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:

Tetraspanins: push and pull in suppressing and promoting metastasis

Nature Reviews Cancer volume 9, pages 40–55 (2009)Cite this article

Key Points

  • The tetraspanins are a family of proteins that cross the membrane four times and have a short amino- and carboxy-terminal tail, a small intracellular loop between transmembrane region 2 (TM2) and TM3, a small extracellular loop (ECL1) between TM1 and TM2 and a large extracellular loop (ECL2) between TM3 and TM4. Palmitoylation of intracellular, juxtamembrane cysteines is thought to be required for initiating tetraspanin–tetraspanin web formation.

  • Tetraspanins form complexes by interacting between themselves and with a variety of transmembrane and cytosolic proteins that are required for their function, including integrins, growth factor receptors, G-protein-coupled receptors and their intracellular associated heterotrimeric G-proteins, several peptidases, transmembrane proteins associated with tumour progression, immunoglobulin superfamily members and cytosolic signal transduction molecules.

  • Tetraspanins also associate with cholesterol and gangliosides, enabling higher order tetraspanin complexes to form in microdomains, termed tetraspanin-enriched membrane microdomains (TEMs), which provide a signalling platform. Although TEMs share several features with lipid rafts, they are independent and different from these structures.

  • Tetraspanins are abundant in membranes of various types of endocytic organelles and in exosomes — 30–100 nm vesicles that are released by many cells. Exosomes are thought to constitute a potent mode of intercellular communication that is also important in tumour progression.

  • Tetraspanins function by modulating, stabilizing or preventing the activities of their associated molecules, which vary depending on the composition of the TEM. Thus, tetraspanins can promote spreading and migration, which mostly rely on compartmentalization of integrins or integrin internalization and recycling or on modulating integrin signalling. However, tetraspanins can also be important in cell adhesion by regulating the trafficking and biosynthesis of associating integrins.

  • The tetraspanins CD82 and CD9 mostly suppress tumour progression. By their interactions with a variety of proteins including integrins, signalling proteins and immunoglobulin superfamily members they suppress motility and promote adherance to the surrounding matrix. Their expression is often reduced in late-stage human tumours.

  • Two tetraspanins, CD151 and tetraspanin 8 (D6.1A in rats), are overexpressed in several human tumours and seem to support tumour progression. CD151 regulates cell migration, mostly through its association with α3β1, α6β4 and matrix metalloproteinases. Additional transmembrane and cytosolic proteins in multimolecular complexes in TEM, contribute. Tetraspanin 8 regulates cell motility and survival and is involved in the promotion of angiogenesis.

  • The opposing effects of CD82 and CD9 versus CD15 and tetraspanin 8 on metastasis suppression and promotion cannot be fully explained by differences in the composition of the TEM. Indeed, there are strong hints that, by their enrichment in exosomes, tetraspanins and associated molecules become engaged in intercellular communication, where their involvement in membrane fusion facilitates message, including mRNA and microRNA, delivery.

  • A more comprehensive picture of the dynamics of TEM and the contribution of tetraspanins to exosome-meditated intercellular communication might allow us to therapeutically dictate the push and pull of tetraspanins in metastasis suppression.

Abstract

Tumours progress through a cascade of events that enable the formation of metastases. Some of the components that are required for this fatal process are well established. Tetraspanins, however, have only recently received attention as both metastasis suppressors and metastasis promoters. This late appreciation is probably due to their capacity to associate with various molecules, which they recruit into special membrane microdomains, and their abundant presence in tumour-derived small vesicles that aid intercellular communication. It is reasonable to assume that differences in the membrane and vesicular web components that associate with individual tetraspanins account for their differing abilities to promote and suppress metastasis.

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: Tetraspanins and associated molecules.
Figure 2: The generation and composition of exosomes.
Figure 3: Modes of CD82-mediated metastasis inhibition: CD82 impairs cell motility through several routes.
Figure 4: The multiple routes of CD9-mediated metastasis suppression.
Figure 5: CD151, matrix metalloproteinses (MMPs) and integrin-promoted cell motility.
Figure 6: Tetraspanins in intercellular communication exemplified for D6.1A.

