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Retinoic acid‐enhanced invasion through reconstituted basement membrane by human SK‐N‐SH neuroblastoma cells involves membrane‐associated tissue‐type plasminogen activator
Author(s) -
Tiberio Antonella,
Farina Antonietta R.,
Tacconelli Antonella,
Cappabianca Lucia,
Gulino Alberto,
Mackay Andrew R.
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19971127)73:5<740::aid-ijc22>3.0.co;2-8
Subject(s) - plasmin , matrix metalloproteinase , basement membrane , plasminogen activator , biology , retinoic acid , urokinase receptor , chemistry , cancer research , cell culture , microbiology and biotechnology , endocrinology , biochemistry , enzyme , genetics
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. Int. J. Cancer 73:740–748, 1997. © 1997 Wiley‐Liss, Inc.