Numerical Simulation Of Hematogenous Metastasis Of Tumor Cells

Cancer is one of the major diseases that seriously threaten human life and health,and 90% of cancer deaths are caused by the metastasis of tumor cells through the blood circulation system(namely hematogenous metastasis).During hematogenous metastasis,tumor cells in the microvessels migrate towards the vessel wall(namely the margination process),and subsequently adhere to the vessel wall(namely the adhesion process).Then the tumor cells are arrested at the vessel wall near the host organs,and eventually extravasate from the blood circulation system to complete the metastasis.Therefore,it is of great significance to study the dynamical behavior of tumor cells in the microvasculature for understanding the mechanism of tumor metastasis.In this thesis,we implement three-dimensional numerical simulations on the hematogenous metastasis of tumor cells,focusing on cell arrest in the microvessels,as well as the margination and adhesion dynamics of tumor cells in the complex microvascular network.The smoothed dissipative particle dynamics is coupled with immersed boundary method(SDPD-IBM)as the main numerical method to simulate the metastasis of tumor cells in the microvascular network,which is a hybrid mesoscopic particle-based method.This method can not only solve the difficulty of discretizing complex regions in the vascular network,but also conveniently solve the fluid-structure coupling problem of deformable cells,and effectively couple various mechanical behaviors of cells.These problems are precisely the challenges of cell flow simulation in complex vascular networks.In addition,another important challenge is to model the cellular behavior details.Because the individual cell behavior is essentially expressed through the microscopic molecular structure,while the behavior of cell populations in the microvascular network is at the macroscopic scale,it is very complicated to model such multi-scale and highly nonlinear problem.We model the mechanical behavior of cells by improving existing models.Firstly,considering the deformability of cells,the discrete elastic model is improved to truly reflect the stress-free state of cells,and to describe the cell deformation;secondly,considering the cell aggregation behavior when a large number of cells flow in microvessels,the Morse potential model is improved to calculate the interaction force between the curved surfaces of cells,so as to more accurately describe the cell aggregation.To describe the adhesion behavior of tumor cells,a stochastic binding model is used to model the dynamic association and dissociation of molecular adhesion bonds between tumor cells and vascular endothelial cells.Based on the improved models and SDPD-IBM method,we perform three-dimensional numerical simulations of the hematogenous metastasis of tumor cells.During hematogenous metastasis,the arrest of tumor cells in the microvasculature is a prerequisite for extravasation from the circulation to a distant host organ.We investigate the tumor cell metastasis in microvessels,and analyze the interactions among mechanical entrapment,adhesion and cell stiffness,as well as their effects on the tumor cell arrest.Two types of vascular configurations qualifying for mechanical entrapment are considered,the constriction and bifurcation structures,where the constriction region in the constriction structure represents the narrow microvessel with the diameter much smaller than the cell diameter.The simulation results indicate that in the constriction tube,as the constriction radius is increased,the tendency that number of adhesion bonds increases with increasing shear modulus becomes more and more obvious.However,the adhesion behavior has little effect on the tumor cell arrest in the constriction region,regardless of the number of adhesion bonds.The mechanical entrapment plays a more important role than the cell stiffness in the tumor cell arrest in the constriction tube.In the bifurcated tube,the tumor cell is more likely to be arrested in the bifurcation region with a small bifurcation angle.Moreover,as the bifurcation angle or shear modulus is decreased,the effect of adhesion behavior on the tumor cell arrest becomes increasingly obvious.Most numerical studies of tumor metastasis focus on the individual behavior of a small number of cells,and the vascular structure is relatively simple.In fact,there are a large number of different kinds of cells in the microvascular network in vivo,and the network structure is very complex,which is geometrically characterized by tortuous,twisting,bifurcating and merging microvessels.Based on this,we start from the real microvascular network to construct a entity model,and choose a portion of the rat mesenteric microvascular system to build a geometric model of the complex vascular network.Then,we perform numerical simulations on a large number of erythrocytes and tumor cells in a complex vascular network,and consider three mechanical behaviors of the cells: deformation,aggregation and adhesion behaviors.We investigate the metastasis preference of tumor cells,cell margination and adhesion behaviors,as well as the effects of hemodynamic factors,such as hematocrit and shear rate of blood flow,on tumor cell metastasis.The results indicate that the tumor cells are found to adhere at the microvascular bifurcations more frequently,and there is a positive correlation between the adhesion of the tumor cells and the wall-directed force from the surrounding red blood cells.The larger the wall-directed force,the closer the tumor cells are to the vascular wall during migration,and the higher the probability of adhesion behavior occur.A relatively low or high hematocrit can help to prevent the adhesion of tumor cells.Increasing the shear rate of blood flow can achieve the same purpose.That is,the tumor cells may be more likely to be arrested in the bifurcation region of the microvascular network due to adhesion and to further extravasate from there,if the blood flow is slow and the hematocrit is moderate.Our results contribute to a deeper understanding of the biomechanical mechanism of tumor metastasis and the analysis of the preferred location where tumor cells extravasate from the blood circulation,thus providing theoretical support for the cancer pathophysiology and its diagnosis and therapy.