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New roles for integrins in squamous-cell carcinoma

Nature Reviews Cancer volume 6, pages 175–183 (2006)Cite this article

Key Points

  • Squamous-cell carcinomas arise from the stratified epithelia of several organs such as the epidermis, oral cavity and oesophagus. Patient prognosis depends on early detection before metastasis, and surgery remains the best chance of cure.

  • Integrin expression is known to predict survival, but new data indicates that rare, activating integrin mutations might also affect tumour behaviour.

  • In tumours, altered integrin expression can provide a growth advantage by protecting from apoptosis. Upregulation of different integrins promotes proliferation and invasion.

  • Abnormal integrin expression on differentiated cells can regulate the clonal expansion of cancers generated from neighbouring progenitor cells.

  • Skin inflammation can be triggered by aberrant integrin expression, contributing to tumour susceptibility.

Abstract

Although integrins are known to mediate invasion and metastasis, recent studies reveal new ways in which they contribute to squamous-cell carcinoma. Integrin mutation or upregulation can expand the tumour stem-cell compartment by inhibiting differentiation or apoptosis. Integrins that are expressed by differentiated cells can stimulate or inhibit the proliferation of neighbouring tumour stem cells. These findings provide a mechanistic basis for the well-established links between altered integrin expression and tumour prognosis.

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Figure 1: Comparison of integrin expression and cellular organization in normal epidermis and squamous-cell carcinoma.
Figure 2: Evidence that αvβ5 might function as a fail-safe device to trigger apoptosis of keratinocytes that are unable to undergo terminal differentiation.
Figure 3: Role of suprabasal integrin expression in squamous-cell carcinoma expression.

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References

  1. Sterlinko. G. H. & Banks, L. HPV proteins as targets for therapeutic intervention. Antivir. Ther. 9, 665–678 (2004).

    Google Scholar 

  2. Backvall, H. et al. Genetic tumor archeology: microdissection and genetic heterogeneity in squamous and basal cell carcinoma. Mutat. Res. 571, 65–79 (2005).

    Article  Google Scholar 

  3. Hunter, K. D., Parkinson, E. K. & Harrison, P. R. Profiling early head and neck cancer. Nature Rev. Cancer 5, 127–135 (2005).

    Article  CAS  Google Scholar 

  4. Owens, D. M. & Watt, F. M. Contribution of stem cells and differentiated cells to epidermal tumours. Nature Rev. Cancer 3, 444–451(2003).

    Article  CAS  Google Scholar 

  5. Watt, F. M. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 21, 3919–3926 (2002).

    Article  CAS  Google Scholar 

  6. Mercurio, A. M., Rabinovitz, I. & Shaw, L. M. The α6β4 integrin and epithelial cell migration. Curr. Opin. Cell Biol. 13, 541–545 (2001).

    Article  CAS  Google Scholar 

  7. Guo, W. & Giancotti, F. G. Integrin signalling during tumour progression. Nature Rev. Mol. Cell Biol. 5, 816–826 (2004).

    Article  CAS  Google Scholar 

  8. van der Flier, A. & Sonnenberg, A. Function and interactions of integrins. Cell Tissue Res. 305, 285–298 (2001).

    Article  CAS  Google Scholar 

  9. Braun, K. M. et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241–5255 (2003). Introduces whole-mount labelling of mouse tail epidermis as a method to examine stem cells and differentiated cells in large areas of the tissue. It is particularly useful for quantitating a subpopulation of stem cells known as label-retaining cells, which are a minor population of cells in hair follicles.

    Article  CAS  Google Scholar 

  10. Jones, J., Sugiyama, M., Watt, F. M. & Speight, P. M. Integrin expression in normal, hyperplastic, dysplastic and malignant oral epithelium. J. Pathol. 169, 235–243 (1993).

    Article  CAS  Google Scholar 

  11. Downer, C. S., Watt, F. M. & Speight, P. M. Loss of α6 and β4 integrin subunits coincides with loss of basement membrane components in oral squamous cell carcinomas. J. Pathol. 171, 183–190 (1993).

    Article  CAS  Google Scholar 

  12. Rabinovitz, I. & Mercurio, A. M. The integrin α6β4 and the biology of carcinoma. Biochem. Cell Biol. 74, 811–821 (1996).