Similar content being viewed by others

References

  1. Garcia-España, A. et al. Appearance of new tetraspanin genes during vertebrate evolution. Genomics 91, 326–334 (2008).

    Article  PubMed  CAS  Google Scholar 

  2. Hemler, M. E. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu. Rev. Cell Dev. Biol. 19, 397–422 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Maecker, H. T., Todd, S. C. & Levy, S. The tetraspanin superfamily: molecular facilitators. FASEB J. 11, 428–442 (1997). The first review to highlight the activity of tetraspanins through associating molecules.

    Article  CAS  PubMed  Google Scholar 

  4. Wright, M. D., Moseley, G. W. & van Spriel, A. B. Tetraspanin microdomains in immune cell signalling and malignant disease. Tissue Antig. 64, 533–542 (2004).

    Article  CAS  Google Scholar 

  5. Hemler, M. E. Tetraspanin functions and associated microdomains. Nature Rev. Mol. Cell Biol. 6, 801–811 (2005).

    Article  CAS  Google Scholar 

  6. Oren, R., Takahashi, S., Doss, C., Levy, R. & Levy, S. TAPA-1, the target of an antiproliferative antibody, defines a new family of transmembrane proteins. Mol. Cell. Biol. 10, 4007–4015 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Levy, S. & Shoham, T. Protein–protein interactions in the tetraspanin web. Physiology (Bethesda) 20, 218–224 (2005).

    CAS  Google Scholar 

  8. Zöller, M. Gastrointestinal tumors: metastasis and tetraspanins. Z. Gastroenterology 44, 573–586 (2006).

    Article  Google Scholar 

  9. Lakkaraju, A. & Rodriguez-Boulan, E. Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol. 18, 199–209 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jackson, P., Marreiros, A. & Russell, P. J. KAI1 tetraspanin and metastasis suppressor. Int. J. Biochem. Cell. Biol. 37, 530–534 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Tonoli, H. & Barrett, J. C. CD82 metastasis suppressor gene: a potential target for new therapeutics? Trends Mol. Med. 11, 563–570 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Liu, W. M. & Zhang, X. A. KAI1/CD82, a tumor metastasis suppressor. Cancer Lett. 240, 183–194 (2006). References 11 and 12 provide a comprehensive overview on the metastasis-suppressing activities of CD82 and highlight potential therapeutic options.

    Article  CAS  PubMed  Google Scholar 

  13. Lazo, P. A. Functional implications of tetraspanin proteins in cancer biology. Cancer Sci. 98, 1666–1677 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Berditchevski, F. & Odintsova, E. Tetraspanins as regulators of protein trafficking. Traffic 8, 89–96 (2007). A comprehensive review on tetraspanin microdomains and their effects on the trafficking and processing of associated proteins including the biochemical background.

    Article  CAS  PubMed  Google Scholar 

  15. Liu, L. et al. Tetraspanin CD151 promotes cell migration by regulating integrin trafficking. J. Biol. Chem. 282, 31631–31642 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Zijlstra, A., Lewis, J., Degryse, B., Stuhlmann, H. & Quigley, J. P. The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151. Cancer Cell 13, 221–234 (2008). Demonstrates in vivo , using intravital imaging, the effect of CD151 on tumour cell migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Stipp, C. S., Kolesnikova, T. V. & Hemler, M. E. Functional domains in tetraspanin proteins. Trends Biochem. Sci. 28, 106–112 (2003). References 5, 7 and 17 provide an overview on tetraspanin structure and the structure–function relationship.

