MELANOCYTE MEDIATED PARACRINE INDUCTION OF EXTRACELLULAR-MATRIX DEGRADING PROTEASES IN SQUAMOUS-CELL CARCINOMA-CELLS

The expression of extracellular-matrix (ECM)-degrading proteases has b een shown to be necessary for invasion of tumor cells into surrounding tissue. For several tumor types, overexpression of these proteases is dependent upon interactions with adjacent fibroblast cell populations . We previously demonstrated activation of matrix metalloprotease (MMP ) and urokinase-type plasminogen activator (uPa) expression in a cocul ture model consisting of squamous cell carcinoma cells (SCC) with derm al fibroblasts. In the present study we have examined whether melanocy tes, which are known to interact closely with keratinocytes of the bas al epidermal layer, might influence ECM-degrading protease expression in SCC cells as well, Upon coculture of the human SCC cell line II-4 w ith the nontumorigenic mouse melanocyte cell line Melan-a or treatment of II-4 cells with Melan-a conditioned media, induction of expression of the MMP matrilysin and uPa was observed. In contrast, no induction was observed for stromelysin-l or 92-kDa type IV collagenase, Matrily sin/uPa-inducing activity was found to act at the level of gene transc ription for both matrilysin and uPa and was ubiquitously expressed amo ng six different human melanocytic cell strains/lines, ranging from pr imary normal melanocytes to cell lines established from metastatic mel anoma lesions. These data demonstrate that melanocytic cells can exert a paracrine influence in SCC cells on the expression of specific prot eases involved in ECM turnover and tumor invasiveness. (C) 1997 Academ ic Press.