There is a close correlation between tumour progression and hyaluronan production, either by tumour cells or stromal cells that are stimulated by tumour−derived factors. Inhibition of tumour stimulation of fibroblast hyaluronan may suppress tumour growth and invasion.

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.

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

4−MU caused a dose−dependent growth inhibition of fibroblast and melanoma cells with maximum inhibition at 0.5 mM 4−MU. At this dose, 4−MU inhibited (3)H−glucosamine incorporation into fibroblast glycosaminoglycans by 49%, and hyaluronan synthesis by 68%. 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.

4−MU is a potent inhibitor of hyaluronan synthesis, induction of stromal hyaluronan accumulation by tumour cells, and fibroblast and melanoma cell proliferation, and suggests that 4−MU may have potential as a tumour cell anti−invasive and anti−proliferative agent.

PMID: 20163414 [PubMed − as supplied by publisher] Source: National Library of Medicine.