    Article  CAS  PubMed  Google Scholar 

  18. Seigneuret, M. Complete predicted three-dimensional structure of the facilitator transmembrane protein and hepatitis C virus receptor CD81: conserved and variable structural domains in the tetraspanin superfamily. Biophys. J. 90, 212–227 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Berditchevski, F., Odintsova, E., Sawada, S. & Gilbert, E. Expression of the palmitoylation-deficient CD151 weakens the association of α3β1 integrin with the tetraspanin-enriched microdomains and affects integrin-dependent signaling. J. Biol. Chem. 277, 36991–37000 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Charrin, S. et al. Differential stability of tetraspanin/tetraspanin interactions: role of palmitoylation. FEBS Lett. 516, 139–144 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Sharma, C., Yang, X. H. & Hemler, M. E. DHHC2 affects palmitoylation, stability, and functions of tetraspanins CD9 and CD151. Mol. Biol. Cell 19, 3415–3425 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Todeschini, A. R., Dos Santos, J. N., Handa, K. & Hakomori, S. I. Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway. Proc. Natl Acad. Sci. USA 105, 1925–1930 (2008). This article demonstrates the importance of gangliosides on the establishment of TEMs and the impact of gangliosides on the cross-talk between tetraspanins and the associated molecules α3β1 and HGFR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marks, M. S., Ohno, H., Kirchnausen, T. & Bonracino, J. S. Protein sorting by tyrosine-based signals: adapting to the Ys and wherefores. Trends Cell Biol. 7, 124–128 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Escola, J. M. et al. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J. Biol. Chem. 273, 20121–20127 (1998). This paper describes the enrichment of tetraspanins in exosomes.

    Article  CAS  PubMed  Google Scholar 

  25. André, M. et al. Proteomic analysis of the tetraspanin web using LC-ESI-MS/MS and MALDI-FTICR-MS. Proteomics 6, 1437–1449 (2006).

    Article  PubMed  CAS  Google Scholar 

  26. Berditchevski, F. Complexes of tetraspanins with integrins: more than meets the eye. J. Cell Sci. 114, 4143–4151 (2001).

    CAS  PubMed  Google Scholar 

  27. Murayama, Y. et al. The tetraspanin CD9 modulates epidermal growth factor receptor signaling in cancer cells. J. Cell. Physiol. 216, 135–143 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Sridhar, S. C. & Miranti, C. K. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases. Oncogene 25, 2367–2378 (2006). Demonstrates in a human prostate cancer line the mitigating impact of CD82 on HGFR and integrin signalling pathways.

    Article  CAS  PubMed  Google Scholar 

  29. Little, K. D., Hemler, M. E. & Stipp, C. S. Dynamic regulation of a GPCR–tetraspanin–G protein complex on intact cells: central role of CD81 in facilitating GPR56-Gαq/11 association. Mol. Biol. Cell 15, 2375–2387 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Le Naour, F., André, M., Boucheix, C. & Rubinstein, E. Membrane microdomains and proteomics: lessons from tetraspanin microdomains and comparison with lipid rafts. Proteomics 6, 6447–6454 (2006). A comprehensive analysis of the multitude of proteins that associate with tetraspanins.

    Article  CAS  PubMed  Google Scholar 

  31. Stipp, C. S., Kolesnikova, T. V. & Hemler, M. E. EWI-2 is a major CD9 and CD81 partner and member of a novel Ig protein subfamily. J. Biol. Chem. 276, 40545–44054 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Claas, C. et al. The tetraspanin D6.1A and its molecular partners on rat carcinoma cells. Biochem. J. 389, 99–110 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, X. A., Bontrager, A. L. & Hemler, M. E. Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific β1 integrins. J. Biol. Chem. 276, 25005–25013 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Claas, C., Stipp, C. S. & Hemler, M. E. Evaluation of prototype transmembrane 4 superfamily protein complexes and their relation to lipid rafts. J. Biol. Chem. 276, 7974–7984 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Kovalenko, O. V., Yang, X., Kolesnikova, T. V. & Hemler, M. E. Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linking. Biochem. J. 377, 407–417 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhou, B., Liu, L., Reddivari, M. & Zhang, X. A. The palmitoylation of metastasis suppressor KAI1/CD82 is important for its motility- and invasiveness-inhibitory activity. Cancer Res. 64, 7455–7463 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Charrin, S. et al. Physical and functional link between cholesterol and tetraspanins. Eur. J. Immunol. 33, 2479–2489 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Miura, Y. et al. Reversion of the Jun-induced oncogenic phenotype by enhanced synthesis of sialosyllactosylceramide (GM3 ganglioside). Proc. Natl Acad. Sci. USA 101, 16204–16209 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Odintsova, E. et al. Gangliosides play an important role in the organization of CD82-enriched microdomains. Biochem. J. 400, 315–325 (2006). This paper highlights the effect of gangliosides on the organization of TEMs and provides evidence that distinct gangliosides differentially regulate individual tetraspanin recruitment and activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schorey, J. S. & Bhatnagar, S. Exosome function: from tumor immunology to pathogen biology. Traffic 9, 871–881 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zakharova, L., Svetlova, M. & Fomina, A. F. T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor. J. Cell Physiol. 212, 174–181 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell. Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. André, F. et al. Tumor-derived exosomes: a new source of tumor rejection antigens. Vaccine 19, A28–31 (2002).

