Journal Article

Integrins in cancer: biological implications and therapeutic opportunities

Desgrosellier, Jay S., Cheresh, David A.

2010

Overview

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. The integrins regulate a diverse array of cellular functions that are crucial to the initiation, progression and metastasis of solid tumours. This Review discusses the exciting developments in targeting integrins, including the recent initiation of a Phase III trial for an integrin antagonist in patients with glioblastoma. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1689/1690 / 631/92/436/108 / 631/92/612/1236 / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Care and treatment / Clinical Trials as Topic / Health aspects / Humans / Integrins / Integrins - antagonists & inhibitors / Integrins - metabolism / Integrins - therapeutic use / Neoplasms - drug therapy / Neoplasms - metabolism / Neoplasms - pathology / Neoplasms - physiopathology / review-article / Signal Transduction