Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Chemotaxis in cancer

Nature Reviews Cancer volume 11, pages 573–587 (2011)Cite this article

Subjects

Key Points

  • 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.

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Regulation of chemotaxis in tumour cells.
Figure 2: Chemotaxis shapes the tumour microenvironment.
Figure 3: Observations of streaming, intravasation and dissemination of tumour cells in mammary tumours.
Figure 4: Multicellular streaming of tumour cells and macrophages leading to intravasation in mammary tumours.

Similar content being viewed by others

References

  1. Condeelis, J., Singer, R. H. & Segall, J. E. The great escape: when cancer cells hijack the genes for chemotaxis and motility. Annu. Rev. Cell Dev. Biol. 21, 695–718 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. McSherry, E. A., Donatello, S., Hopkins, A. M. & McDonnell, S. Molecular basis of invasion in breast cancer. Cell. Mol. Life Sci. 64, 3201–3218 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Farrow, B., Albo, D. & Berger, D. H. The role of the tumor microenvironment in the progression of pancreatic cancer. J. Surg. Res. 149, 319–328 (2008).

    Article  PubMed  Google Scholar 

  4. Condeelis, J. & Segall, J. E. Intravital imaging of cell movement in tumours. Nature Rev. Cancer 3, 921–930 (2003).

    Article  CAS  Google Scholar 

  5. Roussos, E. T. et al. Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. J. Cell Sci. 124, 2120–2131 (2011). This study demonstrates how a MENA invasion-specific isoform promotes multicellular streaming in vivo in mouse models of breast cancer. This was the first study to define multicellular streaming migration of breast tumour cells in vivo by intravital imaging.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Petrie, R. J., Doyle, A. D. & Yamada, K. M. Random versus directionally persistent cell migration. Nature Rev. Mol. Cell Biol. 10, 538–549 (2009).

    Article  CAS  Google Scholar 

  7. Provenzano, P. P., Eliceiri, K. W., Inman, D. R. & Keely, P. J. Engineering three-dimensional collagen matrices to provide contact guidance during 3D cell migration. Curr. Protoc. Cell Biol. 47, 10.17.1–10.17.11 (2010).

    Article  Google Scholar 

  8. Raja, W. K., Gligorijevic, B., Wyckoff, J., Condeelis, J. S. & Castracane, J. A new chemotaxis device for cell migration studies. Integr. Biol. 2, 696–706 (2010).

    Article  CAS  Google Scholar 

  9. Berthier, E., Surfus, J., Verbsky, J., Huttenlocher, A. & Beebe, D. An arrayed high-content chemotaxis assay for patient diagnosis. Integr. Biol. 2, 630–638 (2010).

    Article  CAS  Google Scholar 

  10. Skoge, M. et al. Gradient sensing in defined chemotactic fields. Integr. Biol. 2, 659–668 (2010).

    Article  CAS  Google Scholar 

  11. Bosgraaf, L., Keizer-Gunnink, I. & Van Haastert, P. J. PI3-kinase signaling contributes to orientation in shallow gradients and enhances speed in steep chemoattractant gradients. J. Cell Sci. 121, 3589–3597 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Patel, D. D. et al. Chemokines have diverse abilities to form solid phase gradients. Clin. Immunol. 99, 43–52 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Iglesias, P. A. & Devreotes, P. N. Navigating through models of chemotaxis. Curr. Opin. Cell Biol. 20, 35–40 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sahai, E. Mechanisms of cancer cell invasion. Curr. Opin. Genet. Dev. 15, 87–96 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Smalley, K. S., Lioni, M. & Herlyn, M. Life isn't flat: taking cancer biology to the next dimension. In Vitro Cell. Dev. Biol. Anim. 42, 242–247 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nature Cell Biol. 9, 1392–1400 (2007). This study demonstrates that fibroblasts lead the collective migration of SCC cells through the generation of tracks in the ECM by degradation or matrix remodelling.

    Article  CAS  PubMed  Google Scholar 

  18. Rhee, S. Fibroblasts in three dimensional matrices: cell migration and matrix remodeling. Exp. Mol. Med. 41, 858–865 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Goswami, S. et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 65, 5278–5283 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Kedrin, D. et al. Intravital imaging of metastatic behavior through a mammary imaging window. Nature Methods 5, 1019–1021 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pinner, S. & Sahai, E. Imaging amoeboid cancer cell motility in vivo. J. Microsc. 231, 441–445 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Friedl, P. & Gilmour, D. Collective cell migration in morphogenesis, regeneration and cancer. Nature Rev. Mol. Cell Biol. 10, 445–457 (2009).