    Article  Google Scholar 

  44. Hurley, J. H. & Emr, S. D. The ESCRT complexes: structure and mechanism of a membrane-trafficking network. Annu. Rev. Biophys. Biomol. Struct. 35, 277–298 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fang, Y. et al. Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol. 5, e158 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Bijlmakers, M. J. & Marsh, M. The on-off story of protein palmitoylation. Trends Cell Biol. 13, 32–42 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Linder, M. E. & Deschenes, R. J. Palmitoylation: policing protein stability and traffic. Nature Rev. Mol. Cell. Biol. 8, 74–84 (2007).

    Article  CAS  Google Scholar 

  48. Devaux, P. F. & Morris, R. Transmembrane asymmetry and lateral domains in biological membranes. Traffic 5, 241–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Levy, S. & Shoham, T. The tetraspanin web modulates immune-signalling complexes. Nature Rev. Immunol. 5, 136–148 (2005).

    Article  CAS  Google Scholar 

  50. Winterwood, N. E., Varzavand, A., Meland, M. N., Ashman, L. K. & Stipp, C. S. A critical role for tetraspanin CD151 in α3β1 and α6β4 integrin-dependent tumor cell functions on laminin-5. Mol. Biol. Cell 17, 2707–2721 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sala-Valdés, M. et al. EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin–radixin–moesin proteins. J. Biol. Chem. 281, 19665–19675 (2006).

    Article  PubMed  CAS  Google Scholar 

  52. Tsukita, S. & Yonemura, S. Cortical actin organization: lessons from ERM (ezrin/radixin/moesin) proteins. J. Biol. Chem. 274, 34507–34510 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Runge, K. E. et al. Oocyte CD9 is enriched on the microvillar membrane and required for normal microvillar shape and distribution. Dev. Biol. 304, 317–325 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Kaji, K. et al. The gamete fusion process is defective in eggs of Cd9-deficient mice. Nature Genet. 24, 279–282 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Rubinstein, E., Ziyyat, A., Wolf, J. P., Le Naour, F. & Boucheix, C. The molecular players of sperm–egg fusion in mammals. Semin. Cell Dev. Biol. 17, 254–263 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Zhang, X. A. et al. Function of the tetraspanin CD151-α6β1 integrin complex during cellular morphogenesis. Mol. Biol. Cell. 13, 1–11 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Takeda, Y. et al. Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro. Blood 109, 1524–1532 (2007). This paper provides evidence for the relevance of tetraspanin interactions in non-transformed cells and offers an explanation for the selective requirement of tetraspanins under pathological conditions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. He, B. et al. Tetraspanin CD82 attenuates cellular morphogenesis through down-regulating integrin α6-mediated cell adhesion. J. Biol. Chem. 280, 3346–3354 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Potolicchio, I. et al. Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J. Immunol. 175, 2237–2243 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Arduise, C. et al. Tetraspanins regulate ADAM10-mediated cleavage of TNF-α and epidermal growth factor. J. Immunol. 181, 7002–7013 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Yanez-Mo, M. et al. MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells. Blood 112, 3217–3226 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Bass, R. et al. Regulation of urokinase receptor proteolytic function by the tetraspanin CD82. J. Biol. Chem. 280, 14811–14818 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Hasegawa, M. et al. CD151 dynamics in carcinoma-stroma interaction: integrin expression, adhesion strength and proteolytic activity. Lab. Invest. 87, 882–892 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Ahmad, A. & Hart, I. R. Mechanisms of metastasis. Crit. Rev. Oncol. Hematol. 26, 163–173 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Migrating cancer stem cells — an integrated concept of malignant tumour progression. Nature Rev. Cancer 5, 744–749 (2005).

