4-Methylumbelliferone inhibits tumour cell growth and the activation of stromal hyaluronan synthesis by melanoma cell-derived factors.
BACKGROUND
There is a close correlation between tumour progression and hyaluronan production, either by tumour cells or by stromal cells that are stimulated by tumour-derived factors. Inhibition of tumour stimulation of fibroblast hyaluronan may suppress tumour growth and invasion.


OBJECTIVE
To examine the effect of the hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) on the growth of and hyaluronan synthesis by fibroblasts and C8161 and MV3 melanoma cell lines, invasion, and inhibition of tumour cell-derived factor activation of fibroblasts.


METHODS
Effects of 4-MU on growth and hyaluronan synthesis by fibroblasts and melanoma cells were examined in monolayer culture and fibroblast-contracted collagen lattices, and their effects on the growth and invasion of tumour cells into collagen lattices were also studied.


RESULTS
4-MU caused a dose-dependent growth inhibition of fibroblast and melanoma cells with maximum inhibition at 0·5 mmol L(-1) 4-MU. At this dose, 4-MU inhibited (3) H-glucosamine incorporation into fibroblast glycosaminoglycans by 52%, and hyaluronan synthesis by 64%. The relative inhibition was more pronounced when fibroblasts were stimulated with C8161 melanoma cell-conditioned medium. 4-MU reduced the level of hyaluronan in fibroblast-contracted collagen lattices, and inhibited both the growth on and invasion into the lattices by melanoma cells. This growth inhibition appears to be predominantly independent of inhibition of hyaluronan synthesis. The effect on growth inhibition was reversible, and 4-MU had no effect on apoptosis.


CONCLUSIONS
4-MU is a potent inhibitor of hyaluronan synthesis, induction of stromal hyaluronan accumulation by tumour cells, and fibroblast and melanoma cell proliferation, and results suggest that 4-MU may have potential as a tumour cell anti-invasive and antiproliferative agent.
Edward
M
M
Section of Dermatology, Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, The Robertson Building, University of Glasgow, Glasgow G12 8QQ, UK. m.edward@clinmed.gla.ac.uk
Quinn
J A
JA
Pasonen-Seppänen
S M
SM
McCann
B A
BA
Tammi
R H
RH
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000096:biosynthesis; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000494:pharmacology; D008545:Melanoma / Q000473:pathology*; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D012878:Skin Neoplasms / Q000473:pathology*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D006025:Glycosaminoglycans; D006923:Hymecromone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases