Cell-surface proteolysis, growth factor activation and intercellular communication in the progression of melanoma

Abstract

Normal skin architecture and melanocyte function is maintained by a dynamic interplay between the melanocytes themselves, the epithelial cells between which they are interspersed, and their microenvironment. The microenvironment consists of the extracellular matrix, fibroblasts, migratory immune cells, and neural elements supported by a vascular network, all within a milieu of cytokines, growth factors, and bioactive peptides as well as proteolytic enzymes. Cells interact with the microenvironment via complex autocrine and paracrine mechanisms. Proteolytic enzymes in melanoma may activate or release growth factors from the microenvironment or act directly on the microenvironment itself, thereby facilitating angiogenesis or tumor cell migration. This review summarizes recent findings regarding the expression, structure and function of proteolytic enzymes at or near the cell surface in cell-cell and cell-stroma interactions during melanoma progression. Cell-surface (membrane) peptidases are a multi-functional group of ectoenzymes that have been implicated in the control of growth and differentiation of many cellular systems. The potential, but yet speculative, role of other membrane-bound molecules, such as multifunctional surface proteins with adhesion and protease activity (ADAM gene family) or the ephrin/Eph receptor protein kinases in the pathogenesis of melanoma are discussed.

Fig. 1

Biological events leading to melanoma development and progression. The model, developed by Clark et al. , implies that melanoma commonly develops and progresses in a sequence of steps from nevic lesions, which can be histologically identified in approximately 35% of cases. However, melanoma may also develop directly from normal cells. The role of melanoblasts (immature melanocytes) in melanogenesis remains poorly defined. The progression from normal melanocyte to nevus may be initiated by loss of contact between melanocytes and keratinocytes, i.e. the melanocytes escape from keratinocyte (KC) control. Genetic changes, which are currently not defined, are expected at the transition from common acquired (benign) nevus to dysplastic nevus/RGP/in situ melanoma (left vertical arrow), allowing cells to persist. Additional genetic changes are expected in the progression from RGP/in situ melanoma to VGP (right vertical arrow). At the VGP (tumorigenic) step, increased growth, invasion and stromal ‘landscaping’ by proteolysis occurs.

Fig. 2

Dynamic changes in expression of adhesion receptors, ECM proteins and proteolytic surface enzymes in melanoma progression. Decreased expression (downward arrow) is seen for some cadherins, CAMs, integrins, and cell-surface peptidases. A strong increase (upward arrow) is seen for a variety of adhesion-related molecules and cell-surface peptidases, first in nevi, then in VGP primary melanomas.

Fig. 3

Melanoma-associated cell-surface peptidases. Cleavage site and enzymatic activity (modified from [42]).

Fig. 4

Melanoma-associated ephrins and Eph receptors. The EphA class of receptors bind promiscuously with ephrin-A ligands; EphB receptors bind ephrin-B proteins. EphB5 does not bind to any known ephrin. The affinity of interactions differs between respective receptor–ligand combinations (modified from [101]).

Fig. 5

Structure, interactions and signal transduction of Eph receptors and ephrins. Eph receptors share a number of features, as indicated. Ephrins have conserved residues in the extracellular domain and fall into two structural classes: proteins of the ephrin-A subclass are anchored in the plasma membrane through the covalent attachment of a glycosylphosphatidylinositol (GPI) group. Proteins of the ephrin-B subclass have a transmembrane domain and short cytoplasmatic region. Bidirectional signaling (arrows) can occur upon interaction of cells expressing Eph receptors and ephrins. Modified from , .