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.

  • Opinion
  • Published:

Tumour cell invasion: an emerging role for basal epithelial cell extrusion

Abstract

Metastasis is the leading cause of cancer-related deaths, but it is unclear how cancer cells escape their primary sites in epithelia and disseminate to other sites in the body. One emerging possibility is that transformed epithelial cells could invade the underlying tissue by a process called cell extrusion, which epithelia use to remove cells without disrupting their barrier function. Typically, during normal cell turnover, live cells extrude apically from the epithelium into the lumen and later die by anoikis; however, several oncogenic mutations shift cell extrusion basally, towards the tissue that the epithelium encases. Tumour cells with high levels of survival and motility signals could use basal extrusion to escape from the tissue and migrate to other sites within the body.

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

Access options

Buy this article

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

Figure 1: The direction in which a cell extrudes has important consequences for its fate.
Figure 2: Modes of diverting extrusion basally.
Figure 3: Alternative mechanisms to divert extrusion basally.
Figure 4: Model of single and collective cell-autonomous basal extrusion of tumour cells during tumour invasion.

Similar content being viewed by others

References

  1. Eisenhoffer, G. T. et al. Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484, 546–549 (2012).

    Article  CAS  Google Scholar 

  2. Rosenblatt, J., Raff, M. C. & Cramer, L. P. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr. Biol. 11, 1847–1857 (2001).

    Article  CAS  Google Scholar 

  3. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  Google Scholar 

  4. Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011).

    Article  CAS  Google Scholar 

  5. Kiehart, D. P., Galbraith, C. G., Edwards, K. A., Rickoll, W. L. & Montague, R. A. Multiple forces contribute to cell sheet morphogenesis for dorsal closure in Drosophila. J. Cell Biol. 149, 471–490 (2000).

    Article  CAS  Google Scholar 

  6. Marinari, E. et al. Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding. Nature 484, 542–545 (2012).

    Article  CAS  Google Scholar 

  7. Madara, J. L. Maintenance of the macromolecular barrier at cell extrusion sites in intestinal epithelium: physiological rearrangement of tight junctions. J. Membr. Biol. 116, 177–184 (1990).

    Article  CAS  Google Scholar 

  8. Guan, Y. et al. Redistribution of the tight junction protein ZO-1 during physiological shedding of mouse intestinal epithelial cells. Am. J. Physiol. Cell Physiol. 300, C1404–C1414 (2011).

    Article  CAS  Google Scholar 

  9. Gu, Y., Forostyan, T., Sabbadini, R. & Rosenblatt, J. Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. J. Cell Biol. 193, 667–676 (2011).

    Article  CAS  Google Scholar 

  10. Kuipers, D. et al. Epithelial repair is a two-stage process driven first by dying cells and then by their neighbours. J. Cell Sci. 127, 1229–1241 (2014).

    Article  CAS  Google Scholar 

  11. Andrade, D. & Rosenblatt, J. Apoptotic regulation of epithelial cellular extrusion. Apoptosis 16, 491–501 (2011).

    Article  CAS  Google Scholar 

  12. Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010).

    Article  CAS  Google Scholar 

  13. Slattum, G., McGee, K. M. & Rosenblatt, J. P115 RhoGEF and microtubules decide the direction apoptotic cells extrude from an epithelium. J. Cell Biol. 186, 693–702 (2009).

    Article  CAS  Google Scholar 

  14. Hogan, C. et al. Characterization of the interface between normal and transformed epithelial cells. Nature Cell Biol. 11, 460–467 (2009).

    Article  CAS  Google Scholar 

  15. Kajita, M. et al. Interaction with surrounding normal epithelial cells influences signalling pathways and behaviour of Src-transformed cells. J. Cell Sci. 123, 171–180 (2010).

    Article  CAS  Google Scholar 

  16. Donker, M. et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized Phase III trial. J. Clin. Oncol. 31, 4054–4059 (2013).

    Article  Google Scholar 

  17. Bleyer, A. & Welch, H. G. Effect of three decades of screening mammography on breast-cancer incidence. N. Engl. J. Med. 367, 1998–2005 (2012).

    Article  CAS  Google Scholar 

  18. Hartenstein, V., Younossi-Hartenstein, A. & Lekven, A. Delamination and division in the Drosophila neurectoderm: spatiotemporal pattern, cytoskeletal dynamics, and common control by neurogenic and segment polarity genes. Dev. Biol. 165, 480–499 (1994).

    Article  CAS  Google Scholar 

  19. Kelley, L. C., Lohmer, L. L., Hagedorn, E. J. & Sherwood, D. R. Traversing the basement membrane in vivo: a diversity of strategies. J. Cell Biol. 204, 291–302 (2014).

