During
melanoma progression, tumour cells show increased adhesiveness to the vascular wall, invade the extracellular matrix (ECM) and frequently form functional channels similar to vascular vessels (vasculogenic mimicry). These properties are mainly mediated by the interaction of
integrins with ECM components. Since we had previously identified
neuropilin 1 (NRP-1), a coreceptor of
vascular endothelial growth factor A (
VEGF-A), as an important determinant of
melanoma aggressiveness, aims of this study were to identify the specific
integrins involved in the highly invasive phenotype of NRP-1 expressing cells and to investigate their role as targets to counteract
melanoma progression.
Melanoma aggressiveness was evaluated in vitro as cell ability to migrate through an ECM layer and to form tubule-like structures using transfected cells.
Integrins relevant to these processes were identified using specific
blocking antibodies. The αvβ5
integrin was found to be responsible for about 80% of the capability of NRP-1 expressing cells to adhere on
vitronectin. In these cells αvβ5 expression level was twice higher than in low-invasive control cells and contributed to the ability of
melanoma cells to form tubule-like structures on
matrigel.
Cilengitide, a potent inhibitor of αν
integrins activation, reduced ECM invasion, vasculogenic mimicry and secretion of
VEGF-A and
metalloproteinase 9 by
melanoma cells. In conclusion, we demonstrated that ανβ5
integrin is involved in the highly aggressive phenotype of
melanoma cells expressing NRP-1. Moreover, we identified a novel mechanism that contributes to the antimelanoma activity of the αv
integrin inhibitor
cilengitide based on the inhibition of vasculogenic mimicry.