Differential arrest and adhesion of tumor cells and microbeads in the microvasculature

Abstract

To investigate the mechanical mechanisms behind tumor cell arrest in the microvasculature, we injected fluorescently labeled human breast carcinoma cells or similarly sized rigid beads into the systemic circulation of a rat. Their arrest patterns in the microvasculature of mesentery were recorded and quantified. We found that 93% of rigid beads were arrested either at arteriole–capillary intersections or in capillaries. Only 3% were at the capillary–postcapillary venule intersections and in postcapillary venules. In contrast, most of the flexible tumor cells were either entrapped in capillaries or arrested at capillary or postcapillary venule–postcapillary venule intersections and in postcapillary venules. Only 12% of tumor cells were arrested at the arteriole–capillary intersections. The differential arrest and adhesion of tumor cells and microbeads in the microvasculature was confirmed by a χ2 test (p < 0.001). These results demonstrate that mechanical trapping was responsible for almost all the arrest of beads and half the arrest of tumor cells. Based on the measured geometry and blood flow velocities at the intersections, we also performed a numerical simulation using commercial software (ANSYS CFX 12.01) to depict the detailed distribution profiles of the velocity, shear rate, and vorticity at the intersections where tumor cells preferred to arrest and adhere. Simulation results reveal the presence of localized vorticity and shear rate regions at the turning points of the microvessel intersections, implying that hemodynamic factors play an important role in tumor cell arrest in the microcirculation. Our study helps elucidate long-debated issues related to the dominant factors in early-stage tumor hematogenous metastasis.

Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis

“…On one hand, it is possible that this effect is partly dependent upon a biomechanical influence of microvascular occlusion (Guo et al, 2014). In other words, tumour cells that arrest in the pulmonary microvasculature may be ‘pushed’ into the extra-vascular tissue by these micro-occlusive insults.…”

Effects of flowing RBCs on adhesion of a circulating tumor cell in microvessels

“…In order to step out of the flow, a very important step is the so called “adhesion cascade” (Guo et al 2004; Haier and Nicolson 2001; Stroka and Konstantopoulos 2014; Wirtz et al 2011). Most previous studies have experimentally (Cheung et al 2011; Fu et al 2015; Guo et al 2014; Yan et al 2012; Zhang et al 2016) and numerically (Rejniak 2012; Yan et al 2012; Yan et al 2010) investigated the process of cell adhesion to the blood vessel. The numerical studies simply regarded the blood as a homogenous Newtonian fluid (Rejniak 2012; Yan et al 2010).…”

“…Similarly, shear flow induces the deformation of CTCs and the margination of CTCs towards the vessel wall is also expected primarily in the venular part of microcirculation, which would imply that the tissue invasion by tumor cells in blood largely occurs from venules (Firrell and Lipowsky 1989). In fact, CTCs prefer to adhere to the small venules with relatively low blood flow rates (Guo et al 2014; Zhang et al 2016). Moreover, the increase of WBC margination with reduction in shear rate (<50s −1 ) (Nash et al 2008) is strongly dependent on the occurrence of RBC aggregation.…”

“…In addition to tumor cell properties, the vessel geometry could contribute to tumor cell adhesion (Weiss 1992). In vivo experiments (Guo et al 2014; Yan et al 2012; Zhang et al 2016) have demonstrated that tumor cells prefer to adhere to the curved vessels and at the bifurcations of microvasculature. Previous findings provide valuable premises for the tumor cell firm adhesion.…”

Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity

“…DF regions are prevalent in distant organs where metastasis is more likely to occur, due to the high frequency of branched or curved blood vessels in these organs, which includes the lungs, liver, and several other organs . The branches and curves, as suggested by Guo et al, exhibit localized vorticity and shear rates which are different from the straight sections of the vessel . This suggests that the hemodynamic factors in branched or curved areas are relevant to the spread of cancer.…”