Differential Expression of Angioregulatory Matricellular Proteins in Choroidal Melanoma

Abstract

Abstract: : Purpose: Choroidal melanoma progression depends on tumor angiogenesis. To investigate factors that influence angiogenesis in choroidal melanoma, we studied the expression of the matricellular proteins Secreted Protein Acidic and Rich in Cysteine (SPARC, which tends to support angiogenesis), thrombospondin 1 and thrombospondin 2 (TSP1 and TSP2 respectively, which tend to be anti–angiogenic) in these tumors. Methods: Immunohistochemical analysis of the three glycoproteins was carried out in 27 posterior uveal melanomas and was corroborated with Western blot analysis of fresh–frozen samples from 7 of the tumors. The findings were correlated with patient survival, tumor vascularity and other histologic indices of prognosis. Results: Intracellular SPARC immunoreactivity was detected in all specimens. The proportion of SPARC–positive cells within each neoplasm defined two categories of tumor: SPARC–dense and SPARC–patchy melanomas. SPARC–dense tumors significantly correlated with a higher proportion of specimen area occupied by blood vessels (p=0.04) and showed a positive association with the presence of epithelioid–type of tumor cells (p=0.06). TSP1 was not detected by either of the methods in any of the tumors analysed. Immunopositivity for TSP2 was detected in tumor cells in approximately 40% of specimens. However, TSP2 expression did not associate with survival, tumor vascularity or any other histopathologic index of outcome. Conclusions: The pattern of expression of the three matricellular proteins in choroidal melanoma cells is consistent with a cooperative mechanism for establishing an enhanced environment favorable to the onset of angiogenesis. Moreover, given the formative processes associated with neoplasia and the prominence of matricellular proteins during tissue formation, the overall absence of TSP1 in the lesions suggests a failure of induction of its expression early in the development of this neoplasm. Interventions aiming to induce TSP1 expression and/or to inhibit SPARC expression may be therapeutic candidates for the inhibition of angiogenesis in choroidal melanoma.

Keywords: melanoma • pathobiology • glycoconjugates/glycoproteins