Active Detachment Involves Inhibition of Cell-Matrix Contacts of Malignant Melanoma Cells by Secretion of Melanoma Inhibitory Activity

Abstract

SUMMARY:Melanoma inhibitory activity (MIA) has been identified as a small protein secreted from malignant melanoma cells.Recent results revealed a direct interaction of MIA and epitopes within extracellular matrix proteins including fibronectin. The aim of this study was to analyze functional consequences mediated by this interaction. Here we show that MIA interferes specifically with attachment of melanoma cells to fibronectin, a phenomenon we refer to as active detachment. Antibodies inhibiting binding of ␣4␤1 and ␣5␤1 integrins to fibronectin cross-react specifically with MIA, suggesting that MIA shares significant structural homology with the binding pockets of these integrins and thereby masks the respective epitopes on extracellular matrix molecules. Several peptides derived from fibronectin and from a phage display screening were tested with respect to a potential MIA-inhibitory effect. In vitro tests identified two peptides affecting MIA function; both inhibited growth of melanoma metastases in vivo. In summary, we conclude that MIA may play a role in tumor progression and spread of malignant melanomas via mediating active detachment of cells from extracellular matrix molecules within their local milieu. Further, our results suggest that inhibiting MIA functions in vivo may provide a novel therapeutic strategy for metastatic melanoma disease. (Lab Invest 2003, 83:1583-1594.

Migration-associated secretion of melanoma inhibitory activity at the cell rear is supported by KCa3.1 potassium channels

“…Conversely, retraction of the rear cell end demands the release of adhesion contacts. In line with this assumption, external addition of MIA protein does not support migration but results in unpolarized cell detachment and reduced invasiveness in Boyden chamber assays [2]. To account for the pro-migratory effect of endogenously expressed and secreted MIA protein, we proposed that MIA secretion is directed to the rear end of a migrating cell where it can bind to integrins and thereby promote cell retraction [7].…”

“…MIA protein was described to directly interact with cell adhesion receptors, integrin α 4 β 1 and integrin α 5 β 1 [7], as well as with extracellular matrix molecules including fibronectin, tenascin and laminin [2]. As a result, matrix structures surrounding the cell and integrin adhesion molecules are masked by MIA protein, which consequently impacts melanoma cell attachment.…”

“…Thus, MIA protein serves as a reliable clinical tumor marker to detect and monitor metastatic disease in patients suffering from malignant melanoma [1,5,6]. MIA protein strongly contributes to the invasive and migratory potential of melanoma cells and promotes the formation of tumor metastases [2]; however, the mechanistic link between MIA protein and cell motility remains unclear. Recent data describe a direct interaction of MIA protein with cell adhesion receptors, integrin α 4 β 1 and integrin α 5 β 1 , followed by facilitation of cell detachment [7].…”

“…Previously, MIA has been identified as an 11 kDa protein physiologically produced by cartilage and strongly expressed and secreted by malignant melanoma cells [1,2]. MIA protein is known to play a key role in melanoma development, progression and formation of metastasis [2,3].…”

“…MIA protein is known to play a key role in melanoma development, progression and formation of metastasis [2,3]. Increased MIA protein plasma levels directly correlate with progressive malignancy and a more advanced state of melanocytic tumors [1,4].…”