Regulation of the actin cytoskeleton in cancer cell migration and invasion

Abstract

Malignant cancer cells utilize their intrinsic migratory ability to invade adjacent tissues and the vasculature, and ultimately to metastasize. Cell migration is the sum of multi-step processes initiated by the formation of membrane protrusions in response to migratory and chemotactic stimuli. The driving force for membrane protrusion is localized polymerization of submembrane actin filaments. Recently, several studies revealed that molecules that link migratory signals to the actin cytoskeleton are upregulated in invasive and metastatic cancer cells. In this review, we summarize recent progress on molecular mechanisms of formation of invasive protrusions used by tumor cells, such as lamellipodia and invadopodia, with regard to the functions of key regulatory proteins of the actin cytoskeleton; WASP family proteins, Arp2/3 complex, LIM-kinase, cofilin, and cortactin.

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…The actin assembly and dendritic nucleation involved in the formation of both lamellipodia and invadopodia have been shown to require the actin nucleator Arp2/3, its activator, N-WASP and the stabilizing actin binding protein cortactin [13][14][15][16]. Conversely, the relatively transient and less substantial filopodial membrane extension or ruffle which functions as a pseudo sensory organ that assimilates extracellular stimuli, is made up of bundles of long, cross-linked parallel actin filaments that are nucleated and elongated by the formin family protein, mDia1 and mDia2/DRF3 (Figure 1.1 A, D & E) [13][14][15][16][17][18].…”

“…Conversely, the relatively transient and less substantial filopodial membrane extension or ruffle which functions as a pseudo sensory organ that assimilates extracellular stimuli, is made up of bundles of long, cross-linked parallel actin filaments that are nucleated and elongated by the formin family protein, mDia1 and mDia2/DRF3 (Figure 1.1 A, D & E) [13][14][15][16][17][18].…”

“…As such, an accumulation of evidence correlates an invasive and metastatic state with the dysregulation of signals involved in cell migration [5,7,9,15,19,35,37]. For example, interactions between αvβ3, α5β1 and α6β4 and receptor tyrosine kinases (RTKs) such as ErbB2 and EGFR have been shown to facilitate the proliferation and migration of tumor cells independently of positional constraints in breast cancer [38,39].…”

Cell biology of embryonic migration

“…It has been found that force sensing and substrate stiffness define the formation and turnover of the adhesions to the extracellular matrix and determine the speed of migration, as well as cell shape and ability to differentiate (Engler et al, 2006). Loss of force sensing accompanies adhesive and migratory defects in vitro and in situ, including oncogenic transformation and cancer metastases, closely correlated with the ability of cells for substrate-independent growth (Kedrin et al, 2007;Yamaguchi and Condeelis, 2007).…”

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

“…Motility is initiated by protrusion of the leading edge of the cell, resulting in the production of polarised lamellipodia oriented towards the direction of movement (Yamaguchi and Condeelis, 2007). Cortactin is a ubiquitously expressed Src substrate that engages in several protein -protein interactions that may be functionally relevant to tumoral progression.…”