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Integrin signalling during tumour progression

Nature Reviews Molecular Cell Biology volume 5, pages 816–826 (2004)Cite this article

Key Points

  • Dysregulated combined signalling between integrins and receptor tyrosine kinases (RTKs) promotes the disruption of adherens junctions at the onset of carcinoma invasion. Src-family kinases (SFKs) induce the expression of SNAIL/SLUG transcription factors, which repress transcription of the E-cadherin gene, and also promote — presumably through Hakai — endocytosis of E-cadherin protein. Integrin-linked kinase also promotes transcriptional repression of E-cadherin.

  • The integrins cooperate with RTKs to activate pro-migratory signalling pathways. Whereas focal adhesion kinase (FAK) signalling to Src induces the disassembly of focal adhesions at the rear of the cell, Rho-family GTPases coordinate the changes in the actin cytoskeleton that are necessary to anchor the leading edge of the cell to the matrix and propel the cell forward. The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and Jun amino-terminal kinase (JNK) contribute to cell migration by phosphorylating various cytoskeletal signalling molecules and by promoting AP-1-dependent transcription.

  • The integrins facilitate matrix remodelling and the invasion of tumour cells through the recruitment of matrix-degrading proteases.

  • Tumour cells tend to upregulate or to maintain the expression of integrins that cooperate with RTKs to promote tumour progression, whereas they tend to lose the expression of integrins that exert the opposite effect.

  • Integrins have both adhesive and signalling roles during tumour angiogenesis. Various integrin–RTK pairs are likely to control angiogenesis — this will depend on the angiogenic stimulus, the tissue and the stage of angiogenesis. Integrins are targeted by activators as well as by inhibitors of angiogenesis. Joint integrin–RTK signalling controls the invasion of endothelial cells during angiogenesis, which implies that the invasion of tumour cells and tumour angiogenesis might be regulated by similar signalling mechanisms.

  • Integrins mediate the formation of microemboli, which are composed of tumour cells, platelets and leukocytes. They also facilitate the adhesion of tumour cells to the endothelium, which therefore promotes their docking and extravasation at a metastatic site.

  • Although cancer cells do not rely heavily on adhesion to the matrix for their survival and proliferation, dysregulated integrin–RTK signalling enhances the survival of cancer cells and the growth of primary tumours.

Abstract

During progression from tumour growth to metastasis, specific integrin signals enable cancer cells to detach from neighbouring cells, re-orientate their polarity during migration, and survive and proliferate in foreign microenvironments. There is increasing evidence that certain integrins associate with receptor tyrosine kinases (RTKs) to activate signalling pathways that are necessary for tumour invasion and metastasis. The effect of these integrins might be especially important in cancer cells that have activating mutations, or amplifications, of the genes that encode these RTKs.

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Figure 1: The metastatic cascade.
Figure 2: Integrin–receptor-tyrosine-kinase signalling disrupts cell–cell adhesion.
Figure 3: Integrin–receptor-tyrosine-kinase signalling induces cell migration and invasion.
Figure 4: Integrins and matrix remodelling.
Figure 5: Integrins promote oncogenic signals of activated receptor tyrosine kinases.

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Acknowledgements

Research in the authors' laboratory is supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, Weill Graduate School of Medical Sciences, Sloan-Kettering Institute Cornell University, New York, New York, USA

    Wenjun Guo & Filippo G. Giancotti

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  1. Wenjun Guo
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  2. Filippo G. Giancotti
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DATABASES

Swiss-Prot

AP-1

Cdc42

FAK

Fyn

Hakai

ILK

integrin α1

integrin α2

integrin α3

integrin α5

integrin α6

integrin αv

integrin β1

integrin β3

integrin β4

integrin β6

integrin β8

MMP2

p130CAS

paxillin

SHC

SLUG

SNAIL

uPA

uPAR

Yes

Glossary

INTERSTITIAL MATRIX

The extracellular matrix that resides in connective tissues.

