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Crossing the endothelial barrier during metastasis

Key Points

  • To form metastases, cancer cells twice cross the endothelial cells that line blood vessels (once during intravasation and once during extravasation).

  • Cancer cell extravasation usually occurs in small capillaries, where the cells can be physically trapped by size restriction and can then form stable attachments to endothelial cells.

  • Many pairs of ligand–receptor molecules contribute to the process of extravasation, including selectins, integrins, cadherins, CD44 and immunoglobulin superfamily receptors.

  • Cancer cells that are attached to endothelial cells interact with many other circulating cells in the bloodstream, including platelets, monocytes, neutrophils and natural killer cells, and these cells modulate the efficiency of cancer cell extravasation.

  • Cytokines and chemokines that increase endothelial barrier permeability (and therefore increase the efficiency of cancer cell extravasation) are often secreted by cancer cells or by associated circulating cells.

Abstract

During metastasis, cancer cells disseminate to other parts of the body by entering the bloodstream in a process that is called intravasation. They then extravasate at metastatic sites by attaching to endothelial cells that line blood vessels and crossing the vessel walls of tissues or organs. This Review describes how cancer cells cross the endothelial barrier during extravasation and how different receptors, signalling pathways and circulating cells such as leukocytes and platelets contribute to this process. Identification of the mechanisms that underlie cancer cell extravasation could lead to the development of new therapies to reduce metastasis.

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Figure 1: Cancer cell metastatic dissemination: how cancer cells cross endothelial barriers.
Figure 2: Intravasation: signalling pathways that regulate entry into the vasculature.
Figure 3: Adhesion and signalling molecules that contribute to cancer cell extravasation.
Figure 4: Examples of host–cancer cell interactions that contribute to extravasation.

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Acknowledgements

This work was funded by Cancer Research UK.

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Glossary

Elongated (or mesenchymal) migration

The movement of cells that have elongated morphology and a front-back polarity. This movement involves traction that is generated through integrin-dependent adhesion, requires extracellular proteolysis for cell invasion and depends on RAC1-driven protrusion.

Rounded (or amoeboid) migration

The movement of cells with rounded morphology, which does not require stable integrin-dependent adhesion for traction but depends on RHO–RHO-associated protein kinase (ROCK) signalling to increase actomyosin contractility and allow invasion in the absence of extracellular proteolysis.

Shear stress

The physical force that is exerted on cells in the blood as a result of blood flow.

Integrins

A large family of heterodimeric cell surface adhesion receptors that bind to extracellular matrix and cell surface ligands. They promote stable interactions between cells and their environment, and mediate intracellular signalling.

Kupffer cells

A type of macrophage that lines the sinusoid walls of the liver and removes toxins that are present in blood coming from the digestive tract.

GTPase-activating protein

(GAP). A protein that accelerates the hydrolysis of GTP to GDP, which leads to an increase in the proportion of GDP-bound GTPase molecules and a consequent reduction in their activity.

Pericytes

Mesenchymal cell precursors to vascular smooth muscle that associate with endothelial cells during angiogenesis and provide support to small capillaries.

Cancer stem cells

Cancer cells with self-renewing capacity and the ability to create or sustain a tumour cell population.

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Reymond, N., d'Água, B. & Ridley, A. Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13, 858–870 (2013). https://doi.org/10.1038/nrc3628

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