    Article  CAS  Google Scholar 

  13. van Waes, C. et al. Increase in suprabasilar integrin adhesion molecule expression in human epidermal neoplasms accompanies increased proliferation occurring with immortalization and tumor progression. Cancer Res. 55, 5434–5444 (1995). Shows a clear correlation between suprabasal α 6 β 4 -integrin expression and poor prognosis in human head and neck cancer.

    CAS  PubMed  Google Scholar 

  14. Gomez, M. & Cano, A. Expression of β1 integrin receptors in transformed mouse epidermal keratinocytes: Upregulation of α5β1 in spindle carcinoma cells. Mol. Carcinogen. 12, 153–165 (1995).

    Article  CAS  Google Scholar 

  15. Jones, J., Watt, F. M. & Speight, P. M. Changes in the expression of αv integrins in oral squamous cell carcinomas. J. Oral Pathol. Med. 26, 63–68 (1997).

    Article  CAS  Google Scholar 

  16. Janes, S. M. & Watt, F. M. Switch from αvβ5 to αvβ6 integrin expression protects squamous cell carcinomas from anoikis. J. Cell Biol. 166, 419–431 (2004). Proposes that the upregulation of α v β 6 -integrin expression in human SCCs protects cells from undergoing apoptosis when deprived of contact with the basement membrane.

    Article  CAS  Google Scholar 

  17. Levy, L., Broad, S., Diekmann, D., Evans, R. D. & Watt, F. M. β1 integrins regulate keratinocyte adhesion and differentiation by distinct mechanisms. Mol. Biol. Cell 11, 453–466 (2000).

    Article  CAS  Google Scholar 

  18. Evans, R. D. et al. A tumor-associated β1 integrin mutation that abrogates epithelial differentiation control. J. Cell Biol. 160, 589–596 (2003). Describes an activating integrin mutation in cells derived from a human SCC and provides evidence that the mutation prevents the cells from undergoing normal differentiation.

    Article  CAS  Google Scholar 

  19. Zhu, A. J., Haase, I. & Watt, F. M. Signalling via β1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro. Proc. Natl Acad. Sci. USA 96, 6728–6733 (1999).

    Article  CAS  Google Scholar 

  20. Haase, I., Hobbs, R. M., Romero, M. R., Broad, S. & Watt, F. M. A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis. J. Clin. Invest. 108, 527–536 (2001).

    Article  CAS  Google Scholar 

  21. Takagi, J., Kamata, T., Meredith, J., Puzon-McLaughlin, W. & Takada, Y. Changing ligand specificities of αvβ1 and αvβ3 integrins by swapping a short diverse sequence of the β subunit. J. Biol. Chem. 272, 19794–19800 (1997).

    Article  CAS  Google Scholar 

  22. Xiong, J. P. et al. Crystal structure of the extracellular segment of integrin αVβ3 in complex with an Arg-Gly-Asp ligand. Science. 296, 151–155 (2002).

    Article  CAS  Google Scholar 

  23. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature. 414, 105–111(2001).

    Article  CAS  Google Scholar 

  24. Evans, R. D., Jones, J., Taylor, C. & Watt, F. M. Sequence variation in the I-like domain of the β1 integrin subunit in human oral squamous cell carcinomas. Cancer Lett. 213, 189–194 (2004).

    Article  CAS  Google Scholar 

  25. Kunicki, T. J. The role of platelet collagen receptor (GPIa/IIa; integrin α2β1) polymorphisms in thrombotic disease. Curr. Opin. Hematol. 8, 277–285 (2001).

    Article  CAS  Google Scholar 

  26. López-Rovira, T., Silva-Vargas, V. & Watt, F. M. Different consequences of β1 integrin deletion in neonatal and adult mouse epidermis reveal a context-dependent role of integrins in regulating proliferation, differentiation and intercellular communication. J. Invest. Dermatol. 125, 1215–1227 (2005).

    Article  Google Scholar 

  27. Raghavan, S., Bauer, C., Mundschau, G., Li, Q. & Fuchs, E. Conditional ablation of β1 integrin in skin. Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J. Cell Biol. 150, 1149–1160 (2000).

