MUTANT P53 CORRELATES WITH REDUCED EXPRESSION OF THROMBOSPONDIN-1, INCREASED ANGIOGENESIS, AND METASTATIC PROGRESSION IN MELANOMA

On the basis of reports linking mutant p53 (mp53) to decreased express ion of the angiogenesis inhibitor thrombospondin-l (TSP-1) and increas ed angiogenesis, we compared primary and metastatic melanoma tumor spe cimens to determine if these factors were associated with metastatic p rogression Western blotting, immunohistochemistry (IHC), and image ana lysis (LA) techniques were employed to evaluate the relationship betwe en p53 status and TSP-1 expression in Zaz and M14 melanoma cell lines, and among p53, TSP-I, and angiogenesis in primary and metastatic mela nomas. Zaz cells expressed wild-type p53 (WT p53) and high levels of T SP-1, while the M14 cells expressed mp53 and low TSP-1 levels. Examina tion of clinical melanoma specimens (N = 99) revealed an incidence of mp53 of 48%. Specimens with WT p53 (N = 46) expressed significantly hi gher mean levels of TSP-1 (41 +/- 27 vs. 21 +/- 24; p = 0.0004), and l ower microvessel counts per 200x field (25 +/- 17 vs. 40 +/- 20; p = 0 .0001) than tumors expressing mp53 (N = 42). A significantly higher in cidence of mp53 expression was seen in metastatic tumors (64%, 37/58) than in primary tumors (27%, 11/41)(p < 0.0005). Primary tumors specim ens had higher levels of TSP-1 (40 +/- 27 vs. 25 +/- 25; p = 0.0054) a nd lower microvessel counts (26 +/- 18 vs. 39 +/- 20, p = 0.0013) than metastatic tumors. These data suggest that acquisition of mp53, decre ased TSP-1, and increased microvessel infiltration may be interrelated and associated with the metastatic phenotype in malignant melanoma.