Proteases in cutaneous malignant melanoma: relevance as biomarker and therapeutic target

Abstract

Cutaneous malignant melanoma is the most aggressive skin cancer. It is also the most rapidly spreading cancer in terms of worldwide incidence. Although it is detected by simple inspection and can be relatively easily removed or treated, differential diagnosis to other melanocytic lesions, lack of prognostic markers, and no efficient treatment of advanced melanoma pose problems. Detection and targeting of proteases may represent a useful tool since they play a role in tumor cell metabolism, invasion, angiogenesis and metastasis. This review gives an overview of the role of proteases in development and progression of cutaneous malignant melanoma. In addition, regulation, activation, and interaction of proteases and their inhibitors are explained for tumors in general. The potential use of proteases as differential markers for melanoma mimicking melanocytic lesions, as biomarkers in tissues, and as prognostic serum markers is discussed. Current and future possibilities to target tumor proteases in therapy are presented.

Fig. 1

Transformation of nevus to melanoma according to the model developed by Clark and Elder. Melanocytic nevi progressively transform into melanocytic atypia, radial growth melanoma with in situ growth only, vertical growth melanoma and metastatic melanoma. Upward (pagetoid) spread of melanocytes is not seen predominantly or exclusively in the vertical growth phase. Metastatic melanoma is characterized by invasion of melanoma cells into blood and lymph vessels (arrowheads). The Breslow index, indicating the distance (in mm) from the stratum granulosum to the tumor cells at the invasion front, reflects the increase in malignancy at the transition from the radial to the vertical growth phase

Fig. 2

Protease network at the cellular surface of tumor cells. Pro-cathepsin (pro-CB) is attached via the annexin II/p11 heterotetramer to the plasma membrane: p11 binds pro-CB at one site and plasminogen at another; annexin II attaches the complex to the plasma membrane. Cathepsin D (CD), which is activated by acid pH, cathepsin G (CG) and tissue plasminogen activator (tPA) in the presence of plasminogen cleave pro-CB to active CB. Pro-urokinase plasminogen activator (uPA) is activated after binding to the urokinase plasminogen activator receptor (uPAR) by active CB. Thereafter, uPA activates plasminogen to plasmin. Plasmin cleaves pro-MMP-1, -3, -12 and -13 to generate the respective active enzymes. MMP-3 is also activated directly by CB. MMP-2 is activated by combined action of MT1-MMP and TIMP-2 (see Fig. 3 for detail) and activates MMP-9. Degradation of ECM by CB, plasmin and MMPs is inhibited by cystatins, PAIs and TIMPs, respectively. Extra Extracellular space, PM plasma membrane, Intra intracellular space

Fig. 3

Activation of membrane-associated proteases relevant to tumor propagation. a For activation of MMP-2, the tissue inhibitor of metalloproteinases TIMP-2 binds to the catalytic domain of MT1-MMP. MT1-MMP consists of catalytic domain, hemopexin, transmembrane domain and cytoplasmic tail. Pro-MMP-2 binds to TIMP-2 and the pro-peptide is cleaved by an adjacent active MT1-MMP molecule without TIMP-2. b A disintegrin and metalloproteinases (ADAMs) are composed of a pro-domain and the domains for MMP activity, disintegrin, cysteine-rich, epithelial growth factor (EGF), act like transmembrane domain and cytoplasmic tail. Similar to all MMPs the Pro-domain is cleaved off by furin and other proprotein convertases. c The urokinase plasminogen activator (uPA) system consists of the uPA receptor (uPAR) attached to the plasma membrane by a transmembrane domain, uPA and plasminogen (Plg). This complex generates the active serine protease plasmin. d Pro-cathepsin B (pro-CB) reaches the cell surface via caveolae, lipid rafts with integrated caveolin 1 protein. Caveolae contain the annexin II/p11 complex, where p11 interacts with pro-CB and annexin II attaches the complex to the plasma membrane ( ). Activation of pro-CB is achieved by cathepsins D and G and by the tissue plasminogen activator system (see Fig. 2 for more detail). Extra Extracellular space, PM plasma membrane, Intra intracellular space