Koos Boeve

186 Chapter 9 Figure 1. Schematic overview of protrusive structures of a tumour cell mediated by cortactin. This figure shows the protrusive structures invadopodia at the bottom layer and lammellipodia at the front of a tumour cell. This figure shows the delivery to the invadopodia of the membrane type 1 matrix metalloprotease (MT1-MMP, depicted by the green/red/yellow complex) which exposure results in degradation of the extracellular matrix and is one of the cellular processes involved in cell motility regulated by cortactin [Adapted from Frittoli et al. [87], with permission]. Invadopodia are especially facilitating cell invasion. Formation of invadopodia is reported in a four-stage model by Artym et al. [88] and in the review of Ramos-Garcia et al [82]. During stage I, the invadopia initiation site is characterized by accumulation of cortactin which aggregates with F-actin. During stage II (preinvadopodia), there is more accumulation of the cortactin-F-actin aggregate, resulting in recruitment of membrane type 1 metalloprotease (MT1-MMP). MT1-MMP is an important protein in cell migration by breaking down the extracellular matrix (stage III; mature invadopia) (Figure 1). Cortactin overexpression in stage III promotes also excretion of MT2 and MT3-MMPs into the extracellular matrix and that result in more breakdown [89]. Stage IV (late invadopia) is characterized by the dissolution of cortactin and F-actin while high concentrations of MT1-MMP remain. Lamellipodia are essential for locomotion of cells with an important role for cortactin [82,90]. Protrusion of a lamellipodium starts with actin filament polymerization and elongation which is mediated by cortactin, Arp2/3 complex and the cofilin protein before the other stages of lamellipodium-regulated cell migration take place. In vivo and in vitro studies showed that the expression level of cortactin is related to the cytoplasmic location in squamous cell carcinoma cell lines [82,91,92]. Overexpression of cortactin induces accumulation of cortactin in the cytoskeleton periphery which is essential for the regulation of the protrusive