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Tumour-cell invasion and migration: diversity and escape mechanisms

Nature Reviews Cancer volume 3, pages 362–374 (2003)Cite this article

Key Points

  • The process of tumour-cell invasion and metastasis is conventionally understood as the migration of individual cells that detach from the primary tumour, enter lymphatic vessels or the bloodstream and seed in distant organs.

  • Novel imaging techniques (both in vitro and in vivo), together with re-evaluation of histopathological pattern formation in tumours, have provided a detailed view of cellular and molecular migration dynamics in cancer cells.

  • Cancer cells disseminate from the primary tumour either as individual cells, using amoeboid- or mesenchymal-type movement, or as cell sheets, strands and clusters using collective migration.

  • Cancer-cell migration is typically regulated by integrins, matrix-degrading enzymes, cell–cell adhesion molecules and cell–cell communication.

  • Cancer therapeutics designed to target adhesion receptors or proteases have not yet been show to be effective in clinical trials. This might be due to the fact that the cancer cell's migration mechanisms can be reprogrammed, allowing it to maintain its invasive properties via morphological and functional de-differentiation.

  • These adaptation responses include the epithelial–mesenchymal transition (EMT), the mesenchymal–amoeboid transition (MAT) and the collective–amoeboid transition (CAT).

  • Further studies are required to identify the factors that are involved in each type of cell migration, as well as related escape strategies that are used by cancer cells after pharmacotherapeutic intervention.

Abstract

Cancer cells possess a broad spectrum of migration and invasion mechanisms. These include both individual and collective cell-migration strategies. Cancer therapeutics that are designed to target adhesion receptors or proteases have not proven to be effective in slowing tumour progression in clinical trials — this might be due to the fact that cancer cells can modify their migration mechanisms in response to different conditions. Learning more about the cellular and molecular basis of these different migration/invasion programmes will help us to understand how cancer cells disseminate and lead to new treatment strategies.

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Figure 1: Diversity of tumour invasion mechanisms.
Figure 2: Plasticity of tumour invasion mechanisms.

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Acknowledgements

We gratefully acknowledge E.-B. Bröcker for continuous support. The work from the authors' laboratory is supported by current or previous grants from the Deutsche Forschungsgemeinschaft, the Ministry for Education and Research, the Wilhelm-Sander Foundation, Evangelisches Studienwerk e.V., Haus Villigst and the Interdisciplinary Center for Clinical Research (IZKF), Würzburg.

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Authors and Affiliations

  1. Department of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, Würzburg, 97080, Germany

    Peter Friedl & Katarina Wolf

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  1. Peter Friedl
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Correspondence to Peter Friedl.

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DATABASES

Cancer.gov

breast cancer

colon cancer

gliomas

melanoma

oesophageal cancer

ovarian cancer

prostate cancer

rhabdomyosarcoma

small-cell lung cancer

LocusLink

β1 integrin

α2β1 integrin

β3 integrin

α5β1 integrin

α6β1 integrin

α6β4 integrin

αvβ3 integrin

actin

ALCAM

cadherin-11

CD26

CD44

collagen

E-cadherin

EGF

fibronectin

HGF

IGF1

laminin

MLCK

MMP2

MT1-MMP

N-cadherin

P-cadherin

PI3K

RAC

ROCK

uPA

VE-cadherin

vitronectin

FURTHER INFORMATION

Collective-amoeboid transition

Dicty web site

Mesenchymal–amoeboid transition

Glossary

INVASION

Penetration of tissue barriers, such as basement membrane and interstitial stroma, by cells. Invasion requires adhesion, proteolysis of extracellular-matrix components and migration. It occurs during normal cell morphogenesis and wound healing, and also in malignant cells.

PSEUDOPOD

Cylindrical finger-like protrusions that protrude and retract. Pseudopods are thicker than filopodia. They are termed 'invadopodium' when proteolytic matrix degradation is executed.

LAMELLIPOD

A flat broad sheet of membrane and polymerized actin filaments that flows forward at the front of moving cells on planar substrate. It is a 2D variant of the pseudopod.

FILOPOD

A finger-like, relatively long-lived dynamic protrusion of up to 50 μm length or more. It contains a core of actin filaments that are bundled in parallel. It is most prominent in sprouting axons, dendritic cells and some cancer cells. Early forms are termed 'spikes'.

RUFFLE

A small, short-lived dynamic membrane protrusion that forms at the cell's leading edge. It contains filamentous actin, and retracts or contributes to pseudopod or lamellipod growth.

PODOSOME

Small, dot-like adhesive actin-containing protrusions that form along the lower cell axis towards 2D substrata. They are detected in osteoclasts, macrophages and some cancer cells.

FOCAL COMPLEX

Small and transient cell interactions between the cell and the extracellular-matrix substrate that contain integrins, FAK and talin. They interact with the diffuse actin network at high turnover rates. They can resolve within seconds to minutes, or mature into a focal contact.

FOCAL CONTACT

(syn. focal adhesion) Stable cell–substrate interactions that evolve from a focal complex. They contain integrins, FAK, talin, vinculin, paxillin and many other proteins that couple to the actin filament network. Turnover rates are in the range of at least minutes and longer. They are the insertion place of organized actin filaments, which disassemble or mature into stable adhsion sites.

ACTIN FILAMENT

Elongated polymers of aggregated actin monomers. Filaments aggregate to networks or thicker strands through intercalation of crosslinking proteins.

CORTICAL ACTIN

Meshwork of branched actin filaments that form along the inner leaflet of the plasma membrane. It provides stiffness and contractility, and interacts with integrins and signalling molecules. It can be rapidly remodelled, which is correlated with higher migration dynamics.

STRESS FIBRE

Highly organized, thick fibres of actin filaments that are organized in parallel by crosslinking proteins. They extend between focal adhesions to the cytoplasm. Their formation is correlated with less-dynamic cell anchoring and contractility.

MESENCHYME

Synonomous with mesoderm, a 3D network of undifferentiated migratory fibroblast-like cells and interstitial stroma that forms in the notochord of the developing embryo. It gives rise to all connective tissues, including muscle and bone.

COLLECTIVE MOVEMENT

The migration of a coherent cell group or mass that move as strands, sheets or clusters of up to several hundred cells. Cell junctions are maintained by cell–cell adhesion.

EPITHELIAL MESENCHYMAL TRANSITION

Detachment of individual fibroblast-like moving cells from an epithelial collective. It requires the downregulation of cell–cell junctions, such as cadherins.

CYTOKERATIN

Cytoskeletal proteins that assemble to form the intermediate filament cytoskeleton in sessile, epithelial cells. Cytokeratins anchor to adhesive structures, such as desmosomes and hemidesmosomes.

VIMENTIN

Intermediate filaments in moving non-epithelial cells that lack cell–cell junctions. Vimentin is a (not entirely specific) histological marker for cells of mesenchymal phenotype.

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Friedl, P., Wolf, K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3, 362–374 (2003). https://doi.org/10.1038/nrc1075

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