    Article  CAS  Google Scholar 

  23. Wolf, K. et al. Compensation mechanism in tumor cell migration: mesenchymal–amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 160, 267–277 (2003). A key paper demonstrating that tumour cells can transition between the two types of single cell migration, amoeboid and mesenchymal, through inhibition of pericellular proteolysis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wyckoff, J. B., Pinner, S. E., Gschmeissner, S., Condeelis, J. S. & Sahai, E. ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo. Curr. Biol. 16, 1515–1523 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial–mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Nabeshima, K., Inoue, T., Shimao, Y. & Sameshima, T. Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol. Int. 52, 255–264 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Sahai, E. & Marshall, C. J. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nature Cell Biol. 5, 711–719 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Pankova, K., Rosel, D., Novotny, M. & Brabek, J. The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell. Mol. Life Sci. 67, 63–71 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Valentin, G., Haas, P. & Gilmour, D. The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b. Curr. Biol. 17, 1026–1031 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Schmidt, M. et al. EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development 134, 2913–2923 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Lecaudey, V., Cakan-Akdogan, G., Norton, W. H. & Gilmour, D. Dynamic Fgf signaling couples morphogenesis and migration in the zebrafish lateral line primordium. Development 135, 2695–2705 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Haas, P. & Gilmour, D. Chemokine signaling mediates self-organizing tissue migration in the zebrafish lateral line. Dev. Cell 10, 673–680 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Aman, A. & Piotrowski, T. Wnt/β-catenin and Fgf signaling control collective cell migration by restricting chemokine receptor expression. Dev. Cell 15, 749–761 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Rorth, P. Collective guidance of collective cell migration. Trends Cell Biol. 17, 575–579 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Ilina, O. & Friedl, P. Mechanisms of collective cell migration at a glance. J. Cell Sci. 122, 3203–3208 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Wolf, K. et al. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nature Cell Biol. 9, 893–904 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Packard, B. Z., Artym, V. V., Komoriya, A. & Yamada, K. M. Direct visualization of protease activity on cells migrating in three-dimensions. Matrix Biol. 28, 3–10 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Clark, E. S., Whigham, A. S., Yarbrough, W. G. & Weaver, A. M. Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res. 67, 4227–4235 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Nabeshima, K. et al. Front-cell-specific expression of membrane-type 1 matrix metalloproteinase and gelatinase A during cohort migration of colon carcinoma cells induced by hepatocyte growth factor/scatter factor. Cancer Res. 60, 3364–3369 (2000).

    CAS  PubMed  Google Scholar 

  40. Friedl, P. & Wolf, K. Tube travel: the role of proteases in individual and collective cancer cell invasion. Cancer Res. 68, 7247–7249 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Farooqui, R. & Fenteany, G. Multiple rows of cells behind an epithelial wound edge extend cryptic lamellipodia to collectively drive cell-sheet movement. J. Cell Sci. 118, 51–63 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Giampieri, S. et al. Localized and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility. Nature Cell Biol. 11, 1287–1296 (2009). This study is the first to show active TGFβ signalling in cells undergoing single cell migration in vivo . Importantly, in distant metastasis TGFβ signalling was found to be inactivated, suggesting that microenvironmental chemotaxis signals in primary tumours are transient.

    Article  CAS  PubMed  Google Scholar 

  43. Kriebel, P. W., Barr, V. A. & Parent, C. A. Adenylyl cyclase localization regulates streaming during chemotaxis. Cell 112, 549–560 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Kriebel, P. W., Barr, V. A., Rericha, E. C., Zhang, G. & Parent, C. A. Collective cell migration requires vesicular trafficking for chemoattractant delivery at the trailing edge. J. Cell Biol. 183, 949–961 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li, S., Guan, J. L. & Chien, S. Biochemistry and biomechanics of cell motility. Annu. Rev. Biomed. Eng. 7, 105–150 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Devreotes, P. & Janetopoulos, C. Eukaryotic chemotaxis: distinctions between directional sensing and polarization. J. Biol. Chem. 278, 20445–20448 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Veltman, D. M., Keizer-Gunnik, I. & Van Haastert, P. J. Four key signaling pathways mediating chemotaxis in Dictyostelium discoideum. J. Cell Biol. 180, 747–753 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Annesley, S. J. & Fisher, P. R. Dictyostelium discoideum—a model for many reasons. Mol. Cell. Biochem. 329, 73–91 (2009). References 47 and 48 are comprehensive reviews of how D. discoideum serves as a model for the study of chemotaxis signalling.

