Review Article | Published:

Crossing the endothelial barrier during metastasis

Nature Reviews Cancer volume 13, pages 858870 (2013) | Download Citation

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.

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.

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Acknowledgements

This work was funded by Cancer Research UK.

Author information

Author notes

    • Nicolas Reymond
    •  & Bárbara Borda d'Água

    These authors contributed equally to this work.

Affiliations

  1. Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.

    • Nicolas Reymond
    • , Bárbara Borda d'Água
    •  & Anne J. Ridley
  2. Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique (CNRS) — UMR5237, 1919 Route de Mende, 34293 Montpellier, Cedex 5, France.

    • Nicolas Reymond

Authors

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  3. Search for Anne J. Ridley in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Anne J. Ridley.

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.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrc3628

Further reading