformability and low shear rate of flow promote the firm adhesion of DCC in small vessels (<10μm). Our findings suggest that ligand–receptor bonds of PSGL-1-P-selectin may lead to firm adherence of DCC in smaller vessels and rolling-adhesion of DCC in larger ones where cell velocity drops to facilitate the activation of integrin-ICAM-1 bonds. Conclusions: Our study provides a framework to predict accurately where different DCC-types are likely to adhere firmly in microvasculature and to establish the criteria predisposing cancer cells to such firm adhesion.