Elastin-derived peptides: matrikines critical for glioblastoma cell aggressiveness in a 3-D system.
In the most common primary brain tumors, malignant glioma cells invade the extracellular matrix (ECM) and proliferate rapidly in the cerebral tissue, which is mainly composed of hyaluronan (HA) along with the elastin present in the basement membrane of blood vessels. To determine the role of ECM components in the invasive capacity of glioma cell lines, we developed a 3-D cell-culture system, based on a hydrogel in which HA can be coreticulated with kappa-elastin (HA-kappaE). Using this system, the invasiveness of cells from four glioma cell lines was dramatically increased by the presence of kappaE and a related, specific peptide (VGVAPG)(3). In addition, MMP-2 secretion increased and MMP-12 synthesis occurred. Extracellular injections of kappaE or (VGVAPG)(3) provoked a pronounced and dose-dependent increase in [Ca(2+)](i). kappaE significantly enhanced the expression of the genes encoding elastin-receptor and tropoelastin. We propose the existence of a positive feedback loop in which degradation of elastin generates fragments that stimulate synthesis of tropoelastin followed by further degradation as well as migration and proliferation of the very cells responsible for degradation. All steps in this ECM-based loop could be blocked by the addition of either of the EBP antagonists, lactose, and V-14 peptide, suggesting that the loop itself should be considered as a new therapeutic target.
Groupe de Recherche, Micro-Environnement et Renouvellement Cellulaire Intégré, MERCI UPRES EA3829, Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France. b_coquerel@yahoo.fr
Bérénice
B
Coquerel
Florent
F
Poyer
Frédéric
F
Torossian
Virginie
V
Dulong
Georges
G
Bellon
Isabelle
I
Dubus
Annie
A
Reber
Jean-Pierre
JP
Vannier
D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004549:Elastin / Q000378:metabolism* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014333:Tropoelastin / Q000235:genetics / Q000378:metabolism
D009842:Oligopeptides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014333:Tropoelastin; C054901:elastin-binding proteins; D004549:Elastin; C042635:valyl-glycyl-valyl-alanyl-prolyl-glycine; D020778:Matrix Metalloproteinase 2; D053508:Matrix Metalloproteinase 12; D002118:Calcium