Retinoic acid inhibition of human melanoma cell invasion through a reconstituted basement membrane and its relation to decreases in the expression of proteolytic enzymes and motility factor receptor

• Published in: Cancer research (Chicago, Ill.) Vol. 50; no. 13; pp. 4121 - 4130
• Main Authors: HENDRIX, M. J. C, WOOD, W. R, SOBEL, M. E, RAZ, A, LOTAN, R, SEFTOR, E. A, LOTAN, D, NAKAJIMA, M, MISIOROWSKI, R. L, SEFTOR, R. E. B, STETLER-STEVENSON, W. G, BEVACQUA, S. J, LIOTTA, L. A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-07-1990
• Subjects: Antineoplastic agents; Basement Membrane - drug effects; basement membranes; Biological and medical sciences; Cell Adhesion - drug effects; Cell Division - drug effects; Dose-Response Relationship, Drug; Enzyme Induction - drug effects; General aspects; Humans; Medical sciences; Melanoma - analysis; Melanoma - enzymology; Melanoma - pathology; Microbial Collagenase - analysis; Microbial Collagenase - genetics; Neoplasm Invasiveness; Neoplasm Metastasis; Pharmacology. Drug treatments; Plasminogen Activators - analysis; Receptors, Cell Surface - analysis; Receptors, Immunologic - analysis; Receptors, Laminin; retinoic acid; RNA, Messenger - analysis; Tretinoin - pharmacology; Tumor Cells, Cultured; Human; Cell proliferation; Cell culture; Melanoma; Plasminogen activator; Collagenase; Retinoids; Malignant tumor; Adhesion; In vitro; Invasion; Basement membrane; Proteins; Laminin; Reconstituted system; Inhibition; Mechanism of action; Retinoic acid; Tumor cell; Biological receptor
• ISSN: 0008-5472; 1538-7445

Treatment of four A375 human melanoma sublines (A375, A375P, A375P-5, A375M), exhibiting distinct metastatic potentials in vivo, with beta-all-trans-retinoic acid in vitro caused a dose- and time-dependent inhibition of the ability of these cells to penetrate Matrigel-coated filters using a reconstituted basement membrane invasion assay. The possible mechanisms of action responsible for the antiinvasive effect were further investigated, and the data showed that compared with untreated cells the retinoic acid-treated cells: (a) secreted lower levels of collagenolytic enzymes, as demonstrated by a decreased ability of the cells to degrade [3H]proline-labeled type IV collagen substrate and by a reduction in the activity of a secreted Mr 64,000 collagenolytic enzyme detected in type IV collagen-containing polyacrylamide gels; (b) expressed lower levels of the human type IV collagenase mRNA (except in the A375P cells), as detected by Northern blot analysis; (c) exhibited decreased levels of tissue plasminogen activator activity, as demonstrated by a chromogenic assay; (d) were 10-40% less adhesive to a reconstituted basement membrane matrix, as determined by a 60-min Na2(51)CrO4-labeled cell attachment assay; (e) exhibited an increase in the high affinity metastasis-associated cell surface laminin receptor, as determined by flow cytometry after binding of fluorescently labeled laminin receptor antibody; and (f) expressed decreased amounts of gp78, a cell surface receptor for motility factor, demonstrated by immunoblotting and immunofluorescence. Collectively, these data suggest that retinoic acid inhibits tumor cell invasion through a basement membrane-like matrix by suppressing matrix degradation and by altering cell surface receptors.