    Article  CAS  Google Scholar 

  66. Albini, A., Mirisola, V. & Pfeffer, U. Metastasis signatures: genes regulating tumor-microenvironment interactions predict metastatic behavior. Cancer Metastasis Rev. 27, 75–83 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cells. Nature Rev. Cancer 3, 55–63 2003).

    Article  CAS  Google Scholar 

  68. Stafford, L. J., Vaidya, K. S. & Welch, D. R. Metastasis suppressors genes in cancer. Int. J. Biochem. Cell Biol. 40, 874–891 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Seigneuret, M., Delaguillaumie, A., Lagaudrière-Gesbert, C. & Conjeaud, H. Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion. J. Biol. Chem. 276, 40055–40064 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Dong, J. T. et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268, 884–886 (1995).

    Article  CAS  PubMed  Google Scholar 

  71. Ichikawa, T., Ichikawa, Y. & Isaacs, J. T. Genetic factors and suppression of metastatic ability of prostatic cancer. Cancer Res. 51, 3788–3792 (1991).

    CAS  PubMed  Google Scholar 

  72. Briese, J. et al. Correlations between reduced expression of the metastasis suppressor gene KAI-1 and accumulation of p53 in uterine carcinomas and sarcomas. Virchows Arch. 453, 89–96 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Protzel, C., Kakies, C., Kleist, B., Poetsch, M. & Giebel, J. Down-regulation of the metastasis suppressor protein KAI1/CD82 correlates with occurrence of metastasis, prognosis and presence of HPV DNA in human penile squamous cell carcinoma. Virchows Arch. 452, 369–375 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Takeda, T. et al. Adenoviral transduction of MRP-1/CD9 and KAI1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model. Cancer Res. 67, 1744–1749 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Phillips, K. K. et al. Correlation between reduction of metastasis in the MDA-MB-435 model system and increased expression of the Kai-1 protein. Mol. Carcinog. 21, 111–120 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Shinohara, T. et al. Transduction of KAI1/CD82 cDNA promotes hematogenous spread of human lung-cancer cells in natural killer cell-depleted SCID mice. Int. J. Cancer 94, 16–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Odintsova, E., Sugiura, T. & Berditchevski, F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr. Biol. 10, 1009–1012 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Zhang, X. A., Lane, W. S., Charrin, S., Rubinstein, E. & Liu, L. EWI2/PGRL associates with the metastasis suppressor KAI1/CD82 and inhibits the migration of prostate cancer cells. Cancer Res. 63, 2665–2674 (2003).

    CAS  PubMed  Google Scholar 

  79. Takahashi, M., Sugiura, T., Abe, M., Ishii, K. & Shirasuna, K. Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. Int. J. Cancer 121, 1919–1929 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Wang, X. Q. et al. Suppression of epidermal growth factor receptor signaling by protein kinase C-α activation requires CD82, caveolin-1, and ganglioside. Cancer Res. 67, 9986–9995 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Lee, J. H., Seo, Y. W., Park, S. R., Kim, Y. J. & Kim, K. K. Expression of a splice variant of KAI1, a tumor metastasis suppressor gene, influences tumor invasion and progression. Cancer Res. 63, 7247–7255 (2003).

