Integrins in cancer: biological implications and therapeutic opportunities

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.

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

“…VN is a glycoprotein involved in cell adhesion, extracellular matrix remodeling and in tumor cell migration, principally through its interaction with integrins, the urokinase‐type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor‐1 (PAI‐1) 39. VN has not been studied as a serum marker associated with melanoma prognosis to date; however, VN receptor expression on melanoma cells has been associated with poor disease prognosis 15, 40. Indeed, serum VN might regulate the differentiation of cancer stem cells and promote tumorigenesis through its integrin αVβ3 receptor,41 an interaction that upregulates MMP‐2 expression and leads to degradation of the stroma 42…”

The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin

“…Since integrins are bidirectional signalling molecules, heparin-integrin interaction may also have further consequences beyond the adhesion. Integrins are also involved in the crosstalk with numerous classes of growth factor receptors and cytokine receptors and are able to mediate proangiogenic and proliferative signals to the tumour cells [43][44][45][46][47]. On contrary, integrins can also initiate pro-survival and pro-tumourigenic as well as pro-apoptotic signals [44,48,49].…”

Inhibition of β1 integrin and IL-3Rβ common subunit interaction hinders tumour angiogenesis

“…Growth factors and cytokines released into the tumour microenvironment also act as signalling molecules promoting vessel sprouting by activating endothelial cell migration, proliferation and survival (Peoples et al, 1995;Dentelli et al, 2004). Although growth factors and cytokines act directly to induce angiogenesis, integrin receptors provide a permissive environment (Hutchings et al, 2003;Desgrosellier and Cheresh, 2010). In adherent cells, the interplay between integrins and functional cytokine receptors is required for providing the maximal response to cytokines (Giancotti and Tarone, 2003).…”