Binding of TGF-beta1 latency-associated peptide (LAP) to alpha(v)beta6 integrin modulates behaviour of squamous carcinoma cells.
The integrin alpha(v)beta6 is not detectable on normal keratinocytes in vivo but expression is increased significantly in oral squamous cell carcinoma where this heterodimer has been shown to play a role in cell migration, invasion and protease expression. Although regarded initially as a fibronectin receptor, alpha(v)beta6 may bind to arginine-glycine-aspartic acid sequences in other matrix molecules including tenascin and vitronectin. Interestingly, alpha(v)beta6 has also been shown to have high affinity for the TGF-beta1 latency associated peptide and to participate in the activation of the TGF-beta1 latent complex. Since TGF-beta1 is present in squamous carcinomas, it is possible that latency associated peptide may modulate malignant keratinocyte behaviour independently from the classical TGF-beta signalling pathways through its interaction with integrins. We show here that when latency associated peptide is immobilised onto a surface, it acts as an alpha(v)beta6-specific ligand for oral squamous carcinoma cells promoting adhesion and haptotactic migration in addition to alpha(v)beta6-dependent increase in pro-MMP-9 expression. In contrast, even very low concentrations of soluble latency associated peptide (0.1 microg ml(-1)) inhibited alpha(v)beta6-dependent adhesion, migration and invasion. Thus alpha(v)beta6-dependent processes of oral squamous cell carcinoma, is likely to be modulated, not only by the local concentration of latency associated peptide in the stroma, but also whether it is immobilised in the matrix or released as a soluble protein.
Thomas
G J
GJ
Department of Oral Pathology, Eastman Dental Institute, University College London, UK.
Hart
I R
IR
Speight
P M
PM
Marshall
J F
JF
D000951:Antigens, Neoplasm / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004789:Enzyme Activation; D005353:Fibronectins / Q000037:antagonists & inhibitors; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010446:Peptide Fragments / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D004338:Drug Combinations; D005353:Fibronectins; D016023:Integrins; D007797:Laminin; D010446:Peptide Fragments; D011498:Protein Precursors; D011509:Proteoglycans; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6; C059485:matrigel; D003094:Collagen; D020780:Matrix Metalloproteinase 9