Elastin-derived peptides enhance melanoma growth in vivo by upregulating the activation of Mcol-A (MMP-1) collagenase.
BACKGROUND
Elastin peptides possess several biological activities and in vitro data suggest they could be involved in the early phase of melanoma growth.


METHODS
Using diverse in vitro and in vivo techniques (cell proliferation, invasion and migration assays, zymography, western blots, collagen degradation assay, reverse transcription PCR, melanoma allographs and immunohistochemistry), we analysed the effect of elastin-derived peptides (EDPs) on B16F1 melanoma growth and invasion, as well as on the proteolytic systems involved.


RESULTS
We found that EDPs dramatically promote in vivo tumour development of B16F1 melanoma, as well as their in vitro migration and invasion. The inhibition of serine proteases and matrix metalloproteinases (MMPs) activities, by aprotinin and galardin, respectively, demonstrated that these enzymes were involved in these processes. However, we found that EDPs did not increase urokinase-type plasminogen activator, tissue-type plasminogen activator or MMP-2 expression and/or activation, neither in vitro nor in vivo. Nevertheless, we observed a strong increase of pro-MMP-9 secretion in EDPs-treated tumours and, more importantly, an increase in the expression and activation of the murine counterpart of MMP-1, named murine collagenase-A (Mcol-A). Moreover, we show that plasminogen system inhibition decreases collagen degradation by this enzyme. Finally, the use of a specific blocking antibody against Mcol-A abolished EDP-induced B16F1 invasion in vitro, showing that this MMP was directly involved in this process.


CONCLUSIONS
Our data show that in vivo, EDPs are involved in melanoma growth and invasion and reinforced the concept of elastin fragmentation as a predictive factor.
Université de Reims Champagne Ardenne (URCA), Laboratoire SiRMa, UMR CNRS 6237, IFR 53 Interactions cellules microenvironment, UFR Sciences Exactes et Naturelles, Moulin de la Housse, BP 1039, 51687 Reims Cedex 2, France.
J
J
Devy
L
L
Duca
B
B
Cantarelli
D
D
Joseph-Pietras
A
A
Scandolera
A
A
Rusciani
L
L
Parent
J
J
Thevenard
S Brassart
SB
Pasco
M
M
Tarpin
L
L
Martiny
L
L
Debelle
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D017931:DNA Primers; D004549:Elastin / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D008022:Ligaments / Q000737:chemistry; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008546:Melanoma, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
D017931:DNA Primers; D010455:Peptides; D004549:Elastin; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1