    CAS  PubMed  Google Scholar 

  82. Lee, J. H. et al. KAI1 COOH-terminal interacting tetraspanin (KITENIN), a member of the tetraspanin family, interacts with KAI1, a tumor metastasis suppressor, and enhances metastasis of cancer. Cancer Res. 64, 4235–4243 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Bandyopadhyay, S. et al. Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nature Med. 12, 933–938 (2006). A report on a transaction between CD82 and a chemokine receptor on endothelial cells that provokes tumour cell senescence, with supporting evidence from in vivo studies using DARC−/− mice. Further information is needed regarding this unexpected CD82 activity.

    Article  CAS  PubMed  Google Scholar 

  84. Tagawa, K. et al. Down-regulation of KAI1 messenger RNA expression is not associated with loss of heterozygosity of the KAI1 gene region in lung adenocarcinoma. Jpn. J. Cancer Res. 90, 970–976 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Liu, F. S. et al. Frequent down-regulation and lack of mutation of the KAI1 metastasis suppressor gene in epithelial ovarian carcinoma. Gynecol. Oncol. 78, 10–15 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Jackson, P. et al. Methylation of a CpG island within the promoter region of the KAI1 metastasis suppressor gene is not responsible for down-regulation of KAI1 expression in invasive cancers or cancer cell lines. Cancer Lett. 157, 169–176 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Drucker, L. et al. Promoter hypermethylation of tetraspanin members contributes to their silencing in myeloma cell lines. Carcinogenesis 27, 197–204 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Marreiros, A. et al. KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells. Oncogene 24, 637–649 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Telese, F. et al. Transcription regulation by the adaptor protein Fe65 and the nucleosome assembly factor SET. EMBO Rep. 6, 77–82 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Kim, J. H. et al. Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes. Nature 434, 921–926 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Tsai, Y. C. et al. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nature Med. 13, 1504–1509 (2007). This paper describes CD82 regulation at the transcriptional level, a finding that raises the possibility of attacking metastasis formation.

    Article  CAS  PubMed  Google Scholar 

  92. Yang, X. H. et al. Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization. J. Biol. Chem. 281, 12976–12985 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Furuya, M. et al. Down-regulation of CD9 in human ovarian carcinoma cell might contribute to peritoneal dissemination: morphologic alteration and reduced expression of β1 integrin subsets. Cancer Res. 65, 2617–2625 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Mitsuzuka, K., Handa, K., Satoh, M., Arai, Y. & Hakomori, S. A specific microdomain (“glycosynapse 3”) controls phenotypic conversion and reversion of bladder cancer cells through GM3-mediated interaction of α3β1 integrin with CD9. J. Biol. Chem. 280, 35545–35553 (2005). Using bladder carcinoma lines, this study shows that not only the association between gangliosides and tetraspanins but also changes in the expression level of gangliosides suffice to change metastasis-promoting into metastasis-suppressing activities through differences in TEM organization.

    Article  CAS  PubMed  Google Scholar 

  95. Huang, C. L. et al. MRP-1/CD9 gene transduction downregulates Wnt signal pathways. Oncogene 23, 7475–7483 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. You, Z. et al. Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis. J. Cell Biol. 157, 429–440 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ishitani, T. et al. The TAK1–NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca2+ pathway to antagonize Wnt/β-catenin signaling. Mol. Cell. Biol. 23, 131–139 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yamamoto, H. et al. Association of matrilysin-2 (MMP-26) expression with tumor progression and activation of MMP-9 in esophageal squamous cell carcinoma. Carcinogenesis 25, 2353–2360 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Huang, C. L. et al. MRP-1/CD9 gene transduction regulates the actin cytoskeleton through the downregulation of WAVE2. Oncogene 25, 6480–6488 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Takenawa, T. & Suetsugu, S. The WASP–WAVE protein network: connecting the membrane to the cytoskeleton. Nature Rev. Mol. Cell. Biol. 8, 37–48 (2007).