    Article  CAS  Google Scholar 

  28. Benitah, S. A., Frye, M., Glogauer, M. & Watt, F. M. Stem cell depletion through epidermal deletion of Rac1. Science 309, 933–935 (2005). Shows that deletion of RAC1 from the epidermis of adult mice leads to depletion of stem cells.

    Article  Google Scholar 

  29. Jones, J., Sugiyama, M., Speight, P. M. & Watt, F. M. Restoration of αvβ5 integrin expression in neoplastic keratinocytes results in increased capacity for terminal differentiation and suppression of anchorage-independent growth. Oncogene 12, 119–126 (1996).

    CAS  PubMed  Google Scholar 

  30. Frisch, S. M. & Screaton, R. A. Anoikis mechanisms. Curr. Opin. Cell Biol. 13, 555–562 (2001).

    Article  CAS  Google Scholar 

  31. Grossmann, J. Molecular mechanisms of 'detachment-induced apoptosis — anoikis'. Apoptosis 7, 247–260 (2002).

    Article  CAS  Google Scholar 

  32. Hood, J. D., Frausto, R., Kiosses, W. B., Schwartz, M. A. & Cheresh, D. A. Differential αv integrin-mediated Ras–ERK signaling during two pathways of angiogenesis. J. Cell Biol. 162, 933–943 (2003).

    Article  CAS  Google Scholar 

  33. Stupack, D. G., Puente, X. S., Boutsaboualoy, S., Storgard, C. M. & Cheresh, D. A. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J. Cell Biol. 155, 459–470 (2001).

    Article  CAS  Google Scholar 

  34. Bachelder, R. E., Wendt, M. A., Fujita, N., Tsuruo, T. & Mercurio, A. M. The cleavage of Akt/protein kinase B by death receptor signaling is an important event in detachment-induced apoptosis. J. Biol. Chem. 276, 34702–34707 (2001).

    Article  CAS  Google Scholar 

  35. Cardone, M. H. et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318–1321 (1998).

    Article  CAS  Google Scholar 

  36. Lu, Y. et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 18, 7034–7045 (1999).

    Article  CAS  Google Scholar 

  37. Hood, J. D. & Cheresh, D. A. Role of integrins in cell invasion and migration. Nature Rev. Cancer 2, 91–100 (2002).

    Article  Google Scholar 

  38. McLean, G. W. et al. Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. Genes Dev. 18, 2998–3003 (2004). Demonstrates that focal adhesion kinase has a role in regulating tumour formation in mouse epidermis.

    Article  CAS  Google Scholar 

  39. Hertle, M. D., Kubler, M. -D., Leigh, I. M. & Watt, F. M. Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis. J. Clin. Invest. 89, 1892–1901 (1992).

    Article  CAS  Google Scholar 

  40. Carroll, J. M., Romero, M. R. & Watt, F. M. Suprabasal integrin expression in the epidermis of transgenic mice results in developmental defects and a phenotype resembling psoriasis. Cell 83, 957–968 (1995).

    Article  CAS  Google Scholar 

  41. Owens, D. M. & Watt, F. M. Influence of β1 integrins on epidermal squamous cell carcinoma formation in a transgenic mouse model: α3β1, but not α2β1, suppresses malignant conversion. Cancer Res. 61, 5248–5254 (2001).

    CAS  PubMed  Google Scholar 

  42. Owens, D. M., Romero, M. R., Gardner, C. & Watt, F. M. Suprabasal α6β4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFβ signaling. J. Cell Sci. 116, 3783–3791 (2003). Provides evidence that the mechanism by which suprabasal α 6 β 4 -integrin expression promotes tumour formation is by preventing the underlying basal cells from undergoing growth arrest in response to TGFβ.

    Article  CAS  Google Scholar 

  43. Owens, D. M., Broad, S., Yan, X. -H., Aznar-Benitah, S. & Watt, F. M. Suprabasal α5β1 integrin expression stimulates formation of epidermal squamous cell carcinomas without disrupting TGFβ signaling or inducing spindle cell tumors. Mol. Carcinogen. 44, 60–66 (2005). Provides evidence that the α 5 β 1 integrin is not involved in the formation of epidermal spindle-cell carcinomas.

