Science & Technologies Volume I, Number 1, 2011 Medicine 234 MATRIX METALLOPROTEINSES IN DEVELOPMENT AND PROGRESSION OF SKIN MALIGNANT MELANOMA Asen Anastasov 1 , Pia Vihinen 2 , Joanna Nikkola 2 , Seppo Pyrhonen 2 , Tatyana Vlaykova 1 1 Dept. Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria, 2 Dept. Oncology and Radiotherapy, Turku University, Turku, Finland ABSTRACT Cutaneous malignant melanoma is one of the most life threatening skin cancers. It derives from skin melanocytes and has an unpredictable clinical behavior – it may remain silent for years or it can metastasize aggressively. Melanoma progression and metastases comprise several processes which require differential expression and regulation of several adhesion molecules and proteinases involved in extracellular matrix (ECM) proteolysis and cell-cell and cell-matrix contacts. MMPs are family of highly homologous extracellular or intracellular, secreted or membrane-bound, Zn 2+ dependent neutral endopeptidases, which are capable to degrade virtually all protein components of ECM, basement membrane, clotting factors, cell-cell and cell-matrix adhesion molecules, cell-membrane attached precursors of growth factors, growth factor binding proteins, growth factor receptors, other proteinases and proteinase inhibitors, as well as their own inactive zymogene forms. In the current report we attempt to summarize our previous results and information from the literature concerning the role of differential expression and activation of particular members of MMP family for development, aggressiveness, metastatic capacity, melanoma progression, survival and therapeutic response. Key words: cutaneous melanoma, matrix metalloproteinases, adhesion molecules, progression Introduction Origin of melanoma Cutaneous malignant melanoma is one of the most life threatening skin cancers. It derives from skin melanocytes and has an unpredictable clinical behavior – it may remain silent for years or it can metastasize aggressively. Melanocytes are highly differentiated cells specialized to synthesize the natural UV protector known as melanin (65). Melanin is a pigment biopolymer, which is derived from the amino acid tyrosine. The production of melanin is a highly complex oxidative process with number of steps that can either proceed enzymatically or non-enzymatically (71). Melanocytes originate from the embryonal neural crest cells and migrate to the basal cell layer of epidermis and hair follicules (64,40,71). Melanocytes have special organelles, melanosomes, where the melanin is synthesized by the catalytic activity of the key enzyme tyrosinase (40). Melanin is transported to surrounding keratinocytes via dendrites of the melanocytes. Normally, skin melanocytes are mitotically inactive or can proliferate briefly, due to external signals such as sun exposure; nevertheless follicular melanocytes have cyclical proliferative and melanogenic activity (64). Cutaneous malignant melanoma in 70% of cases arises from normal epidermal melanocytes and the rest of 30% of the cases derive from nevus melanocytes. The preinvasive melanocytic neoplasm is called melanoma in situ. The invasive primary melanomas are divided into four subtypes based on their growth pattern: superficial spreading melanoma (SSM); lentigo maligna melanoma (LMM); nodular melanoma (NM); and acral letiginous melanoma (ALM) (3,23). Model of melanoma development and progression Melanoma, like other neoplasms, develops via transformation of normal cells into cancer cells: a multiple step process, which involves a loss of growth control and acquisition of immortality due to uncontrolled proliferation and/or impaired apoptosis (28,48,7). Tumor progression in melanocytic system is accompanied by several genetic and biological events such as genetic instability, impaired expression of cell cycle positive and negative regulators, activation of