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Every step of the way: integrins in cancer progression and metastasis

An Author Correction to this article was published on 31 January 2019

This article has been updated

Abstract

Cell adhesion to the extracellular matrix is fundamental to tissue integrity and human health. Integrins are the main cellular adhesion receptors that through multifaceted roles as signalling molecules, mechanotransducers and key components of the cell migration machinery are implicated in nearly every step of cancer progression from primary tumour development to metastasis. Altered integrin expression is frequently detected in tumours, where integrins have roles in supporting oncogenic growth factor receptor (GFR) signalling and GFR-dependent cancer cell migration and invasion. In addition, integrins determine colonization of metastatic sites and facilitate anchorage-independent survival of circulating tumour cells. Investigations describing integrin engagement with a growing number of versatile cell surface molecules, including channels, receptors and secreted proteins, continue to lead to the identification of novel tumour-promoting pathways. Integrin-mediated sensing, stiffening and remodelling of the tumour stroma are key steps in cancer progression supporting invasion, acquisition of cancer stem cell characteristics and drug resistance. Given the complexity of integrins and their adaptable and sometimes antagonistic roles in cancer cells and the tumour microenvironment, therapeutic targeting of these receptors has been a challenge. However, novel approaches to target integrins and antagonism of specific integrin subunits in stringently stratified patient cohorts are emerging as potential ways forward.

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Fig. 1: Integrin involvement in many of the steps of cancer progression.
Fig. 2: Unconventional integrin signalling contributes to cancer cell survival, stemness and drug resistance.
Fig. 3: Integrins in extravasation.

Change history

  • 31 January 2019

    In the originally published article, pertuzumab was incorrectly described as an anti-PI3K therapy in the section ‘Integrins in anticancer therapy’. The sentence should read ‘In mouse mammary tumour models, increased collagen levels and increased β1 integrin and SRC activity have been demonstrated to accompany, and promote, combined resistance to anti-human epidermal growth factor receptor 2 (HER2; also known as ERBB2) (trastuzumab and pertuzumab) and anti-PI3K (buparlisib) therapies164.’ This has now been corrected in all versions of the original article.

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Acknowledgements

The authors apologize to all colleagues whose work was not mentioned here owing to space limitations. The authors thank the Ivaska laboratory members for their constructive criticisms of this review and J. Marshall for insightful discussion and contributions to Supplementary Table 1. Work in the authors’ laboratory was supported by funding from the Academy of Finland, a European Research Council (ERC) Consolidator Grant, the Sigrid Juselius Foundation and the Cancer Society of Finland.

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Nature Reviews Cancer thanks D. Calderwood, D. Cheresh and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Contributions

J.I. researched the data for the article and wrote the body of the manuscript before submission. H.H. assembled the table, drafted the display items and contributed to writing of the manuscript before submission. J.I. and H.H. equally contributed to revising and editing of the manuscript.

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Correspondence to Johanna Ivaska.

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Glossary

Angiogenesis

A physiological process characterized by the formation of new blood vessels from pre-existing vasculature, which can be deregulated during disease to promote the spread of cancer cells.

Intravasation

The invasion of cancer cells through a basement membrane to enter blood or lymphatic vessels.

Extravasation

The movement of cells out of a blood vessel, which involves traversing an endothelial cell layer and basement membrane, into the surrounding tissue.

Anoikis

A specialized form of programmed cell death, which occurs upon loss of integrin-mediated adhesion to the extracellular matrix.

Thrombus

Also known as a blood clot, a structure that is the final result of blood coagulation. A thrombus consists of aggregated platelets and red blood cells and a mesh of crosslinked fibrin.

Desmoplasia

The growth of fibrous or connective tissue wherein resident cells produce excess fibrous matrix components such as collagen.

Mechanoreceptors

A term used to define receptors capable of receiving and translating mechanical cues from the environment.

Focal adhesion

Integrin-mediated cell–extracellular matrix contact that is connected to the actin cytoskeleton and acts as both a physical anchor and a signalling hub to regulate the cell’s response to extracellular cues.

Lysyl oxidase (LOX) enzymes

Extracellular copper-dependent enzymes that act on lysine residues in collagen and elastin to promote crosslinking of these matrix molecules.

Haptotaxis

Directional cell migration on an extracellular matrix gradient towards higher matrix concentrations.

Filopodia

Actin-rich, finger-like membrane protrusions that extend out of the cell to probe the extracellular matrix.

Invadopodia

Actin-based membrane protrusions found in invasive carcinoma cells and associated with sites of extracellular matrix degradation.

Glycocalyx

Also known as the pericellular matrix, an external cell layer that contains a fibrous meshwork of carbohydrates (oligosaccharides, glycoproteins and mucins). This layer projects from the cell surface to cover the cell membrane in many animal cells and bacteria.

Photodynamic therapy

A medical treatment that uses a photosensitizing molecule (frequently a drug that becomes activated by light exposure) and a light source to activate the administered drug.

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Hamidi, H., Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer 18, 533–548 (2018). https://doi.org/10.1038/s41568-018-0038-z

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