Role of Melanoma Inhibitory Activity in Early Development of Malignant Melanoma

Abstract

Despite its ambiguous name, the protein melanoma inhibitory activity (MIA) was identified as a key molecule involved in the progression and metastasis of malignant melanomas. In this review, we update current knowledge on MIA with a focus on its role in early development of malignant melanoma. A search for autocrine growth-regulatory factors secreted by melanoma cells identified MIA, which was purified in 1989 and cloned in 1994. Subsequent analyses of nonneoplastic tissues revealed specific expression of MIA in cartilage. In neoplastic tissues, MIA expression was detected in malignant melanomas and chondrosarcomas. In melanoma cells, the regulation of MIA expression is controlled at the level of messenger RNA transcription by defined transcription factors. Probably, the same transcription factors regulating MIA expression also have an impact on the expression of other melanoma-associated molecules. Evidence obtained from in vitro and in vivo experiments indicated that MIA plays an important functional role in melanoma metastasis and invasion. Determination of the three-dimensional structure in solution identified MIA as the first member of a novel family of secreted extracellular proteins adopting an SH3 domain-like fold. These findings suggest specific protein-protein interactions with components of the extracellular matrix and possibly epitopes on cellular surfaces. The exact mechanisms of these interactions are unknown but certainly attract further investigations. A number of studies from different laboratories evaluated MIA as a highly specific and sensitive prognostic marker, clinically useful for follow-up and therapy monitoring of patients with malignant melanomas.