The plasticity of cytoskeletal dynamics underlying neoplastic cell migration

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Due to the use of intra-vital imaging techniques and assays for cell migration into 3D matrices there has recently been much interest in different modes of tumour cell migration. Individually moving tumour cells can move either in an elongated-protrusive manner or in rounded, so-called ‘amoeboid’ modes. This review summarises ongoing efforts to delineate the cell signalling pathways that underlie these different forms of movement.

Introduction

Abnormal cell migration and tissue invasion occurs in many diseases, including cancer. In cancer abnormal cell migration is an essential component of metastasis, the major clinical problem in cancer. It is likely that mechanisms underlying abnormal cell migration share many of the same aspects as the fundamental mechanisms of migration of normal cells but are dys-regulated. Thus mechanisms of cell migration observed in cancer cells probably reflect processes that occur in normal development and homeostasis. For example epithelial–mesenchymal transition (EMT) has received much attention as a key process in metastasis due to the loss of cell–cell adhesion and the acquisition of migratory behaviour; EMTs are essential components of normal development [1]. In cancer it is now well recognised that tumour cells have multiple forms of movement, cancer cells can move as collective groups or as individual cells [2]. A recent study has demonstrated that while collective cell movement permits entry into the lymphatic system, individual cell movement is necessary for tumour cells to cross basement membranes and enter blood vessels to enable dissemination to distant organs [3]. In this review we concentrate on signalling for different modes of individual tumour cell movement because of the increasing interest in this area.

Actin assembly to generate protrusions and actomyosin contractility to create traction forces and oppose actin assembly-based protrusion are key processes in cell migration [4]. In appropriate experimental circumstances blocking actin-based protrusions or actomyosin contractility does not prevent cell migration showing that neither of these processes on its own is an essential component of cell migration, however movement cannot occur without one of them [5••]. Actomyosin contractility can be used by cells to squeeze through voids in 3D matrices or can generate blebs in the plasma membrane through hydrostatic pressure breaking the linkage between plasma membrane and cortical actin [5••, 6]. Thus blebbing is a contractility driven form of protrusion into the matrix and may generate traction forces for cell movement [5••]. In movement driven by high levels of actomyosin contractility cells are less adhesive and have a round shape. Several years ago it was clearly demonstrated that individual tumour cells could move through a 3D matrix in either elongated or mesenchymal-like mode characterised by dependence on extra-cellular proteolysis or in a rounded, ‘amoeboid’, mode of migration [7••]. Fibrosarcoma, glioblastoma and anaplastic tumour cells move in an elongated fashion while lymphoma, leukaemia, small cell lung and prostate carcinoma cells move in a rounded fashion [2]. The elongated mode of movement seems likely to have many parallels to extensively studied mechanisms of cell migration on rigid 2D surfaces involving the production of actin assembly driven protrusions at the front and actomyosin-contractility driven cell retraction at the rear [4]. Importantly elongated and rounded forms of movement are inter-convertible or plastic, as first shown by the demonstration that treatment with protease inhibitors results in conversion of the elongated mode into the rounded [7••]. Melanoma cells have been shown to spontaneously convert between modes of movement [8••]. While the term ‘amoeboid’ is often used to describe a non-protrusive form of movement driven by high actomyosin contractility it is somewhat confusing since amoeboid movement seen in organisms such as Dictyostelium discoideum depends on the production of actin-dependent protrusions at the leading edge [5••]. We prefer the term rounded movement for movement driven by actomyosin contractility but it is important to bear in mind that this encompasses different subtypes such as blebbing and non-blebbing [5••]. In many studies of rounded movement there is little distinction between different subtypes even though they may have mechanistic differences.

Different modes of individual cell migration have not only been described for cancer cells but also in migratory processes during development and in the immune system. EMT during neural crest development has been extensively studied where epithelial cells lose E-cadherin-based cell–cell adhesion and migrate through actin-dependent protrusions at the leading edge [1]. Migration of avian muscle precursors from the somite into the forelimb is initiated by the formation of a relatively large and long-lived membrane protrusion that results from a localized activation of the GTPase Rac [9]. A rounded-blebbing form of cell movement was first described by Trinkaus many years ago in Fundulus blastula-stage and gastrula-stage deep cells [10]. Zebrafish primordial germ cells directionally migrate to the gonads adopting an actomyosin-dependent, migratory strategy in which the cells have a round morphology [11]. Neutrophils, dendritic cells, B-lymphoblasts and T-lymphoblasts can all use migratory mechanisms driven by high levels of actomyosin contractility [5••, 12]. Just as tumour cells can switch between different modes of movement [7••, 8••] this is also seen with normal cells in development; deep cells of killifish embryos naturally shift between blebbing and protrusive structures [13]. Mesodermal cells convert from rounded to mesenchymal morphology during gastrulation and both behaviours are highly migratory [14].

Section snippets

Molecular mechanisms of rounded and elongated cell migration

Key questions in the field are the underlying signalling mechanisms that drive different cell morphologies and forms of movement and how different modes of movement are inter-converted? Since cell migration and morphology depend on the actin cytoskeleton and actomyosin contractility there has been much interest how they are controlled by cell signalling mechanisms. Seminal studies on the three prototypical members of the Rho family of small GTPases showed that they each coordinate specific

Conclusions

Given the existence of alternative modes of cell migration the natural question is why? One clear difference is speed; when measured in vivo rounded tumour cell movement can be 10–100 times faster than Rac-dependent protrusive movement of around 100 μm per day. However it should be noted that in tissue culture rounded movement of tumour cells is much slower [8••] and lacks persistence perhaps due to the lack of suitable chemotactic gradients. While the rounded form of movement can be much

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank Cancer Research UK and the EU for support. CJM is a Cancer Research UK Gibb life fellow,

References (41)

  • F. Sabeh et al.

    Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited

    J Cell Biol

    (2009)
  • R. Torka et al.

    ROCK signaling mediates the adoption of different modes of migration and invasion in human mammary epithelial tumor cells

    Exp Cell Res

    (2006)
  • S. Giampieri et al.

    Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility

    Nat Cell Biol

    (2009)
  • A.J. Ridley et al.

    Cell migration: integrating signals from front to back

    Science

    (2003)
  • G.T. Charras et al.

    Reassembly of contractile actin cortex in cell blebs

    J Cell Biol

    (2006)
  • K. Wolf et al.

    Compensation mechanism in tumor cell migration: mesenchymal–amoeboid transition after blocking of pericellular proteolysis

    J Cell Biol

    (2003)
  • V. Sanz-Moreno et al.

    Rac activation and inactivation control plasticity of tumor cell movement

    Cell

    (2008)
  • T. Lammermann et al.

    Cdc42-dependent leading edge coordination is essential for interstitial dendritic cell migration

    Blood

    (2009)
  • H. Blaser et al.

    Migration of zebrafish primordial germ cells: a role for myosin contraction and cytoplasmic flow

    Dev Cell

    (2006)
  • R. Fink

    Run Silent, Run Deep

    (2007)
  • Cited by (0)

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