    Article  CAS  PubMed  Google Scholar 

  49. Swaney, K. F., Huang, C. H. & Devreotes, P. N. Eukaryotic chemotaxis: a network of signaling pathways controls motility, directional sensing, and polarity. Annu. Rev. Biophys. 39, 265–289 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chung, C. Y., Funamoto, S. & Firtel, R. A. Signaling pathways controlling cell polarity and chemotaxis. Trends Biochem. Sci. 26, 557–566 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Janetopoulos, C. & Firtel, R. A. Directional sensing during chemotaxis. FEBS Lett. 582, 2075–2085 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. King, J. S. & Insall, R. H. Chemotaxis: finding the way forward with Dictyostelium. Trends Cell Biol. 19, 523–530 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Jin, T. et al. How human leukocytes track down and destroy pathogens: lessons learned from the model organism Dictyostelium discoideum. Immunol. Res. 43, 118–127 (2009).

    Article  PubMed  Google Scholar 

  54. Zicha, D. et al. Chemotaxis of macrophages is abolished in the Wiskott-Aldrich syndrome. Br. J. Haematol. 101, 659–665 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Weiner, O. D. Regulation of cell polarity during eukaryotic chemotaxis: the chemotactic compass. Curr. Opin. Cell Biol. 14, 196–202 (2002). A comprehensive review of the signalling components that regulate chemosensing and polarization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mouneimne, G. et al. Spatial and temporal control of cofilin activity is required for directional sensing during chemotaxis. Curr. Biol. 16, 2193–2205 (2006). This study demonstrates that local activation of cofilin by PLC and its global inactivation by LIMK1 phosphorylation combine to generate a local asymmetry of actin polymerization that is required for chemotaxis.

    Article  CAS  PubMed  Google Scholar 

  57. Desmarais, V. et al. N-WASP and cortactin are involved in invadopodium-dependent chemotaxis to EGF in breast tumor cells. Cell Motil. Cytoskeleton 66, 303–316 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang, W., Eddy, R. & Condeelis, J. The cofilin pathway in breast cancer invasion and metastasis. Nature Rev. Cancer 7, 429–440 (2007).

    Article  CAS  Google Scholar 

  59. van Rheenen, J., Condeelis, J. & Glogauer, M. A common cofilin activity cycle in invasive tumor cells and inflammatory cells. J. Cell Sci. 122, 305–311 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Shields, J. D. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11, 526–538 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Ramjeesingh, R., Leung, R. & Siu, C. H. Interleukin-8 secreted by endothelial cells induces chemotaxis of melanoma cells through the chemokine receptor CXCR1. FASEB J. 17, 1292–1294 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Reiland, J., Furcht, L. T. & McCarthy, J. B. CXC-chemokines stimulate invasion and chemotaxis in prostate carcinoma cells through the CXCR2 receptor. Prostate 41, 78–88 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Liu, Y. et al. Down-regulation of PKCzeta expression inhibits chemotaxis signal transduction in human lung cancer cells. Lung Cancer 63, 210–218 (2009).

    Article  PubMed  Google Scholar 

  64. Liu, Z. & Klominek, J. Chemotaxis and chemokinesis of malignant mesothelioma cells to multiple growth factors. Anticancer Res. 24, 1625–1630 (2004).

    CAS  PubMed  Google Scholar 

  65. Tong, G. M., Rajah, T. T., Zang, X. P. & Pento, J. T. The effect of antiestrogens on TGF-β-mediated chemotaxis of human breast cancer cells. Anticancer Res. 22, 103–106 (2002).