    Article  CAS  Google Scholar 

  101. Shi, W., Fan, H., Shum, L. & Derynck, R. The tetraspanin CD9 associates with transmembrane TGF-α and regulates TGF-α-induced EGF receptor activation and cell proliferation. J. Cell Biol. 148, 591–602 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Fan, H. & Derynck, R. Ectodomain shedding of TGF-α and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J. 18, 6962–6972 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Herrlich, A., Klinman, E., Fu, J., Sadegh, C. & Lodish, H. Ectodomain cleavage of the EGF ligands HB-EGF, neuregulin1-β, and TGF-α is specifically triggered by different stimuli and involves different PKC isoenzymes. FASEB J. 29 Aug 2008 (doi: 10.1096/fj.08-113852).

  104. Imhof, I., Gasper, W. J. & Derynck, R. Association of tetraspanin CD9 with transmembrane TGFα confers alterations in cell-surface presentation of TGFα and cytoskeletal organization. J. Cell Sci. 121, 2265–2274 (2008). References 103 and 104 demonstrate the effect of CD9-associated TGFα on EGFR signalling exhaustion and elucidate the contribution of CD9 to stabilizing membrane-bound TGFα and the resulting modulation in signal transduction.

    Article  CAS  PubMed  Google Scholar 

  105. Saito, Y. et al. Absence of CD9 enhances adhesion-dependent morphologic differentiation, survival, and matrix metalloproteinase-2 production in small cell lung cancer cells. Cancer Res. 66, 9557–9565 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Hong, I. K., Kim, Y. M., Jeoung, D. I., Kim, K. C. & Lee, H. Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells. Exp. Mol. Med. 37, 230–239 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Longo, N. et al. Regulatory role of tetraspanin CD9 in tumor-endothelial cell interaction during transendothelial invasion of melanoma cells. Blood 98, 3717–3726 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Sauer, G et al. Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion. Clin. Cancer Res. 9, 6426–6431 (2003).

    CAS  PubMed  Google Scholar 

  109. De Bruyne, E. et al. Endothelial cell-driven regulation of CD9 or motility-related protein-1 expression in multiple myeloma cells within the murine 5T33MM model and myeloma patients. Leukemia 20, 1870–1879 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Nakazawa, Y. et al. Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis. Blood 112, 1730–1739 (2008). This paper provides evidence that, outside the mainstream of tetraspanin functions, CD9 interferes with platelet aggregation by its interaction with podoplanin, the metastasis-inhibiting effect being confirmed in a mouse model.

    Article  CAS  PubMed  Google Scholar 

  111. Suzuki-Inoue, K. et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 107, 542–549 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Pols, M. S. & Klumperman, J. Trafficking and function of the tetraspanin CD63. Exp. Cell Res. 7 Oct 2008 (doi:10.1016/j.yexcr.2008.09.020).

  113. Mazzocca, A., Liotta, F. & Carloni, V. Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma. Gastroenterology 135, 244–256 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Xu, L. & Hynes, R. O. GPR56 and TG2: possible roles in suppression of tumor growth by the microenvironment. Cell Cycle 6, 160–165 (2007). This article reviews the importance of the interaction of the metastasizing tumour cell with the stroma, as exemplified by the interaction of a CD81-associated GPCR with TG2, a crosslinking enzyme in the matrix.

    Article  CAS  PubMed  Google Scholar 

  115. Testa, J. E., Brooks, P. C., Lin, J. M. & Quigley, J. P. Eukaryotic expression cloning with an antimetastatic monoclonal antibody identifies a tetraspanin (PETA-3/CD151) as an effector of human tumor cell migration and metastasis. Cancer Res. 59, 3812–3820 (1999).

    CAS  PubMed  Google Scholar 

  116. Shiomi, T. et al. Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151. Lab. Invest. 85, 1489–1506 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Hong, I. K. et al. Homophilic interactions of Tetraspanin CD151 up-regulate motility and matrix metalloproteinase-9 expression of human melanoma cells through adhesion-dependent c-Jun activation signaling pathways. J. Biol. Chem. 281, 24279–24292 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Fitter, S., Tetaz, T. J., Berndt, M. C. & Ashman, L. K. Molecular cloning of cDNA encoding a novel platelet-endothelial cell tetra-span antigen, PETA-3. Blood 86, 1348–1355 (1995).