    Article  CAS  Google Scholar 

  20. 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  Google Scholar 

  21. Friedl, P., Locker, J., Sahai, E. & Segall, J. E. Classifying collective cancer cell invasion. Nature Cell Biol. 14, 777–783 (2012).

    Article  Google Scholar 

  22. Marshall, T. W., Lloyd, I. E., Delalande, J. M., Nathke, I. & Rosenblatt, J. The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium. Mol. Biol. Cell 22, 3962–3970 (2011).

    Article  CAS  Google Scholar 

  23. Slattum, G., Gu, Y., Sabbadini, R. & Rosenblatt, J. Autophagy in oncogenic K-Ras promotes basal extrusion of epithelial cells by degrading S1P. Curr. Biol. 24, 19–28 (2014).

    Article  CAS  Google Scholar 

  24. Clevers, H. Wnt breakers in colon cancer. Cancer Cell 5, 5–6 (2004).

    Article  CAS  Google Scholar 

  25. Oving, I. M. & Clevers, H. C. Molecular causes of colon cancer. Eur. J. Clin. Invest. 32, 448–457 (2002).

    Article  CAS  Google Scholar 

  26. van Es, J. H., Giles, R. H. & Clevers, H. C. The many faces of the tumor suppressor gene APC. Exp. Cell Res. 264, 126–134 (2001).

    Article  CAS  Google Scholar 

  27. Kita, K., Wittmann, T., Nathke, I. S. & Waterman-Storer, C. M. Adenomatous polyposis coli on microtubule plus ends in cell extensions can promote microtubule net growth with or without EB1. Mol. Biol. Cell 17, 2331–2345 (2006).

    Article  CAS  Google Scholar 

  28. Mogensen, M. M., Tucker, J. B., Mackie, J. B., Prescott, A. R. & Nathke, I. S. The adenomatous polyposis coli protein unambiguously localizes to microtubule plus ends and is involved in establishing parallel arrays of microtubule bundles in highly polarized epithelial cells. J. Cell Biol. 157, 1041–1048 (2002).

    Article  CAS  Google Scholar 

  29. Zumbrunn, J., Kinoshita, K., Hyman, A. A. & Nathke, I. S. Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 β phosphorylation. Curr. Biol. 11, 44–49 (2001).

    Article  CAS  Google Scholar 

  30. Minde, D. P., Anvarian, Z., Rudiger, S. G. & Maurice, M. M. Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? Mol. Cancer 10, 101 (2011).

    Article  CAS  Google Scholar 

  31. Schepers, A. & Clevers, H. Wnt signaling, stem cells, and cancer of the gastrointestinal tract. Cold Spring Harb. Perspect. Biol. 4, a007989 (2012).

    Article  Google Scholar 

  32. Neuzillet, C., Hammel, P., Tijeras-Raballand, A., Couvelard, A. & Raymond, E. Targeting the Ras-ERK pathway in pancreatic adenocarcinoma. Cancer Metastasis Rev. 32, 147–162 (2013).

    Article  CAS  Google Scholar 

  33. Aviel-Ronen, S., Blackhall, F. H., Shepherd, F. A. & Tsao, M. S. K-ras mutations in non-small-cell lung carcinoma: a review. Clin. Lung Cancer 8, 30–38 (2006).

    Article  CAS  Google Scholar 

  34. Jiang, Y., Kimchi, E. T., Staveley-O'Carroll, K. F., Cheng, H. & Ajani, J. A. Assessment of K-ras mutation: a step toward personalized medicine for patients with colorectal cancer. Cancer 115, 3609–3617 (2009).

    Article  CAS  Google Scholar 

  35. Liu, J. S., Farlow, J. T., Paulson, A. K., Labarge, M. A. & Gartner, Z. J. Programmed cell-to-cell variability in Ras activity triggers emergent behaviors during mammary epithelial morphogenesis. Cell Rep. 2, 1461–1470 (2012).

    Article  CAS  Google Scholar 

  36. White, E. Exploiting the bad eating habits of Ras-driven cancers. Genes Dev. 27, 2065–2071 (2013).

    Article  CAS  Google Scholar 

  37. Mathew, R. & White, E. Autophagy, stress, and cancer metabolism: what doesn't kill you makes you stronger. Cold Spring Harb. Symp. Quant. Biol. 76, 389–396 (2011).

    Article  CAS  Google Scholar 

  38. Mancias, J. D. & Kimmelman, A. C. Targeting autophagy addiction in cancer. Oncotarget 2, 1302–1306 (2011).

    Article  Google Scholar 

  39. Cufi, S. et al. The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer. Sci. Rep. 3, 2469 (2013).

    Article  Google Scholar 

  40. Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013).