    CAS  PubMed  Google Scholar 

  66. Hayashibara, T. et al. Vascular endothelial growth factor and cellular chemotaxis: a possible autocrine pathway in adult T-cell leukemia cell invasion. Clin. Cancer Res. 7, 2719–2726 (2001).

    CAS  PubMed  Google Scholar 

  67. Bailly, M. et al. Epidermal growth factor receptor distribution during chemotactic responses. Mol. Biol. Cell 11, 3873–3883 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hurst, J. H. & Hooks, S. B. Regulator of G-protein signaling (RGS) proteins in cancer biology. Biochem. Pharmacol. 78, 1289–1297 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Insall, R. H. & Machesky, L. M. Actin dynamics at the leading edge: from simple machinery to complex networks. Dev. Cell 17, 310–322 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Hoeller, O. & Kay, R. R. Chemotaxis in the absence of PIP3 gradients. Curr. Biol. 17, 813–817 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Balkwill, F. Cancer and the chemokine network. Nature Rev. Cancer 4, 540–550 (2004).

    Article  CAS  Google Scholar 

  72. Murphy, P. M. Chemokines and the molecular basis of cancer metastasis. N. Engl. J. Med. 345, 833–835 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001). A seminal paper that demonstrates the role of chemokine receptors in the mediation of breast cancer metastasis. This is the first paper to suggest that the expression of chemokines and their receptors can determine the metastatic destination of tumour cells.

    Article  CAS  PubMed  Google Scholar 

  74. Lazennec, G. & Richmond, A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol. Med. 16, 133–144 (2010). A comprehensive review of the role of chemokines and their receptors in cancer and cancer-associated inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Koshiba, T. et al. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin. Cancer Res. 6, 3530–3535 (2000).

    CAS  PubMed  Google Scholar 

  76. Balkwill, F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin. Cancer Biol. 14, 171–179 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Scotton, C. J. et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res. 62, 5930–5938 (2002).

    CAS  PubMed  Google Scholar 

  78. Ghosh, M. et al. Cofilin promotes actin polymerization and defines the direction of cell motility. Science 304, 743–746 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Oser, M. et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J. Cell Biol. 186, 571–587 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Van Goethem, E. et al. Macrophage podosomes go 3D. Eur. J. Cell Biol. 90, 224–236 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Price, L. S. & Collard, J. G. Regulation of the cytoskeleton by Rho-family GTPases: implications for tumour cell invasion. Semin. Cancer Biol. 11, 167–173 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Bravo-Cordero, J. J. et al. A novel spatiotemporal RhoC activation pathway locally regulates cofilin activity at invadopodia. Curr. Biol. 21, 635–644 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sarmiento, C. et al. WASP family members and formin proteins coordinate regulation of cell protrusions in carcinoma cells. J. Cell Biol. 180, 1245–1260 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Scott, R. W. et al. LIM kinases are required for invasive path generation by tumor and tumor-associated stromal cells. J. Cell Biol. 191, 169–185 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. DesMarais, V., Ghosh, M., Eddy, R. & Condeelis, J. Cofilin takes the lead. J. Cell Sci. 118, 19–26 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. van Rheenen, J. et al. EGF-induced PIP2 hydrolysis releases and activates cofilin locally in carcinoma cells. J. Cell Biol. 179, 1247–1259 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Miki, H., Yamaguchi, H., Suetsugu, S. & Takenawa, T. IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 408, 732–735 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Abou-Kheir, W., Isaac, B., Yamaguchi, H. & Cox, D. Membrane targeting of WAVE2 is not sufficient for WAVE2-dependent actin polymerization: a role for IRSp53 in mediating the interaction between Rac and WAVE2. J. Cell Sci. 121, 379–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Mader, C. C. et al. An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Cancer Res. 71, 1730–1741 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Weaver, A. M. et al. Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr. Biol. 11, 370–374 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Weaver, A. M. et al. Interaction of cortactin and N-WASp with Arp2/3 complex. Curr. Biol. 12, 1270–1278 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Yoo, S. K. et al. Differential regulation of protrusion and polarity by PI3K during neutrophil motility in live zebrafish. Dev. Cell 18, 226–236 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Andrew, N. & Insall, R. H. Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions. Nature Cell Biol. 9, 193–200 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Bailly, M., Yan, L., Whitesides, G. M., Condeelis, J. S. & Segall, J. E. Regulation of protrusion shape and adhesion to the substratum during chemotactic responses of mammalian carcinoma cells. Exp. Cell Res. 241, 285–299 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Falk, D. L. et al. Shared, unique and redundant functions of three members of the class I myosins (MyoA, MyoB and MyoF) in motility and chemotaxis in Dictyostelium. J. Cell Sci. 116, 3985–3999 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Chan, K. T., Bennin, D. A. & Huttenlocher, A. Regulation of adhesion dynamics by calpain-mediated proteolysis of focal adhesion kinase (FAK). J. Biol. Chem. 285, 11418–11426 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Philippar, U. et al. A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev. Cell 15, 813–828 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Neel, N. F. et al. VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis. J. Cell Sci. 122, 1882–1894 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Goswami, S. et al. Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin. Exp. Metastasis 26, 153–159 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Soria, G. & Ben-Baruch, A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 267, 271–285 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sica, A. et al. Macrophage polarization in tumour progression. Semin. Cancer Biol. 18, 349–355 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Gu, L. et al. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404, 407–411 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Tazzyman, S., Lewis, C. E. & Murdoch, C. Neutrophils: key mediators of tumour angiogenesis. Int. J. Exp. Pathol. 90, 222–231 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pollard, J. W. Macrophages define the invasive microenvironment in breast cancer. J. Leukoc. Biol. 84, 623–630 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sinha, P. et al. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J. Immunol. 181, 4666–4675 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239–252 (2009).

