Cutaneous and uveal melanomas display different patterns of metastatic spread in patients. This study has compared these two melanoma types and investigated parameters identifiable with the metastatic phenotype. A number of investigations were performed, and it was determined that most uveal melanomas were diploid and displayed high proliferation rates; high levels of plasminogen activator activity and the expression of the 92 kDa gelatinase were associated with tumors most likely to invade the sclera and cause metastatic disease. In addition, unique patterns of chromosomal alterations were associated with this tumor type.
Further studies were undertaken using the cutaneous melanoma cell lines, A375 and its related sub-line A375/NUPRl, which was derived from A375 following subcutaneous passage in nude mice. A375/NUPRI showed an increased "experimental" metastatic potential in congenitally athymic nude mice, but expressed similar levels of a number of melanoma associated markers: MHC class I and II and lCAM-l, and a similar proliferation rate in vitro. The 92 kDa gelatinase was found to be expressed by A375/NUPRl but not the parental A375 line. Doubling times for tumors implanted at subcutaneous and intradermal sites were also similar, as was the spontaneous metastatic potential for both cell lines.
Modulation of these melanoma associated markers by TNFα and IL-l showed that whilst MHC expression was unaltered, proliferation rates were reduced and lCAM-1 expression increased by both cytokines on both cell lines, IL-I having the greater effect. Induction of 92 kDa gelatinase was observed in both cell lines following 24 hour incubation with TNFα, but only A375/NUPRI responded to IL-I stimulation. The alterations in A375 cell phenotype following TNFα treatment did not alter the experimental metastatic potential of this cell line.
In depth studies of 92 kDa gelatinase modulation identified synergy between TNFα and TGFβ this was observed in melanoma celllines of both cutaneous and uveal origin.