Review Article | Published:

The cofilin pathway in breast cancer invasion and metastasis

Nature Reviews Cancer volume 7, pages 429440 (2007) | Download Citation

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Abstract

Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.

Key points

  • A pattern of changes in gene expression clustered in the cofilin pathway is consistently observed in mammary tumours and cells derived from them.

  • The cofilin pathway has emerged as having a central role in the generation of free actin filament ends resulting in actin filament remodelling by polymerization and depolymerization. Filament remodelling is essential during the formation and retraction of path-finding structures used in the chemotaxis, cell migration and invasion of tumour cells.

  • The spatial localization of cofilin activity is required for chemotaxis by tumour cells in response to epidermal growth factor, and fits a local excitation global inhibition (LEGI)-type model of chemotaxis.

  • A balance of the stimulatory and inhibitory branches of the cofilin pathway must be achieved for protrusion, cell migration and chemotaxis to occur optimally. Too much or too little activity will inhibit all of these essential steps in motility and invasion.

  • As there are four regulatory mechanisms for cofilin activity which seem to be uncoupled, the activity status of cofilin in a cell cannot be assessed by measuring the ratio of dephosphorylated cofilin to the total cofilin present.

  • An important implication of recent studies of the cofilin pathway is that looking at the expression status of a single gene can be misleading when interpreting phenotype, as it is the collective activity of multiple genes of the pathway that determines the integrated output of the pathway and therefore phenotype.

  • The rational design of inhibitors of the cofilin pathway is possible. Measuring the output of the cofilin pathway directly in living cells isolated from invasive tumours will be necessary to assess the efficacy of the inhibitors. New technologies for intravital imaging, invasive tumour cell collection and expression profiling, and for measuring cofilin pathway activity, make inhibitor design and testing possible.

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Acknowledgements

This work was supported by grants CA100324 and GM38511.

Author information

Affiliations

  1. Experimental Therapeutics, ImClone Systems Incorporated, New York, New York, USA.

    • Weigang Wang
  2. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York, USA.

    • Robert Eddy
    •  & John Condeelis
  3. Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York, USA.

    • John Condeelis

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to John Condeelis.

Glossary

Motility cycle

The motility cycle consists of a minimum of four steps starting with protrusion, which is essential for determining subsequent cell direction. Protrusion is followed by the adhesion of the new protrusion, contraction and tail retraction. See reference 35 for more details.

Lamellipodium

A 1–5 μm wide cytoplasmic projection at the leading edge of the cell that contains a dendritic network of actin filaments (see Box 1). The force of actin polymerization extends the lamellapodium forward and advances the cell front, setting the direction of cell migration.

Invadopodium

A cytoplasmic projection from tumour cells into the extracellular matrix, which contain a core of actin filaments. Invadopodia can secrete proteases that degrade the extracellular matrix and whose formation is associated with increased tumour cell invasiveness.

Filopodium

A finger-shaped cytoplasmic projection that can extend from the leading edge of migrating cells. Filopodia contain actin filaments that are crosslinked into bundles by actin-binding proteins such as fimbrin.

Off rate constant

Also known as the dissociation constant (Kd), for actin filaments it measures the rate of dissociation of actin monomers from free filament ends.

Caged

A protein or compound conjugated with a chromophore that allows for the controlled photorelease of a biologically active protein or compound with high temporal and spatial precision.

Vitronectin

An abundant adhesive glycoprotein found in blood plasma and the extracellular matrix. Vitronectin contains an RGD sequence that is a binding site for membrane-bound integrins, which serve to anchor cells to the extracellular matrix.

Neural crest

A component of the ectoderm that is found between the neural tube and the epidermis of an embryo. Shortly after neural tube formation, neural crest cells migrate and give rise to neurons and glia of the peripheral nervous system, skeletal and smooth muscle, and other specialized cells.

Neural tube

A developmental precursor of the central nervous system that will form the mature brain and spinal cord.

Visuospatial cognition

The ability to distinguish the orientation of objects in space; for example, depth perception.

Dendritic spine

A small (<1 μm) membranous extension that protrudes from a dendrite and forms one half of a synapse. Changes in dendritic spine density underlie many brain functions, including long-term memory and learning.

Osteolytic

Having the property of osteolysis, which is defined as the active resorption or dissolution of bone tissue as part of normal bone remodelling and some disease processes.

Paracrine

Signalling between two different types of cells through secreted molecules.

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https://doi.org/10.1038/nrc2148