    Article  CAS  Google Scholar 

  109. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  Google Scholar 

  110. Mantovani, A. et al. The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev. 21, 27–39 (2009). References 108–110 are comprehensive reviews about how chemokines influence the tumour microenvironment.

    Article  PubMed  CAS  Google Scholar 

  111. Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29, 15–18 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Salcedo, R. et al. Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J. Immunol. 166, 7571–7578 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Mehrad, B., Keane, M. P. & Strieter, R. M. Chemokines as mediators of angiogenesis. Thromb. Haemost. 97, 755–762 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kryczek, I. et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 65, 465–472 (2005).

    CAS  PubMed  Google Scholar 

  115. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005). This study demonstrates that CXCL12, which is secreted by CAFs, mediates the recruitment of EPCs to promote angiogenesis and growth in primary breast tumours.

    Article  CAS  PubMed  Google Scholar 

  116. Chen, H. et al. Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis. Blood 113, 1992–2002 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ostman, A. & Augsten, M. Cancer-associated fibroblasts and tumor growth — bystanders turning into key players. Curr. Opin. Genet. Dev. 19, 67–73 (2009).

    Article  PubMed  CAS  Google Scholar 

  119. Ben-Baruch, A. Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin. Exp. Metastasis 25, 345–356 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Koizumi, K., Hojo, S., Akashi, T., Yasumoto, K. & Saiki, I. Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Sci. 98, 1652–1658 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002).

    Article  CAS  Google Scholar 

  122. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Wyckoff, J. et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004). A seminal paper demonstrating that a paracrine interaction between macrophages and breast tumour cells is required for in vivo invasion and metastasis.

    Article  CAS  PubMed  Google Scholar 

  124. Kacinski, B. M. CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract. Mol. Reprod. Dev. 46, 71–74 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Patsialou, A. et al. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 69, 9498–9506 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hernandez, L. et al. The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin-β1 and CXCL12. Cancer Res. 69, 3221–3227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wyckoff, J. B. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649–2656 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Entenberg, D. et al. Set up and use of a two laser multiphoton microscope for multichannel intravital fluorescence imaging. Nature Protoc. doi:10.1038/nprot.2011.376 (2011).

  129. Roussos, E. T. et al. Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors. Breast Cancer Res. 12, R101 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Robinson, B. D. et al. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin. Cancer Res. 15, 2433–2441 (2009). This study demonstrates that the density of TMEM predicts the development of systemic, haematogenous metastases in human breast tumours. These findings highlight the clinical relevance of chemotaxis-mediated streaming between tumour cells and macrophages, which was previously observed in mouse models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Roussos, E. T. et al. Mena invasive (MenaINV) and Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM. Clin. Exp. Metastasis 12 Apr 2011 (doi:10.1007/s10585-011-9388-9386).