    Article  CAS  Google Scholar 

  44. Tennenbaum, T. et al. The suprabasal expression of α6β4 integrin is associated with a high risk for malignant progression in mouse skin carcinogenesis. Cancer Res. 53, 4803–4810 (1993).

    CAS  PubMed  Google Scholar 

  45. Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Gen. 29, 117–129 (2001).

    Article  CAS  Google Scholar 

  46. Wakefield, L. M. & Roberts, A. B. TGF-β signaling: positive and negative effects on tumorigenesis. Curr. Opin. Gen. Dev. 12, 22–29 (2002).

    Article  CAS  Google Scholar 

  47. Edlund, S., Landstrom, M., Heldin, C. H. & Aspenstrom, P. Transforming growth factor-β-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol. Biol. Cell 13, 902–914 (2002).

    Article  CAS  Google Scholar 

  48. Danen, E. H. et al. Integrins control motile strategy through a Rho-cofilin pathway. J. Cell Biol. 169, 515–526 (2005). Demonstrates that different integrins affect motility in different ways through their interaction with the Rho–cofilin pathway.

    Article  CAS  Google Scholar 

  49. He, W., Cao, T., Smith, D. A., Myers, T. E. & Wang, X. J. Smads mediate signaling of the TGFβ superfamily in normal keratinocytes but are lost during skin chemical carcinogenesis. Oncogene 20, 471–483 (2001).

    Article  CAS  Google Scholar 

  50. Sheppard, D. Integrin-mediated activation of latent transforming growth factor β. Cancer Metastasis Rev. 24, 395–402 (2005).

    Article  CAS  Google Scholar 

  51. Reynolds, L. E. et al. Accelerated re-epithelialization in β3-integrin-deficient- mice is associated with enhanced TGF-β1 signaling. Nature Med. 11, 167–174 (2005).

    Article  CAS  Google Scholar 

  52. Dajee, M. et al. NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639–643 (2003). Describes a mechanistic basis for the role of α 6 β 4 -integrin expression in development of human SCC.

    Article  CAS  Google Scholar 

  53. Mariotti, A. et al. EGF-R signalling through Fyn kinase disrupts the function of integrin α6β4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J. Cell Biol. 155, 447–457 (2001).

    Article  CAS  Google Scholar 

  54. Santoro, M. M., Gaudino, G. & Marchisio, P. C. The MSP receptor regulates α6β4 and α3β1 integrins via 14–3-3 proteins in keratinocyte migration. Dev. Cell 5, 257–271 (2003).

    Article  CAS  Google Scholar 

  55. Trusolino, L., Berlotti, A. & Comoglio, P. M. A signalling adapter function for α6β4 integrin in the control of HGF-dependent invasive growth. Cell 107, 643–654 (2001). References 53–55 make a compelling case that release of α 6 β 4 from hemidesmosomes and association with receptor tyrosine kinases enhances growth-factor signalling.

    Article  CAS  Google Scholar 

  56. Romero, M. R., Carroll, J. M. & Watt, F. M. Analysis of cultured keratinocytes from a transgenic mouse model of psoriasis: effects of suprabasal integrin expression on keratinocyte adhesion, proliferation and terminal differentiation. Exp. Dermatol. 8, 53–67 (1999).

    Article  CAS  Google Scholar 

  57. Hobbs, R. M., Silva-Vargas, V., Groves, R. & Watt, F. M. Expression of activated MEK1 in differentiating epidermal cells is sufficient to generate hyperproliferative and inflammatory skin lesions. J. Invest. Dermatol. 123, 503–515 (2004).

    Article  CAS  Google Scholar 

  58. Scholl, F. A., Dumesic, P. A. & Khavari, P. A. Mek1 alters epidermal growth and differentiation. Cancer Res. 64, 6035–6040 (2004).

    Article  CAS  Google Scholar 

  59. Hobbs, R. M. & Watt, F. M. Regulation of interleukin-1α expression by integrins and epidermal growth factor receptor in keratinocytes from a mouse model of inflammatory skin disease. J. Biol. Chem. 278, 19798–19807 (2003). Provides evidence that suprabasal β 1 integrin expression in the epidermis triggers inflammation by stimulating keratinocyte production of IL-1α.