TYPE-I TRANSMEMBRANE PROTEIN

A protein that contains a single membrane-spanning domain, with the carboxyl terminus orientated towards the cytoplasm and the amino terminus orientated towards the lumen of membrane compartments or in an extracellular direction.

SRC FAMILY KINASES

(SFKs). Kinases that belong to the Src family of tyrosine kinases, the largest of the non-receptor-tyrosine-kinase families. SFKs include Src, Yes, Fyn, Lck, Lyn, Blk, Hck, Fgr and Yrk.

PALMITOYLATED

The post-translational modification of a protein with palmitic acid.

LIPID RAFTS

Membrane microdomains that are enriched in cholesterol, sphingolipids and lipid-modified proteins such as GPI-linked proteins and palmitoylated proteins. These microdomains often function as platforms for signalling events.

TIGHT JUNCTION

A belt-like region of adhesion between adjacent epithelial or endothelial cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing in the plane of the membrane.

PLATELETS

The smallest blood cells, which are important in haemostasis and blood coagulation.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

(GEF). A protein that facilitates the exchange of GDP (guanine diphosphate) for GTP (guanine triphosphate) in the nucleotide-binding pocket of a GTP-binding protein.

CARCINOMA

A malignant tumour that originates from epithelial tissue.

ADENOMA

A benign tumour that arises from glandular epithelium.

HEMIDESMOSOMES

Adhesion complexes that connect intracellular keratin filaments with extracellular matrix in the basement membrane, and thereby mediate stable cell–matrix adhesion. These multiprotein complexes are assembled by integrin α6β4, BP180 and plectins.

EPITHELIAL–MESENCHYMAL TRANSITION

(EMT). The transformation of an epithelial cell into a mesenchymal cell with migratory and invasive properties.

ADHERENS JUNCTION

A cell–cell adhesion complex that contains cadherins and catenins that are attached to cytoplasmic actin filaments.

MATRIGEL

The extracellular matrix secreted by the Engelbrecht–Holm–Swarm mouse sarcoma cell line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and so resembles the basement membrane.

ACINI

Differentiated epithelial structures in which a single layer of polarized epithelial cells encompasses a hollow lumen.

RHO-FAMILY GTPASES

Ras-related GTPases that are involved in controlling the dynamics of the actin cytoskeleton.

E3 UBIQUITIN PROTEIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that are responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

FILOPODIA

Long, thin protrusions at the periphery of cells and growth cones. They are composed of F-actin bundles.

FOCAL ADHESION

An integrin-mediated cell–substrate adhesion structure that anchors the ends of actin filaments (stress fibres) and mediates strong attachments to substrates. It also functions as an integrin signalling platform.

LAMELLIPODIA

Flattened, sheet-like structures — which are composed of a crosslinked F-actin meshwork — that project from the surface of a cell. They are often associated with cell migration.

STRESS FIBRE

A bundle of parallel filaments that contain F-actin and other contractile molecules. It often stretches between cell attachments as if under stress.

ARP2/3 PROTEIN COMPLEX

A complex that consists of two actin-related proteins, ARP2 and ARP3, along with five smaller proteins. When activated, the ARP2/3 complex binds to the side of an existing actin filament and nucleates the assembly of a new actin filament. The resulting branch structure is Y-shaped.

RGD SEQUENCE

The primary adhesive motif in many extracellular-matrix molecules, which contains the amino-acid triplet Arg-Gly-Asp.

TRANSIT-AMPLIFYING CELLS

Progenitor cells that are able to divide only 3–5 times before all of their daughters terminally differentiate.

DOMINANT-NEGATIVE

A defective protein that inhibits the function of normal proteins often by competing with normal proteins for interacting molecules through retained interaction capabilities.

ANOIKIS

Induction of programmed cell death by detachment of cells from the extracellular matrix.

SELECTINS

A family of adhesion receptors that bind to the carbohydrate groups of heavily glycosylated counter-receptors through their lectin domain. Selectins mediate the adhesion of leukocytes to endothelium.

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Guo, W., Giancotti, F. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 5, 816–826 (2004). https://doi.org/10.1038/nrm1490

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