  132. Gerber, P. A., Hippe, A., Buhren, B. A., Muller, A. & Homey, B. Chemokines in tumor-associated angiogenesis. Biol. Chem. 390, 1213–1223 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Lurje, G. et al. Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma. Ann. Oncol. 21, 78–86 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Wang, W. et al. Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res. 64, 8585–8594 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Wang, W. et al. Coordinated regulation of pathways for enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors. Cancer Res. 67, 3505–3511 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ellis, L., Hammers, H. & Pili, R. Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett. 280, 145–153 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Hurwitz, H. Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. Clin. Colorectal Cancer 4, S62–S68 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. Huang, S. et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am. J. Pathol. 161, 125–134 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Mian, B. M. et al. Fully human anti-interleukin 8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metalloproteases and nuclear factor-κB. Clin. Cancer Res. 9, 3167–3175 (2003).

    CAS  PubMed  Google Scholar 

  143. Husemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).

    Article  PubMed  CAS  Google Scholar 

  144. Goss, P. E. & Chambers, A. F. Does tumour dormancy offer a therapeutic target? Nature Rev. Cancer 10, 871–877 (2010).

    Article  CAS  Google Scholar 

  145. Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009). This is the first demonstration that tumour cells from secondary metastasis can seed back to the permissive microenvironment of the primary tumour. This study could have major implications for the role of tumour cell dissemination from secondary deposits or micrometastases in patients after the resection of the primary tumour.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Pantel, K. & Alix-Panabieres, C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol. Med. 16, 398–406 (2011).

    Article  Google Scholar 

  147. Cristofanilli, M. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Cohen, S. J. et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann. Oncol. 20, 1223–1229 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Rack, B. K. et al. Use of circulating tumor cells (CTC) in peripheral blood of breast cancer patients before and after adjuvant chemotherapy to predict risk of relapse: the SUCCESS trial. J. Clin. Oncol. 28 (Suppl.) Abstract 1003 (2010).

    Article  Google Scholar 

  150. Sleeman, J. & Steeg, P. S. Cancer metastasis as a therapeutic target. Eur. J. Cancer 46, 1177–1180 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Steeg, P. S. Tumor metastasis: mechanistic insights and clinical challenges. Nature Med. 12, 895–904 (2006). References 150 and 151 are comprehensive reviews about how dissemination and metastasis should be considered as clinically relevant targets for cancer therapy.

    Article  CAS  PubMed  Google Scholar 

  152. Wiegand, S., Kruse, J., Gronemann, S. & Hammann, C. Efficient generation of gene knockout plasmids for Dictyostelium discoideum using one-step cloning. Genomics 97, 321–325 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Koonce, M. P. & Graf, R. Dictyostelium discoideum: a model system for ultrastructural analyses of cell motility and development. Methods Cell Biol. 96, 197–216 (2010).

    Article  PubMed  Google Scholar 

  154. Williams, J. G. Dictyostelium finds new roles to model. Genetics 185, 717–726 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Whitney, T. J., Gardner, D. G., Mott, M. L. & Brandon, M. Identifying the molecular basis of functions in the transcriptome of the social amoeba Dictyostelium discoideum. Genet. Mol. Res. 9, 394–415 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. van Hemert, F., Lazova, M. D., Snaar-Jagaska, B. E. & Schmidt, T. Mobility of G proteins is heterogeneous and polarized during chemotaxis. J. Cell Sci. 123, 2922–2930 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. Stephens, L., Milne, L. & Hawkins, P. Moving towards a better understanding of chemotaxis. Curr. Biol. 18, R485–R494 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Alvarez-Curto, E. et al. cAMP production by adenylyl cyclase G induces prespore differentiation in Dictyostelium slugs. Development 134, 959–966 (2007).

    Article  CAS  PubMed  Google Scholar 

  159. Charest, P. G. et al. A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration. Dev. Cell 18, 737–749 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Cai, H. et al. Ras-mediated activation of the TORC2-PKB pathway is critical for chemotaxis. J. Cell Biol. 190, 233–245 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Liu, L., Das, S., Losert, W. & Parent, C. A. mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev. Cell 19, 845–857 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Kay, R. R., Langridge, P., Traynor, D. & Hoeller, O. Changing directions in the study of chemotaxis. Nature Rev. Mol. Cell Biol. 9, 455–463 (2008).

