Regulation of vascular permeability in cancer metastasis

Abstract

Enhancement of vascular permeability is indispensable for cancer metastasis. Weakened endothelial barrier function enhances vascular permeability. Circulating tumor cells moving in the microvasculature tend to invade into stromal tissue at the location where vascular permeability is enhanced. Many basic studies have identified permeability factors by using gene-modified animals and cells. These factors directly/indirectly interact with endothelial cells. Here, we review vascular permeability factors and their molecular mechanisms. Interactions between tumor cells and endothelial cells are also discussed in the process of extravasation, one of the most critical steps in tumor metastasis. In some cases, primary tumors can manipulate permeability in a remote organ by secreting permeability factors. In addition, the importance of glycocalyx, which covers the endothelial cell surface, in controlling vascular permeability and tumor metastasis is also described. Furthermore, analysis of the hyperpermeable region found in a mouse model study is introduced. It clearly showed that tumor-bearing mouse lungs had a hyperpermeable region due to the influence of a remote primary tumor, and fibrinogen deposition was observed in that region. Given that fibrinogen was reported to be a permeability factor and a key regulator of inflammation, eliminating fibrinogen deposition may prevent future metastasis.

Keywords: endothelial cell; fibrinogen; metastasis; permeability; premetastatic soil.

FIGURE 1

Mechanisms of vascular permeability and tumor metastasis. A, Five types of paracellular permeability are illustrated. B, Interactions between tumor cells and endothelial cells are depicted. In B‐2, tumor cell–secreted factors are derived from the primary tumor and circulating tumor cells. C, Glycocalyx protects endothelial cells from tumor cell–secreted factors and tumor cells

FIGURE 2

Hyperpermeability regions in the premetastatic phase. Lungs isolated from tumor‐bearing mouse after Evans blue dye was injected via the tail vein. Hyperpermeable regions were stained deeply. Note that these regions were not observed in non–tumor‐bearing mouse lungs. In the case of CCL2 knockout mice, such hyperpermeable regions were not observed because tumor‐dependent vascular permeability was mediated by the CCL2‐CCR2 signaling pathway. Immunostaining revealed that CCL2 expression was upregulated in the hyperpermeable region. In this region, fibrinogen deposition was also observed (upper panel). The CCL2 and CCR2 system regulates permeability accompanied by cytokines and inflammatory factors via the toll‐like 4/MD2 complex. Endothelial contractility is regulated by focal adhesion kinase (FAK) (lower panel)

FIGURE 3

Hepato‐entrained natural killer (NK) cells. System‐tracing NK cells in liver to lungs. The liver of mice expressing the photoconvertible protein Kikume Green‐Red (KikGR) was exposed to violet light. Some of the liver NK cells were educated by primary tumor–derived factors exhibiting FX expression and relocated to the lungs (upper panel). In the lungs, educated NK cells were observed in the hyperpermeable region where fibrinogen deposits accumulated (middle panel). The fibrinogen was eliminated by FXa in the NK cells, resulting in the suppression of metastasis (lower panel)