Elastin-Derived Peptides Upregulate Matrix Metalloproteinase-2-ediated Melanoma Cell Invasion Through Elastin-Binding Protein

Abstract

Type I collagen mediates melanoma cells invasion through upregulation of matrix metalloproteinases-1 and -2 (MMP-1 and -2) expression and activation. We investigated here the contribution of elastin-derived peptides (ED), degradation products of elastin, the main component of elastic fibers in melanoma cells invasion and MMP-1 and -2 expression. Our results evidenced fragmentation of elastin at the invasive front of melanoma, particularly in the most invasive tumors where those fibers nearly totally vanished. By electron microscopy, elastolysis was found to occur mainly at the periphery of melanoma cells, where close contact between elastic fibers and cells could be noticed. Therefore, we showed in vitro that plating melanoma cells high tumorigenic potential on ED-coated dishes, selectively enhanced MMP-2, as membrane-type MMP-1 (MT1-MMP) production and activation. Nevertheless, pro-MMP-2 activation was not observed owing to the parallel increase in tissue inhibitor of metalloproteinase (TIMP)-2 expression. The effects of ED on melanoma cells were found to be mediated by splicing form of beta-galactosidase (S-Gal) occupancy, as being suppressed by lactose. Supplementing collagen lattices with ED led to consistent activation of MMP-2 that can be attributed to TIMP-2 downregulation. Upregulation of MMP-2 activation by ED led to enhanced melanoma cells invasion through S-Gal occupancy. Immunohistochemistry studies, confirmed that S-Gal expression was more prominent at the melanoma invasion site associated with a strong expression of MMP-2 and MT1-MMP. We hypothesize that ED following interactions with S-Gal elastin receptor can favor melanoma cells invasion through a three-dimensional type I collagen matrix by upregulating MMP-2 activation.

Elastin-derived peptides enhance angiogenesis by promoting endothelial cell migration and tubulogenesis through upregulation of MT1-MMP

“…of four experiments. ***P<0.001. mediated angiogenic phenotype and also tumor progression (Brassart et al, 1998;Huet et al, 2002;Ntayi et al, 2004), such a siRNA-MT1-MMP silencing strategy might represent a more suitable alternative to the use of MMP inhibitors in treating tumors in clinical settings.…”

“…Preparation of cell extracts Gelatinolytic activities of MT1-MMP and EBP associated with plasma membranes were identified by gelatin zymography and western blot analysis as previously described (Brassart et al, 1998;Ntayi et al, 2004). Quantitative determination of total MT1-MMP was performed using the Biotrak MT1-MMP activity assay system (Amersham Biosciences Europe, Orsay, France) according to the manufacturer's instructions.…”

“…Thus, any sign of its degradation can represent a vital signal for organisms to initiate effective repair processes. Overall, those peptides were reported to display a wide range of biological activities, influencing cell migration (Senior et al, 1980;Hinek et al, 1992), differentiation (Grant et al, 1989), proliferation and chemotaxis (Kamoun et al, 1995;Ghuysen et al, 1992), tumor progression (Lapis and Timar, 2002;Timar et al, 1991;Huet et al, 2002;Ntayi et al, 2004), aneurysm formation and atherogenesis (Nackman et al, 1997;Hance et al, 2002;Robert, 1996). With regard to tumor invasion, soluble peptides from alkaline (κ-elastin) or elastase hydrolysis of insoluble elastin, as well as tropoelastin were shown to increase MMP-2 and MMP-3 production by human skin fibroblasts Huet et al, 2001); similarly, κ-elastin stimulated MMP-2, MT1-MMP and TIMP-2 expression in human HT-1080 fibrosarcoma cell lines and, as a consequence, could promote the invasive metastatic ability of tumor cells (Huet et al, 2002;Brassart et al, 1998).…”

Influence de l'élastolyse dans la physiopathologie gingivale

“…Ce dernier est exprimé de façon ubiquitaire par plusieurs types cellulaires en culture avec un effet sur l'expression des MMPs qui peut être différent selon les cellules. La liaison de l'élastine à S-Gal entraîne une augmentation de la production et de l'activation de MT1-MMP et de MMP2 aussi bien par les méla-nocytes que pour les cellules endothéliales alors qu'elle n'a pas ou peu d'influence sur la production des autres MMPs [13,25] . Dans des lignées de fibrosarcome, HT1080, MT1-MMP, MMP-2, MMP-1 et TIMPs sont sur-exprimés sous l'action des peptides d'élastine [17] .…”

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

“…[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][18][19][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.…”