MIA - a new target protein for malignant melanoma therapy

Abstract

Malignant melanoma, a malignancy of pigment producing cells, causes the greatest number of skin cancer-related deaths worldwide. The tumor is characterized by its aggressive phenotype and can metastasize at very early stages of the disease. Since metastatic lesions are usually characterized by an intrinsic resistance to standard radiation and chemotherapy, the prognosis of this tumor remains very poor in advanced stages. Melanoma inhibitory activity (MIA), an 11 kDa protein expressed and secreted by melanoma cells after their malignant transformation, is known to play a key role in melanoma development, progression and tumor cell invasion. After its secretion, which is restricted to the rear pole of migrating cells, MIA protein directly interacts with cell adhesion receptors and extracellular matrix molecules. By this mechanism, MIA protein actively facilitates focal cell detachment from surrounding structures at the cell rear and strongly promotes tumor cell invasion and formation of metastases. It has further been demonstrated that MIA contributes to immunosuppression frequently seen in malignant melanomas by binding to integrin α4ß1 expressed by leukocytes and thus inhibiting cellular antitumor immune response. Analyses at the molecular level revealed that MIA protein reaches functional activity by self assembly. Functional inactivation of MIA protein by dodecapeptides that directly bind to the dimerization interface leads to a strongly reduced tumor cell invasion in an in vivo mouse melanoma model. The molecular understanding of the contribution of MIA protein to formation of metastases provides an excellent starting point for the development of a new strategy in malignant melanoma therapy.