Retinoic acid-enhanced invasion through reconstituted basement membrane by human SK-N-SH neuroblastoma cells involves membrane-associated tissue-type plasminogen activator.
Al-trans retinoic acid (RA) enhanced human, S-type, SK-N-SH neuroblastoma cell invasion of reconstituted basement membrane in vitro but did not induce terminal differentiation of this cell line. In contrast to basal invasion, which was urokinase (uPA)- and plasmin-dependent, RA-enhanced invasion was dependent on tissue-type plasminogen activator (t-PA) and plasmin activity. Neither basal nor RA-enhanced invasion involved TIMP-2 inhibitable metalloproteinases. Enhanced invasion was associated with the induction of t-PA expression, increased expression of the putative t-PA receptor amphoterin, increased association of t-PA with cell membranes and increased net membrane-associated PA activity. Enhanced invasion was not associated with significant changes in the expression of uPA or its membrane receptor UPAR; plasminogen activator inhibitors PAI-1 and PAI-2; metalloproteinases MMP-1, MMP-2, MMP-3, MMP-9 and membrane type MMP1; or tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. RA stimulated the association of t-PA with the external cell membrane surface, which could be inhibited by heparin sulphate but not by mannose sugars or chelators of divalent cations, consistent with a role for amphoterin. Our data indicate that RA can promote the malignant behavior of S-type neuroblastoma cells refractory to RA-mediated terminal differentiation by enhancing their basement membrane invasive capacity. We suggest that this results from the action of a novel, RA-regulated mechanism involving stimulation of t-PA expression and its association with the cell membrane leading to increased PA-dependent matrix degradation.
Tiberio
A
A
Department of Experimental Medicine, University of L'Aquila, Italy.
Farina
A R
AR
Tacconelli
A
A
Cappabianca
L
L
Gulino
A
A
Mackay
A R
AR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001672:Biocompatible Materials; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D006801:Humans; D007797:Laminin; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism; D011509:Proteoglycans; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020813:Receptor, trkB; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D019208:Brain-Derived Neurotrophic Factor; D004338:Drug Combinations; D007797:Laminin; D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D011509:Proteoglycans; D017475:Receptors, Nerve Growth Factor; D019714:Tissue Inhibitor of Metalloproteinases; C059485:matrigel; D014212:Tretinoin; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D020813:Receptor, trkB; D010959:Tissue Plasminogen Activator; D008666:Metalloendopeptidases