Chemotaxis is the phenomenon by which cell movement is directed in response to an extracellular chemical gradient. Factors that mediate chemotaxis are frequently mutated in cancer. Although most of the factors have dual roles in cell growth and survival, they also mediate cytoskeletal dynamics that results in chemotaxis, thus suggesting a potentially important role of chemotaxis in cancer.
Tumour cells in vivo can move both randomly and directionally. However, invasion, migration and dissemination are most efficient when the cell is involved in directed migration. Different modes of directed migration have been described for tumour cells (amoeboid migration or mesenchymal migration for single cells and collective or streaming migration for groups of cells). The occurrence and frequency of these modes of migration in cancer is dependent on the type of cancer and the surrounding factors within the tumour microenvironment.
Despite the various patterns of directed migration during tumour cell dissemination, the intracellular processes that direct the cell motility cycle in response to the chemoattractant are probably similar and are comprised of three steps: chemosensing, polarization and locomotion. First, polarized intracellular signals lead to asymmetric actin polymerization resulting in extension of the cell membrane in the direction of movement, thus creating the leading-edge protrusion. This is followed by integrin-mediated adhesion to the substrate on which the cell is moving, and then by detachment from the substrate and contraction of the trailing edge of the cell.
In addition to cancer cells, directional migration to a chemokine source is observed in stromal cells, which frequently shape the tumour microenvironment to a more pro-metastatic state. A complex network of chemokines and growth factors is involved in the communication of tumour cells with stromal cells. This leads to several major events of cancer progression, such as immune evasion, angiogenesis, invasion and dissemination.
Despite the strong experimental evidence for the involvement of chemotaxis signalling pathways in tumour cell dissemination, therapeutics under development are tested only for their ability to reduce the tumour size in patients with late-stage disease. A lack of relevant therapeutic end points in clinical practice, together with the current belief that dissemination occurs early in tumour progression, before clinical presentation, have brought scepticism to the development of anti-invasion and anti-dissemination drugs.
We speculate that dissemination is not only a feasible but also a necessary therapeutic target if efficient long-term management of minimal residual disease is a goal in cancer treatment. The identification of therapeutic end points relevant to tumour cell dissemination will facilitate the development and appropriate use of therapeutics.
Chemotaxis of tumour cells and stromal cells in the surrounding microenvironment is an essential component of tumour dissemination during progression and metastasis. This Review summarizes how chemotaxis directs the different behaviours of tumour cells and stromal cells in vivo, how molecular pathways regulate chemotaxis in tumour cells and how chemotaxis choreographs cell behaviour to shape the tumour microenvironment and to determine metastatic spread. The central importance of chemotaxis in cancer progression is highlighted by discussion of the use of chemotaxis as a prognostic marker, a treatment end point and a target of therapeutic intervention.
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The authors would like to thank members of the Condeelis laboratory for helpful discussions. We thank especially J. Wyckoff and D. Entenberg, associates at the Gruss Lipper Biophotonics Center (GLBC) of the Albert Einstein College of Medicine, for their critical comments and suggestions for this manuscript and their help in figure preparation. The authors apologize to those whose work is not cited owing to space limitations. The authors' research is funded by grants CA150344 (to E.T.R), CA100324 (to J.S.C.) and CA113395 (to A.P.) from the US National Institutes of Health.
John S. Condeelis acknowledges a financial interest in MetaStat, Inc. The other authors declare no competing financial interests.
Polarized migration in response to soluble extracellular cues.
The process by which a cell invades through the basement membrane and the endothelium to enter blood vessels.
The process by which a cell exits a blood vessel or capillary to enter a tissue.
A family of inducible chemoattractant cytokines that regulate the chemotaxis of tumour cells and other cell types. Chemokines also affect processes such as proliferation, migration and invasion.
- Growth factors
Can be considered chemokines that specifically but not exclusively affect cell proliferation.
Migration in response to a solid state, extracellular cue. These cues include graded adhesion within the substrate or anchored chemotactic factors within the extracellular matrix.
Migration in response to changes in electric fields.
Migration in response to mechanical signals within the microenvironment.
Small, secreted proteins produced by immune cells that are used in cellular communication.
The process by which a cell senses the direction of a gradient source.
The process by which a cell becomes polarized towards a sensed gradient source.
Migration towards a gradient source, which involves retraction of the back of the cell.
- Amoeboid migration
Leading-edge protrusion of a rounded or ellipsoid cell, usually characterized by many protrusions, which result in a high turning frequency. The formation of a dominant protrusion is followed by the retraction of the trailing edge and the inhibition of randomly directed lateral pseudopod extensions.
- Mesenchymal migration
The formation of a single or few actin-rich leading-edge protrusions, usually characterized by a low turning frequency, giving rise to a more polarized cell. Leading-edge protrusion is followed by adhesive interactions of the leading edge with the extracellular matrix, which triggers the contraction of the rear of the cell and finally cell displacement.
- Collective migration
The movement of groups of cells with functionally intact cell–cell adhesions that coordinate multicellular leading-edge protrusions and trailing-edge retraction. This type of cell movement usually occurs at very low velocities (∼0.1 μm min−1).
- Cell streaming
The movement of a group of individual carcinoma cells, the vector paths of which point in the same direction. Cell movement is usually coordinated by chemotaxis, whereby the cells align and move in single file but do not require intact junctions or even contact between carcinoma cells. Streaming cells have velocities of migration 10–100 times more rapid than cells undergoing collective migration.
- Leading-edge protrusion
A protrusion at the leading edge of a cell. The term includes all locomotory protrusions, such as lamellipodia and pseudopodia, that are used by chemotaxing cells.
Actin-based membrane protrusions with matrix metalloproteinase activity that degrades the extracellular matrix. Shapes of invadopodia vary and can involve either a large area of the leading-edge protrusion when cells are in three-dimensional culture conditions, or small dots on the ventral surface of the cell when cultured in two-dimensional conditions.
- Tolerogenic response
An acquired specific failure of the immune system to respond to a given antigen. In the case of cancer, the tumour cells secrete factors that manipulate the immune system into inhibiting cytotoxic activities.
- T helper 2
(TH2). T cells that help B cells to make antibodies and suppress the action of cytotoxic T cells. By contrast, T helper 1 (TH1) cells are at the other end of the functional spectrum and activate macrophages and cytotoxic T cells.
- Tissue tropism
An affinity of cells or microorganisms for specific host tissues. In cancer it refers to the selectivity of metastasis formation in specific organs.
- Relay chemotaxis
The asymmetric propagation of a chemotactic signal, resulting in collective and streaming migration.
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Roussos, E., Condeelis, J. & Patsialou, A. Chemotaxis in cancer. Nat Rev Cancer 11, 573–587 (2011). https://doi.org/10.1038/nrc3078
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