Abnormal expression of proteoglycans has been implicated in cancer and metastasis primarily because these macromolecules are involved in the control of cell growth and matrix assembly. In this report, we have investigated the expression and immunolocalization of perlecan, a major heparan sulfate proteoglycan of basement membranes and pericellular matrices, in human metastatic melanomas. Twenty-six of the 27 tumor samples showed a significant increase (up to 15-fold) in the perlecan mRNA levels when compared with normal tissue. This change correlated with a vast deposition of perlecan protein core in the pericellular matrix of metastatic melanomas. Furthermore, we have established a relationship between perlecan expression in clonal melanoma cells (70W) stimulated with neurotrophins and their increased invasiveness. Interestingly, perlecan mRNA levels were up-regulated within 10 min of neurotrophin stimulation, indicating that perlecan is an early response gene. This upregulation also occurred prior to heparanase production, suggesting that perlecan expression and its regulation might play a pivotal role in the initial onset of invasion.