Abstract
BackgroundMelanoma cells are usually characterized by a strong proliferative potential and efficient invasive migration. Among the multiple molecular changes that are recorded during progression of this disease, aberrant activation of receptor tyrosine kinases (RTK) is often observed. Activation of matrix metalloproteases goes along with RTK activation and usually enhances RTK-driven migration. The purpose of this study was to examine RTK-driven three-dimensional migration of melanocytes and the pro-tumorigenic role of matrix metalloproteases for melanocytes and melanoma cells.ResultsUsing experimental melanocyte dedifferentiation as a model for early melanomagenesis we show that an activated EGF receptor variant potentiates migration through three-dimensional fibrillar collagen. EGFR stimulation also resulted in a strong induction of matrix metalloproteases in a MAPK-dependent manner. However, neither MAPK nor MMP activity were required for migration, as the cells migrated in an entirely amoeboid mode. Instead, MMPs fulfilled a function in cell cycle regulation, as their inhibition resulted in strong growth inhibition of melanocytes. The same effect was observed in the human melanoma cell line A375 after stimulation with FCS. Using sh- and siRNA techniques, we could show that MMP13 is the protease responsible for this effect. Along with decreased proliferation, knockdown of MMP13 strongly enhanced pigmentation of melanocytes.ConclusionsOur data show for the first time that growth stimuli are mediated via MMP13 in melanocytes and melanoma, suggesting an autocrine MMP13-driven loop. Given that MMP13-specific inhibitors are already developed, these results support the evaluation of these inhibitors in the treatment of melanoma.
Highlights
Melanoma cells are usually characterized by a strong proliferative potential and efficient invasive migration
We found that Xiphophorus melanoma receptor kinase (Xmrk) activation induced melanocyte migration in an amoeboid manner which is entirely independent of matrix metalloproteases (MMPs) activity
EGF stimulation of melanocytes leads to MAPK- and PI3K-independent migration on collagen To monitor the effects of signalling of the oncogenic receptor tyrosine kinases (RTK) Xmrk we used HERmrk-transgenic melanocytes
Summary
Melanoma cells are usually characterized by a strong proliferative potential and efficient invasive migration. Activation of matrix metalloproteases goes along with RTK activation and usually enhances RTK-driven migration. The purpose of this study was to examine RTKdriven three-dimensional migration of melanocytes and the pro-tumorigenic role of matrix metalloproteases for melanocytes and melanoma cells. Growth factors control the fate of many cell types in the body and usually stimulate proliferation, survival and motility in cells that express the adequate receptor on their surface. Many tumors have developed mechanisms that render them independent of exogenous growth factors. Activation of growth factor receptors, can both protect the cells from apoptosis and induce migration in a threedimensional collagen environment [17,18,19]. The best studied targets of these proteases are various matrix components, a growing body of evidence reveals the importance of MMPdependent cleavage of other extra- and intracellular substrates that have various cellular effects [21,22,23]
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