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Role of integrins in cell invasion and migration

Key Points

  • As cancer cells become metastatic and as endothelial cells become angiogenic, they develop altered affinity and avidity for their extracellular matrix. Some of these changes are mediated by alterations in the expression of cell-surface molecules known as integrins.

  • Numerous studies have documented dramatic differences in surface expression and distribution of integrins in malignant cells compared with pre-neoplastic tumours of the same type.

  • Integrins are also involved in regulating the activities of proteolytic enzymes that degrade the basement membrane — the initial barrier to surrounding tissue.

  • Integrins are essential for cell migration and invasion, not only because they directly mediate adhesion to the extracellular matrix, but also because they regulate intracellular signalling pathways that control cytoskeletal organization, force generation and survival.

  • Integrins not only send signals to the cell in response to the extracellular environment, but they also respond to intracellular cues and alter the way that they interact with the extracellular environment.

  • Integrin binding to ligands in the extracellular matrix initiates several pro-survival mechanisms to prevent apoptosis.

  • Over the past several years, research has led to the development of integrin and protease inhibitors that are now being tested in clinical trials.

Abstract

As cancer cells undergo metastasis — invasion and migration of a new tissue — they penetrate and attach to the target tissue's basal matrix. This allows the cancer cell to pull itself forward into the tissue. The attachment is mediated by cell-surface receptors known as integrins, which bind to components of the extracellular matrix. Integrins are crucial for cell invasion and migration, not only for physically tethering cells to the matrix, but also for sending and receiving molecular signals that regulate these processes.

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Figure 1: Regulation of intracellular signalling by integrins.
Figure 2: Regulation of integrin function by intracellular signals.
Figure 3: Integrin binding to extracellular matrix ligands prevents apoptosis.

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Acknowledgements

The authors would like to thank K. Spencer, J. Condelis and M. Bailey for assistance with figures.

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DATABASES

CancerNet:

breast tumours

gliomas

melanoma

pancreatic carcinoma

thyroid carcinoma

 LocusLink:

α-actinin

ABL

actin

calpain

CAS

caspase-8

CDC42

collagen

CRK

DOCK-180

EGF

entactin

ERK

FAK

FGF

fibrinogen

fibronectin

GRB2

heregulin

HRAS

α1β1 integrin

α4β1 integrin

α5β1 integrin

α6β4 integrin

α6Aβ1 integrin

α6Aβ3 integrin

α6Bβ3 integrin

αIIbβ3 integrin

αvβ3 integrin

laminin

MEK

MLCK

MMP-2

MMP-9

MT1-MMP

myosin

osteonectin

PAK

paxillin

PI3K

PKC

RAC

RAF

RRAS

SHC

SRC

syndecan-4

tensin

TIMP2

VEGF

vinculin

vitronectin

von Willebrand factor

FURTHER INFORMATION

The integrin page

Photos of the basal lamina

TheWWW.virtuallibraryofcellbiology—theextracellularmatrix

Glossary

INTEGRIN AFFINITY

The strength of the attraction of an integrin for its ligand. Signalling at the integrin's cytoplasmic tail alters the conformation of its extracellular domain, changing the affinity of the integrin for its ligand and the adhesive capacity of the cell.

INTEGRIN AVIDITY

An increase in the overall strength of cell adhesion, which is caused by the facilitation of lateral diffusion and/or clustering of integrins into multimeric complexes.

STROMA

Loose, largely acellular, connective tissue.

LAMELLIPODIUM

A broad membrane projection at the leading edge of the cell in the direction of movement.

HEMIDESMOSOME

A specialized cell junction that is found on the basal surface of epithelial cells that anchors these cells to the basal lamina.

MEMBRANE RUFFLE

A characteristic phenotype of migrating cells in which the cell has regions of the leading edge that are dynamically alternating between adherent and non-adherent states, thereby giving the impression of a 'ruffling' edge.

HAPTOTAXIS

Migration on an extracellular matrix gradient in the absence of chemotactic stimuli.

CHEMOTAXIS

Migration by a cell in the direction of a chemical gradient.

FILOPODIUM

A small membrane projection that emanates from the leading edge of the cell in the direction of movement.

TETRASPANIN

Transmembrane-4 superfamily proteins, including CD9, CD53, CD81, CD82 and CD151. These proteins regulate the association of protein kinase C with specific integrins.

CHELATE AND RE-BINDING EFFECTS

The factors that underlie the increased cell adhesive strength caused by avidity changes. Chelate denotes that a large extracellular matrix protein, which presents many potential integrin-binding sites, can bind several integrins if they are in sufficiently close proximity. Re-binding effects are those in which a ligand that is displaced from one integrin will rapidly re-bind a neighbouring integrin if it is in sufficiently close proximity.

ANOIKIS

Apoptosis that is induced when anchorage-dependent cells detach from their extracellular matrix.

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Hood, J., Cheresh, D. Role of integrins in cell invasion and migration. Nat Rev Cancer 2, 91–100 (2002). https://doi.org/10.1038/nrc727

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