Locally generated VGVAPG and VAPG elastin‐derived peptides amplify melanoma invasion via the galectin‐3 receptor

Abstract

Melanomas containing more elastin are associated with higher stages of the disease. The interaction between elastin-derived peptides and melanoma cells appears to play an important role in the progression of melanomas. The effects of the elastin-derived peptides VGVAPG and VAPG have been investigated on the migration, invasion, adhesion and angiogenesis of human melanoma cells of different invasive potential. Elastin, tropoelastin and VGVAPG peptide were demonstrated at the invasion site of melanoma using histochemistry and immunohistochemistry. Not only the VGVAPG elastin-derived peptide, which exhibits the XGXXPG consensus sequence in its primary structure, but also the shorter VAPG bind directly to 3 cell surface receptors: galectin-3, integrin avb3 and elastin-binding protein. Our results suggest that the increased levels of elastin-derived peptides facilitate the invasion of melanoma cells: (i) VGVAPG and VAPG elastin-derived peptides are chemotactic for melanoma cells; (ii) they can increase the migration of melanoma cells and the expression of CXCR-4 and CXCL-12 chemokines; (iii) they enhance the expression of the elastin-degrading MMP-2 and MMP-3; (iv) they increase the attachment of melanoma cells and the expression of different adhesion molecules; (v) they increase the expression of the lymphangiogenic VEGF-C and (vi) the galectin-3 receptor can mediate all these effects. Clinical and therapeutic aspects are also discussed. ' 2007 Wiley-Liss, Inc.Key words: melanoma; invasion; elastin; galectin-3 Recently, the incidence of melanomas has significantly increased, and patients have a reduced life expectancy. 1 Malignant melanomas are characterized as tumors of aggressive biological behavior with high motility and metastatic potential. 2,3 The extracellular matrix (ECM) plays a key role in the growth and invasion of tumor cells. Melanoma cells specifically interact with unique matrix proteins such as elastin, especially in elastin-rich organs such as the skin, lung and blood vessels. 4,5 Melanomas containing more elastin are associated with higher stages of the disease: lymph node or distant metastases, higher Clark-level and greater tumor thickness. 6 Several enzymes belonging to the matrix metalloproteinases (MMPs), serine and cysteine proteases superfamily mediate the degradation of elastin. [7][8][9] The level of these enzymes is increased in various stages of the disease 10,11 and leads to the generation of elastin-derived peptides (EDPs), which alter tissue homeostasis. EDPs have several biological effects on a wide range of cells including normal and tumor cells, 12 for example cell proliferation, 13,14 migration and chemotaxis, 15,16 tumor progression, 5,17-20 endothelial cell migration and angiogenesis. 21 These effects of EDPs are mediated predominantly by 3 cellsurface receptors: elastin binding protein (EBP), integrin avb3 and galectin-3 receptors. EBP is a 67-kDa multifunctional receptor containing lectin-binding site [22][23][24][25] and further identified as an enzymatically inactive form of...

Interaction between the Elastin Peptide VGVAPG and Human Elastin Binding Protein

“…EBP has also been reported to bind the shorter VGV and VAPG peptides (32,38). The fact that these shorter segments exhibit biological activities related to those VGVAPG possesses suggest that they share a common binding site.…”

Dynamic expression of chymotrypsin-like elastase 1 over the course of murine lung development

“…Reduced matrix metalloproteinase (MMP)-2 and MMP14 activity impairs alveolar septation (4,30), and pulmonary epithelial cells (30), vascular cells (37), and macrophages (26) all remodel lung matrix during saccular and alveolar lung development. Because elastin plays a critical mechano-developmental role in the lung (1), and remodeling of elastin is angiogenic (31)(32)(33), we asked whether elastin remodeling might provide a mechanistic link between matrix remodeling, alveolar growth, and microvascular expansion.…”

“…In addition to its role in alveolar septation (36,40), elastin may also play a role in pulmonary microvascular development by one of three mechanisms. First, elastin degradation products containing the valine-glycine-valine-alanine-glycine-proline motif may directly stimulate angiogenesis as they do in cancers of some elastin-rich tissues (31,33). Second, elastin remodeling may release elastin-bound vascular endothelial growth factor as occurs in proximal airways (32).…”

Elastin peptides in aging and pathological conditions

“…This recognition does not always require the presence of the classic integrin RGD motif that is absent in tropoelastin. Galectin-3, a multifunctional protein involved in cellular interactions, cell cycle, apoptosis, and intracellular trafficking, has also been suggested as an elastin receptor; however, the evidence remains mostly circumstantial (72) . Finally, a lactoseinsensitive elastin receptor has also been suggested (62) .…”