    Article  CAS  Google Scholar 

  60. Balkwill, F. & Coussens, L. M. Cancer: an inflammatory link. Nature 431, 405–406 (2004).

    Article  CAS  Google Scholar 

  61. Corbi, A. L., Jensen, U. B. & Watt, F. M. The α2 and α5 integrin genes: identification of transcription factors that regulate promoter activity in epidermal keratinocytes. FEBS Lett. 474, 201–207 (2000).

    Article  CAS  Google Scholar 

  62. Frye, M., Gardner, C., Li, E. R., Arnold, I. & Watt, F. M. Evidence that Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment. Development 130, 2793–2808 (2003).

    Article  CAS  Google Scholar 

  63. Gebhardt, A. et al. Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1. J. Cell Biol. 172, 139–149 (2006). Demonstrates that integrin genes are direct transcriptional targets of MYC and that MYC-mediated repression of gene expression is through formation of a complex with MIZ1.

    Article  CAS  Google Scholar 

  64. Ortiz-Urda, S. et al. Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science 307, 1773–1776 (2005). Describes how collagen fragments can promote tumour formation.

    Article  CAS  Google Scholar 

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Acknowledgements

We are deeply grateful to all the members of F.M.W.'s laboratory and our collaborators, past and present, who have contributed to the work described in this review. This work was supported by Cancer Research UK and the European Union. S.M.J. is the recipient of a MRC Clinician Scientist Fellowship.

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Author notes

  1. Sam M. Janes

    Present address: Rayne Institute, University College London, Gower Street, London, WC1E 6BT, UK

Authors and Affiliations

  1. Keratinocyte Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Sam M. Janes & Fiona M. Watt

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Correspondence to Fiona M. Watt.

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DATABASES

National Cancer Institute

oesophageal cancer

oral cavity cancer

skin tumours

Glossary

Keratinocytes

The epithelial cells that form stratified squamous epithelia such as the epidermis.

Integrins

Heterodimeric, transmembrane glycoprotein receptors for extracellular matrix proteins and immunoglobulin-superfamily counter-receptors.

Hemidesmosome

Specialized junction that mediates the attachment of an epithelial cell to the basement membrane. The hemidesmosomal integrin is α6β4.

Focal adhesion

A protein complex containing integrins that mediates cell attachment to the extracellular matrix. Although focal adhesions are defined in cultured cells, there is evidence that they also exist in vivo — for example, in the epidermis.

Apoptosome

A caspase-activating system that is formed when cytochrome c is released from mitochondria. It initiates oligomerization of apoptotic peptidase-activating factor 1, which binds pro-caspase 9 and thereby initiates the caspase cascade that leads to programmed cell death.

Involucrin

A cytoplasmic protein that is expressed in differentiating cells of the epidermis. Involucrin becomes incorporated into the cornified envelope, the protective barrier assembled in the outermost epidermal layers.

DMBA

Bay-region diol-epoxide-type carcinogen. Induces an A–T transversion of codon 61 in HRAS.

TPA

A phorbol-ester tumour promotor that induces epigenetic changes that select for clonal expansion of mutated cells. Used in epidermal carcinogenesis experiments.

T lymphocytes

A class of white blood cells present in blood and lymphoid tissues. Whereas B lymphocytes are stimulated by antigens to produce the precursors of antibody-generating plasma cells, T lymphocytes attack and destroy antigen-bearing cells directly.

Dendritic cells

Specialized antigen-presenting cells whose immunogenicity leads to the induction of antigen-specific immune responses. Dendritic cells have been used in numerous clinical trials to induce anti-tumour immune responses in cancer patients.

Neutrophils

The most numerous white blood cells in human peripheral blood (>70%). Neutrophils are phagocytes and have an important role in engulfing and killing extracellular pathogens. They can migrate into tissues, under the influence of chemotactic stimuli, where they phagocytose materials.

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Janes, S., Watt, F. New roles for integrins in squamous-cell carcinoma. Nat Rev Cancer 6, 175–183 (2006). https://doi.org/10.1038/nrc1817

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