    Article  CAS  Google Scholar 

  163. Iglesias, P. A. Spatial regulation of PI3K signaling during chemotaxis. Wiley Interdiscip. Rev. Syst. Biol. Med. 1, 247–253 (2009).

    Article  CAS  PubMed  Google Scholar 

  164. Rericha, E. C. & Parent, C. A. Steering in quadruplet: the complex signaling pathways directing chemotaxis. Sci. Signal. 1, pe26 (2008).

    Article  PubMed  Google Scholar 

  165. Comer, F. I. & Parent, C. A. PI 3-kinases and PTEN: how opposites chemoattract. Cell 109, 541–544 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. Funamoto, S., Meili, R., Lee, S., Parry, L. & Firtel, R. A. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109, 611–623 (2002).

    Article  CAS  PubMed  Google Scholar 

  167. Huang, Y. E. et al. Receptor-mediated regulation of PI3Ks confines PI(3,4,5)P3 to the leading edge of chemotaxing cells. Mol. Biol. Cell 14, 1913–1922 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Hannigan, M. et al. Neutrophils lacking phosphoinositide 3-kinase-γ show loss of directionality during N-formyl-Met-Leu-Phe-induced chemotaxis. Proc. Natl Acad. Sci. USA 99, 3603–3608 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Loovers, H. M. et al. Distinct roles of PI(3,4,5)P3 during chemoattractant signaling in Dictyostelium: a quantitative in vivo analysis by inhibition of PI3-kinase. Mol. Biol. Cell 17, 1503–1513 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Yip, S. C. et al. The distinct roles of Ras and Rac in PI 3-kinase-dependent protrusion during EGF-stimulated cell migration. J. Cell Sci. 120, 3138–3146 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Soon, L. L. A discourse on cancer cell chemotaxis: where to from here? IUBMB Life 59, 60–67 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Siegert, F. & Weijer, C. J. Three-dimensional scroll waves organize Dictyostelium slugs. Proc. Natl Acad. Sci. USA 89, 6433–6437 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Killich, T. et al. The locomotion, shape and pseudopodial dynamics of unstimulated Dictyostelium cells are not random. J. Cell Sci. 106, 1005–1013 (1993).

    PubMed  Google Scholar 

  174. Friedl, P., Borgmann, S. & Brocker, E. B. Amoeboid leukocyte crawling through extracellular matrix: lessons from the Dictyostelium paradigm of cell movement. J. Leukoc. Biol. 70, 491–509 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Anatomy and Structural Biology, Program in Tumor Microenvironment and Metastasis, Albert Einstein College of Medicine of Yeshiva University, Bronx, 10461, New York, USA

    Evanthia T. Roussos, John S. Condeelis & Antonia Patsialou

Authors
  1. Evanthia T. Roussos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John S. Condeelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonia Patsialou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to John S. Condeelis or Antonia Patsialou.

Ethics declarations

Competing interests

John S. Condeelis acknowledges a financial interest in MetaStat, Inc. The other authors declare no competing financial interests.

Related links

FURTHER INFORMATION

John S. Condeelis's homepage

Supplementary information

Supplementary information S1 (table)

Chemokines and Growth Factors involved in Chemotaxis in Cancer. (PDF 500 kb)

Supplementary information S2 (movie)

Intravital imaging of multicellular streaming migration in a mammary tumour (AVI 949 kb)

Glossary

Chemotaxis

Polarized migration in response to soluble extracellular cues.

Intravasation

The process by which a cell invades through the basement membrane and the endothelium to enter blood vessels.

Extravasation

The process by which a cell exits a blood vessel or capillary to enter a tissue.

Chemokines

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.

Haptotaxis

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.

Electrotaxis

Migration in response to changes in electric fields.

Durotaxis

Migration in response to mechanical signals within the microenvironment.

Cytokines

Small, secreted proteins produced by immune cells that are used in cellular communication.

Chemosensing

The process by which a cell senses the direction of a gradient source.

Polarization

The process by which a cell becomes polarized towards a sensed gradient source.

Locomotion

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.

Invadopodia

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roussos, E., Condeelis, J. & Patsialou, A. Chemotaxis in cancer. Nat Rev Cancer 11, 573–587 (2011). https://doi.org/10.1038/nrc3078

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3078

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer