Plasminogen activation in melanocytic neoplasia

Abstract

A large body of experimental evidence suggests that plasminogen acti vators provide tumoral cells with efficient means to degrade extracellular matrix constituents and thereby facilitate their dissemination to distant sites. Melanocytic neoplasia encompass a spectrum of lesions exhibiting diverse clinical behavior that remain difficult to predict with current histopathological evaluations. Little information concerning the contribu tion of plasminogen activation in diagnostic specimens of human melanocytic tumors is presently available. We thus analyzed biopsy specimens of pigmented skin lesions by histológica! techniques that identify the cellular sites of synthesis of plasminogen activators and of their inhibitors and that localize the sites of plasminogen activators-catalyzed enzymatic activities. We found that urokinase-type plasminogen activators (uPA) and plasmin ogen activator inhibitor type 1 mRNAs accumulate in atypical nevocytes and in melanoma cells, but not in benign nevocytes. However, uPAcatalyzed proteolytic activity was detected exclusively in melanomas.These observations suggest that up-regulation of the uPA gene is an early feature of melanocyte transformation and that unbalanced enzyme/ inhibitor activity is associated with the malignant phenotype. By support ing a role for uPA in melanoma invasiveness, they provide a novel tool for the evaluation of atypia in nevi.

Role of Angiogenesis and Microenvironment in Melanoma Progression

“…Urokinase Plasminogen Activator and Its Receptor (uPA/uPAR) have been demonstrated to play a crucial role in several stages of melanoma progression including tumour cell migration, invasion, and metastasis. uPA secreted from melanoma cells is able to regulate endothelial cell functions including migration and the organization of endothelial cells into tube-like structures (Mueller, 1996;Delbaldo et al, 1994;Hearing et al, 1988). The extracellular matrix enzymes and their inhibitors play also an important role in cancer dysregulated angiogenesis (Roy et al, 2009;Huang et al, 2009).…”

The Plasminogen Activation System in Tumour Invasion and Metastasis

“…Plasminogen activator activity can be detected either in a frozen section (in situ zymography) 42,44,45,193,194 or in electrophoresis gels in tissue homogenates, the latter technique allowing visualization of enzymatic ac tivity of plasminogen activators complexed with PA *201. t-PA and u-PA can be distinquished through anti-catalytic antibodies anti-t-PA or u-PA, or by add ing specific t-PA or u-PA inhibitors.…”

Molecular Pathology of Malignant Melanoma

“…* 124 The expression of the cell adhesion molecules ICAM-1 and MUC18 on melanoma cells increases with increased tumor thickness and development of metastatic disease. 125,126 Increased serum levels of ICAM-1 suggest a poor prognosis.…”