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Integrins in cancer: biological implications and therapeutic opportunities

A Corrigendum to this article was published on 24 November 2010

Key Points

  • Integrin signalling regulates diverse functions in tumour cells, including migration, invasion, proliferation and survival. In several tumour types, the expression of particular integrins correlates with increased disease progression and decreased patient survival.

  • In addition to tumour cells, integrins are also found on tumour-associated host cells, such as the vascular endothelium, perivascular cells, fibroblasts, bone marrow-derived cells and platelets. Integrin signalling crucially regulates the contribution of these cell types to cancer progression. Therefore, integrin antagonists may inhibit tumour progression by blocking crucial signalling events in both the tumour microenvironment and the tumour cells themselves.

  • Integrins have a profound influence on tumour cells, both in the ligated and unligated states, in which they regulate tumour cell survival and malignancy.

  • Although integrins alone are not oncogenic, recent data have found that some oncogenes may require integrin signalling for their ability to initiate tumour growth and invasion. These effects may be due to the important contribution of integrin signalling in maintaining the cancer stem cell population in a given tumour.

  • Crosstalk between integrins and growth factor or cytokine receptors on both tumour and host cell types is vital for many aspects of tumour progression. Mechanisms of crosstalk include both direct and indirect association of integrins with growth factor or cytokine receptors, which affects the expression, ligand affinity and signalling of the receptors.

  • The important contribution of integrins to the biology of both tumour cells and tumour-associated cell types has made them appealing targets for the design of specific therapeutics. Of particular interest, the integrin αv inhibitor cilengitide is now in a Phase III clinical trial in glioblastoma, and because this is the first integrin antagonist to achieve this milestone it places anti-integrin therapy on the doorstep of clinical availability.

  • In addition to their use as therapeutic targets, integrins can be imaging biomarkers for assessing the efficacy of anti-angiogenic and anti-tumour agents. Integrin-targeted nanoparticles with a diverse array of anti-tumour payloads also represent a particularly promising area of research that may decrease the toxicities associated with systemic delivery of radiation or chemotherapy.

Abstract

The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the αvβ3 and αvβ5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.

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Figure 1: Integrin-mediated survival versus apoptotic pathways.
Figure 2: An integrin αvβ3–SRC oncogenic unit promotes anchorage independence.
Figure 3: Integrins in the host response to cancer.
Figure 4: Integrin–growth factor and integrin–cytokine receptor crosstalk.

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Acknowledgements

D.A.C. was supported by grants CA50286 and CA45726 from the US National Institutes of Health.

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DATABASES

National Cancer Institute Drug Dictionary

ATN-161

bevacizumab

cilengitide

CNTO 95

doxorubicin

etaracizumab

fluorouracil

temozolomide

trastuzumab

volociximab

FURTHER INFORMATION

David A. Cheresh's homepage

Glossary

Desmoplasia

The growth of fibrous or connective tissue.

Cilengitide

An RGD-containing cyclic pentapeptide that inhibits ligand binding to αv integrins.

Glioblastoma

The most common human brain tumour, it originates from glial cells and has no known cure.

Focal adhesions

Dynamic, macromolecular protein complexes that link the ECM to the actin cytoskeleton through integrins.

Intrinsic apoptosis

Cell death initiated by cell stress or DNA damage and induced by mitochondrial release of cytochrome c and activation of pro-apoptotic caspases.

Extrinsic apoptosis

Cell death induced by ligand binding to transmembrane death receptors and the activation of caspases, including caspase 8.

Integrin-mediated death

(IMD). Apoptotic cell death resulting from the recruitment and activation of caspase 8 by unligated integrins on otherwise adherent cells.

Dasatinib

A dual ABL1 and SFK inhibitor manufactured by Bristol-Meyers Squibb and approved for treatment of patients with chronic myelogenous leukaemia.

Vascular normalization

The process of restoring the integrity and function of the vasculature through 'pruning' immature vessels and increasing pericyte and basement membrane coverage of the remaining vessels.

Tumour stroma

The fibroblasts, immune cells, pericytes, endothelial cells and inflammatory cells that surround a tumour and have a major role in tumour growth and progression.

Polyoma middle T

Derived from the polyomavirus, the middle T antigen is commonly used to induce spontaneous tumorigenesis in mouse mammary epithelial cells as a model of breast cancer.

Trastuzumab

A humanized monoclonal antibody that binds ErbB2 on tumour cells and prevents uncontrolled proliferation caused by aberrant ErbB2 signalling.

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Desgrosellier, J., Cheresh, D. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10, 9–22 (2010). https://doi.org/10.1038/nrc2748

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