Microvascular transport and tumor cell adhesion in the microcirculation

Abstract

One critical step in tumor metastasis is tumor cell adhesion to the endothelium forming the microvessel wall. Understanding this step may lead to new therapeutic concepts for tumor metastasis. Vascular endothelium forming the microvessel wall and the glycocalyx layer at its surface are the principal barriers to, and regulators of the material exchange between circulating blood and body tissues. The cleft between adjacent ECs (interendothelial cleft) is the principal pathway for water and solutes transport through the microvessel wall in health. It is also suggested to be the pathway for high molecular weight plasma proteins, leukocytes and tumor cells across microvessel walls in disease. Thus the first part of the review introduced the mathematical models for water and solutes transport through the interendothelial cleft. These models, combined with the experimental results from in vivo animal studies and electron microscopic observations, are used to evaluate the role of the endothelial surface glycocalyx, the junction strand geometry in the interendothelial cleft, and the surrounding extracellular matrix and tissue cells, as the determinants of microvascular transport. The second part of the review demonstrated how the microvascular permeability, hydrodynamic factors, microvascular geometry and cell adhesion molecules affect tumor cell adhesion in the microcirculation.

FIGURE 1

(a) A typical mesenteric post-capillary venule of diameter 30 µm, whose wall consists of ECs. The gap between adjacent ECs is called inter-endothelial cleft. (b) Ultrastructural organization of junction strands in the inter-endothelial cleft and the ESG. Revised from Bundgaard.

FIGURE 2

(a) 3-dimensional sketch of the junction-orifice-matrix entrance layer model for the interendothelial cleft. 2B is the width of the cleft. Large junction breaks observed in Adamson et al. are 2d × 2B, while the small continuous slit in the junction strand is 2b_s. (b) plane view of the model. Junction strand with periodic openings lies parallel to the luminal front of the cleft. L₂, depth of pores in junction strand. L₁ and L₃, depths between junction strand and luminal and abluminal fronts of the cleft, respectively. 2D, distance between adjacent large junction breaks. At the entrance of the cleft on luminal side, cross-bridging structures are represented by a periodic square array of cylindrical fibers. a, radius of these fibers, Δ, gap spacing between fibers, and L_f, thickness of entrance fiber layer (from Fu et al.^–,). The fiber matrix (surface glycocalyx) carries negative charge due to its molecular composition.^, The charge density of the surface glycocalyx is in the range of 20–30 mEq/L for mesenteric and brain microvessels.^,

FIGURE 3

Photomicrographs showing in vivo MDA-MB-435s tumor cell adhesion to a single perfused microvessel under control with 1% BSA Ringer perfusate and under treatment with 1 nM VEGF perfusate after (a) ~15 min and (b) ~60 min perfusion. The perfusion velocity is ~1000 µm/s, which is the mean normal flow velocity in post-capillary venules. Bright spots indicate adherent tumor cells labeled with fluorescence. From Shen et al.

FIGURE 4

Schematic diagram of the adhesive dynamics model. ${\stackrel{\rightharpoonup }{F}}_{\mathrm{h}}$ is the hydrodynamic force which can be calculated by momentum exchange method, ${\stackrel{\rightharpoonup }{F}}_{\mathrm{v}}$ is the repulsive van der Waals force which can be derived by the Derjaguin approximation, ${\stackrel{\rightharpoonup }{F}}_{\mathrm{s}}$ is the total spring force that contributed by the adhesive receptor–ligand bonds, and T_h and T_s are the torques induced by the hydrodynamic force and spring force, respectively. ε is the bond length. From Yan et al.^,

FIGURE 5

Comparison of bond formation probabilities and the ratio of the probabilities between the straight and curved microvessels for a single cell in the vessel 1. From Yan et al.

FIGURE 6

Comparison of bond formation probabilities and the ratio of the probabilities between the straight and curved microvessels for two cells in the vessel. From Yan et al.

FIGURE 7

The history of the trajectory of the tumor cell along the inner wall of a curved vessel, (a) case 1, (b) case 2, and (c) case 3. From Yan et al.