    Article  CAS  Google Scholar 

  41. Royer, C. & Lu, X. Epithelial cell polarity: a major gatekeeper against cancer? Cell Death Differ. 18, 1470–1477 (2011).

    Article  CAS  Google Scholar 

  42. Macara, I. G. & McCaffrey, L. Cell polarity in morphogenesis and metastasis. Phil. Trans. R. Soc. B 368, 20130012 (2013).

    Article  Google Scholar 

  43. Gildea, J. J. et al. RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res. 62, 6418–6423 (2002).

    CAS  PubMed  Google Scholar 

  44. Struckhoff, A. P., Rana, M. K. & Worthylake, R. A. RhoA can lead the way in tumor cell invasion and metastasis. Front. Biosci. 16, 1915–1926 (2011).

    Article  CAS  Google Scholar 

  45. Plodinec, M. et al. The nanomechanical signature of breast cancer. Nature Nanotechnol. 7, 757–765 (2012).

    Article  CAS  Google Scholar 

  46. Lee, M. H. et al. Mismatch in mechanical and adhesive properties induces pulsating cancer cell migration in epithelial monolayer. Biophys. J. 102, 2731–2741 (2012).

    Article  CAS  Google Scholar 

  47. Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  49. Yilmaz, M., Christofori, G. & Lehembre, F. Distinct mechanisms of tumor invasion and metastasis. Trends Mol. Med. 13, 535–541 (2007).

    Article  CAS  Google Scholar 

  50. Kissa, K. & Herbomel, P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464, 112–115 (2010).

    Article  CAS  Google Scholar 

  51. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    Article  CAS  Google Scholar 

  52. Chambers, K. F. et al. Stroma regulates increased epithelial lateral cell adhesion in 3D culture: a role for actin/cadherin dynamics. PLoS ONE 6, e18796 (2011).

    Article  CAS  Google Scholar 

  53. Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    Article  CAS  Google Scholar 

  54. Perez-Enciso, M. & Tenenhaus, M. Prediction of clinical outcome with microarray data: a partial least squares discriminant analysis (PLS-DA) approach. Hum. Genet. 112, 581–592 (2003).

    PubMed  Google Scholar 

  55. Livasy, C. A. et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod. Pathol. 19, 264–271 (2006).

    Article  CAS  Google Scholar 

  56. Prat, A., Ellis, M. J. & Perou, C. M. Practical implications of gene-expression-based assays for breast oncologists. Nature Rev. Clin. Oncol. 9, 48–57 (2012).

    Article  CAS  Google Scholar 

  57. Zomer, A. et al. Intravital imaging of cancer stem cell plasticity in mammary tumors. Stem Cells 31, 602–606 (2013).

    Article  CAS  Google Scholar 

  58. 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  Google Scholar 

  59. Nakasone, E. S. et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).

    Article  CAS  Google Scholar 

  60. Condeelis, J. & Weissleder, R. In vivo imaging in cancer. Cold Spring Harb. Perspect. Biol. 2, a003848 (2010).

    Article  CAS  Google Scholar 

  61. 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  Google Scholar 

  62. Boimel, P. J. et al. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res. 14, R23 (2012).

    Article  CAS  Google Scholar 

  63. Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).

    Article  CAS  Google Scholar 

  64. White, R., Rose, K. & Zon, L. Zebrafish cancer: the state of the art and the path forward. Nature Rev. Cancer 13, 624–636 (2013).

    Article  CAS  Google Scholar 

  65. Jung, D.-W. et al. A novel zebrafish human tumor xenograft model validated for anti-cancer drug screening. Mol. BioSyst. 8, 1930–1939 (2012).

    Article  CAS  Google Scholar 

  66. Konantz, M. et al. Zebrafish xenografts as a tool for in vivo studies on human cancer. Ann. NY Acad. Sci. 1266, 124–137 (2012).

    Article  Google Scholar 

  67. 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  Google Scholar 

  68. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  CAS  Google Scholar 

  69. Nieto, M. A. The early steps of neural crest development. Mech. Dev. 105, 27–35 (2001).

    Article  CAS  Google Scholar 

  70. Wang, W. et al. Tumor cells caught in the act of invading: their strategy for enhanced cell motility. Trends Cell Biol. 15, 138–145 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the US National Institutes of Health (NIH) for an Innovator Award DP2OD002056-01 and an RO1 1R01GM102169-01 to J.R., and for an NIH Developmental Biology Training Grant 5T32 HDO7491 to G.M.S.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jody Rosenblatt.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Slattum, G., Rosenblatt, J. Tumour cell invasion: an emerging role for basal epithelial cell extrusion. Nat Rev Cancer 14, 495–501 (2014). https://doi.org/10.1038/nrc3767

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3767

This article is cited by

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