The Walter Herbert Lecture. Control of cell motility and tumour invasion by extracellular matrix interactions.

E Ruoslahti

doi:10.1038/bjc.1992.250

Abstract

Integrins are heterodimeric transmembrane proteins with large ectodomains and a short cytoplasmic tail inside the cell. They mediate cell adhesion to extracellular matrix proteins and to the surfaces of other cells. In many cases the sequence recognised by the integrins in the extracellular matrix proteins is the tripeptide Arg-Gly-Asp (RGD). Short synthetic peptides containing this sequence can inhibit invasion in vitro and tumour dissemination in vivo. Thus, the alpha 5 beta 1 fibronectin binding integrin appears to be the key integrin in the invasion of at least melanoma, osteosarcoma and glioblastoma cells. Modulation of the level and activities of this integrin can suppress invasion, whereas the alpha v beta 3 vitronectin binding integrin appears to be associated with increased invasiveness. There is increasing evidence that some of these effects are mediated through signals elicited by the binding of integrins to their target proteins. This possibility has generated a great deal of interest in the cytoplasmic molecules that might mediate the integrin-associated signalling.

Highlights

FN RGDOf the peptides in the invasion assay is receptor-specific; peptides that inhibit the fibronectin receptor (C5PI integrin) best are most active, whereas a peptide that inhibits the vitronectin receptor (4vp3) better than the fibronectin receptor (Pierschbacher & Ruoslahti, 1988) has much less of an effect on the invasion
Adhesion receptors generate regulatory signals in cells and that it is those signals that control cell migration and invasion
This protein may be present in the adhesion plaques where the fibronectinbinding integrin is concentrated when cells attach to a fibronectin surface

Summary

FN RGD

Of the peptides in the invasion assay is receptor-specific; peptides that inhibit the fibronectin receptor (C5PI integrin) best are most active, whereas a peptide that inhibits the vitronectin receptor (4vp3) better than the fibronectin receptor (Pierschbacher & Ruoslahti, 1988) has much less of an effect on the invasion. It is possible that the existing RGD peptides have that kind of an effect because they inhibit tumour cell (melanoma, glioma, sarcoma) invasion through amniotic membranes (Gehlsen et al, 1988), and through matrigel (Seftor et al, 1992), which does not contain fibronectin. These observations suggest two modes of RGD peptide action in cancer therapy; they can be competitive inhibitors of adhesion or deliver inhibitory signals by acting as integrin agonists

Possible mechanisms of integrin signalling

Normal Migration t

Conclusion