EFFECT OF RETINOIC ACID ON MELANOMA CELL-DERIVED FACTOR STIMULATION OF FIBROBLAST GLYCOSAMINOGLYCAN SYNTHESIS

The hyaluronan-rich matrix that surrounds many tumours and facilitates tumour cell growth and invasion is thought to be predominantly synthe sized by normal stromal cells stimulated by tumour cell-derived factor s. This study examines the possibility that the production of tumour c ell-derived factors that stimulate fibroblast glycosaminoglycan (GAG) synthesis may be blocked by exposure to differentiation-inducing agent s such as retinoic acid. We have demonstrated that Hs294T, C8161 and A 375 human melanoma cell lines release factors into their medium that s timulate normal fibroblast GAG synthesis. Exposure of these melanoma c ells to retinoic acid failed to mediate any significant reduction in g rowth over a 7-day period. Retinoic acid failed to block the tumour ce ll production of GAG-stimulating activities and even enhanced the acti vities produced by the C8161 cell line, particularly at low retinoic a cid concentrations (48% stimulation at 10(-9) M retinoic acid; P < 0.0 2). Addition of retinoic acid directly to fibroblast cultures exposed to fibroblast-conditioned medium resulted in an inhibition of GAG synt hesis with a 33% inhibition observed at 10(-5) M. Addition of retinoic acid to fibroblast cultures exposed to the tumour cell-conditioned me dium failed to inhibit the stimulation of GAG synthesis. Other differe ntiation-inducing agents, such as hexamethylene-bis-acetamide and buty rate, also failed to block the production of tumour cell-derived GAG-s timulating activities. These results demonstrate that retinoic acid an d other differentiation-inducing agents fail to inhibit melanoma cell production of fibroblast GAG synthesis-stimulating factors or their ac tion upon fibroblasts.