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Review
, 171 (24), 5507-23

Movers and Shakers: Cell Cytoskeleton in Cancer Metastasis

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Review

Movers and Shakers: Cell Cytoskeleton in Cancer Metastasis

C M Fife et al. Br J Pharmacol.

Erratum in

  • Erratum.
    Br J Pharmacol. 2017 Jan;174(1):116. doi: 10.1111/bph.13672. Br J Pharmacol. 2017. PMID: 27933607 Free PMC article. No abstract available.

Abstract

Metastasis is responsible for the greatest number of cancer deaths. Metastatic disease, or the movement of cancer cells from one site to another, is a complex process requiring dramatic remodelling of the cell cytoskeleton. The various components of the cytoskeleton, actin (microfilaments), microtubules (MTs) and intermediate filaments, are highly integrated and their functions are well orchestrated in normal cells. In contrast, mutations and abnormal expression of cytoskeletal and cytoskeletal-associated proteins play an important role in the ability of cancer cells to resist chemotherapy and metastasize. Studies on the role of actin and its interacting partners have highlighted key signalling pathways, such as the Rho GTPases, and downstream effector proteins that, through the cytoskeleton, mediate tumour cell migration, invasion and metastasis. An emerging role for MTs in tumour cell metastasis is being unravelled and there is increasing interest in the crosstalk between key MT interacting proteins and the actin cytoskeleton, which may provide novel treatment avenues for metastatic disease. Improved understanding of how the cytoskeleton and its interacting partners influence tumour cell migration and metastasis has led to the development of novel therapeutics against aggressive and metastatic disease.

Linked articles: This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24.

Figures

Figure 1
Figure 1
The metastatic cascade. For cancer cells to metastasize, they must successfully complete all of the steps of the metastatic cascade. (i) Cancer cells in the primary tumour acquire the ability to detach from the primary tumour and migrate through the surrounding ECM and stroma. (ii) Degradation of the vascular basement membrane and travel across the endothelium, termed intravasation. (iii) Tumour cells transport through the vasculature, arrest in a capillary bed and cross the vasculature (termed extravasation). (iv) Disseminated cells grow and interact with the extracellular environment to form metastatic tumours. Image modified from (Ara and DeClerck, 2006).
Figure 2
Figure 2
The cell cytoskeleton and four steps of cell migration. A cartoon schematic shows a migrating cell (direction of migration is indicated by the arrow). Four steps of cell migration shown: protrusion, adhesion, contraction, retraction. F-actin is shown in purple (short, branched F-actin at the leading edge, and long, unbranched F-actin stress fibres at the rear). Microtubules are shown in blue, with ends emanating from the MTOC (yellow circle) near the nucleus (grey ellipse). Strong and weak focal adhesions are shown as either dark or light green circles respectively. Cytoskeletal regulatory and associated proteins are shown (myosin II, cofilin/ADF, LIMK, ROCK, stathmin). The gradients of active Rho (orange) and Rac (blue) are shown. Adapted from Akhshi et al. (2014).
Figure 3
Figure 3
Typical protrusive structures in invasive cancer cells. Cancer cell invasive phenotypes involve the formation of typical protrusive structures, such as plasma membrane blebs, invadopodia or pseudopodia, which are dependent on the nucleation and assembly of filamentous actin. Non-apoptotic blebs are highly dynamic protrusions in which the plasma membrane bulks out owing to increased hydrostatic pressure on regions of weak cortical actin (Fackler and Grosse, 2008). The initial, protruding bleb is devoid of detectable F-actin, which becomes repolymerized during bleb retraction by unknown actin nucleation factors. Ezrin is recruited into the growing bleb, and formins seem to have a role in bleb formation through mechanisms that still need to be defined (Charras and Paluch, 2008). Invadopodia are actin-rich cellular protrusions that are tailored for the degradation of the extracellular matrix. The formation of invadopodia relies on N-WASP–Arp2/3-driven actin assembly (Figure 4) and requires cortactin for invadopodia initiation and stabilization. Pseudopodia of cancer cells are lamellipodia-like structures and depend on the polymerization and assembly of actin by the WAVE–Arp2/3 nucleation machinery.
Figure 4
Figure 4
Rho GTPases and their effector proteins that mediate actin cytoskeletal regulation. Actin cytoskeletal regulation downstream of the Rho GTPases CDC42, RAC1 and Rho A (RHOA) is facilitated by numerous effector proteins. CDC42, via activation of WASP (Wiskott-Aldrich syndrome protein), activates the Arp2/3 complex result in actin polymerization and branched actin structures. RAC1 also activates the Arp2/3 via the WASP-relate WAVE (WASP family verprolin homologous protein) family of proteins. Both CDC42 and RAC1 activate DIAP3 (or mDIA2), resulting in unbranched actin filament nucleation. Additionally, CDC42 and RAC1 activate the PAK family kinases, which, via phosphorylation, activate LIMK (LIM domain kinase), which subsequently, via phosphorylation, inhibits cofilin. Cofilin facilitates actin filament severing and depolymerization; therefore, its inhibition results in elevated polymerized actin stability. Additionally, LIMK is also activated by ROCK (Rho-associated coiled-coil-containing protein kinase), which is a downstream kinase effector of Rho A. ROCK elevated MLC phosphorylation via the inhibition of myosin light chain phosphatase (MLCP). MLC phosphorylation results in its increased association with actin filaments. Lastly, PAK lessens ROCK function via MLC kinase (MLCK) inhibition, thus reducing MLC phosphorylation. Adapted from Tybulewicz and Henderson (2009).

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