    CAS  PubMed  Google Scholar 

  119. Karamatic Crew, V. et al. CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin. Blood 104, 2217–2223 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Wright, M. D. et al. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol. Cell. Biol. 24, 5978–5988 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sachs, N. et al. Kidney failure in mice lacking the tetraspanin CD151. J. Cell Biol. 175, 33–39 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sela, B. A., Steplewski, Z. & Koprowski, H. Colon carcinoma-associated glycoproteins recognized by monoclonal antibodies CO-029 and GA22–22 Hybridoma 8, 481–491 (1989).

    Article  CAS  PubMed  Google Scholar 

  123. Kanetaka, K. et al. Possible involvement of tetraspanin CO-029 in hematogenous intrahepatic metastasis of liver cancer cells. J. Gastroenterol. Hepatol. 18, 1309–1314 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Huerta, S. et al. Gene expression profile of metastatic colon cancer cells resistant to cisplatin-induced apoptosis. Int. J. Oncol. 22, 663–670 (2003).

    CAS  PubMed  Google Scholar 

  125. Claas, C. et al. Association between the rat homologue of CO-029, a metastasis-associated tetraspanin molecule and consumption coagulopathy. J. Cell Biol. 141, 267–280 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Herlevsen, M., Schmidt, D. S., Miyazaki, K. & Zöller, M. The association of the tetraspanin D6.1A with the α6β4 integrin supports cell motility and liver metastasis formation. J. Cell Sci. 116, 4373–4390 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Gesierich, S. et al. Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility. Clin. Cancer Res. 11, 2840–2852 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Nakatsu, F. & Ohno, H. Adaptor protein complexes as the key regulators of protein sorting in the post-Golgi network. Cell Struct. Funct. 28, 419–429 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Caswell, P. T. & Norman, J. C. Integrin trafficking and the control of cell migration. Traffic 7, 14–21 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Kuhn, S. et al. A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol. Cancer Res. 5, 553–567 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Ladwein, M. et al. The cell–cell adhesion molecule EpCAM interacts directly with the tight junction protein claudin-7. Exp. Cell. Res. 309, 345–357 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. De Cicco, M. The prothrombotic state in cancer: pathogenic mechanisms. Crit. Rev. Oncol. Hematol. 50, 187–196 (2004).

    Article  PubMed  Google Scholar 

  133. Gesierich, S., Berezovskiy, I., Ryschich, E. & Zöller, M. Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer Res. 66, 7083–7094 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Gesierich, S. Das Tetraspanin CO-029/D6.1A in Membrankomplexen und Exosomen: Einfluss auf Tumorprogression und Angiogenese. Thesis, Univ. Karlsruhe (2006).

    Google Scholar 

  135. van Niel, G., Porto-Carreiro, I., Simoes, S. & Raposo, G. Exosomes: a common pathway for a specialized function. J. Biochem. 140, 13–21 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Janowska-Wieczorek, A. et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int. J. Cancer 113, 752–760 (2005). This paper demonstrates the effect of exosomes on angiogenesis and metastasis formation.

    Article  CAS  PubMed  Google Scholar 

  137. Hao, S. et al. Epigenetic transfer of metastatic activity by uptake of highly metastatic B16 melanoma cell-released exosomes. Exp. Oncol. 28, 126–131 (2006).

    CAS  PubMed  Google Scholar 

  138. Goody, R. S., Rak, A. & Alexandrov, K. The structural and mechanistic basis for recycling of Rab proteins between membrane compartments. Cell Mol. Life Sci. 62, 1657–1670 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Soldati, T. & Schliwa, M. Powering membrane traffic in endocytosis and recycling. Nature Rev. Mol. Cell. Biol. 7, 897–908 (2006).

    Article  CAS  Google Scholar 

  140. Cai, H., Reinisch, K. & Ferro-Novick, S. Coats, tethers, Rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev. Cell 12, 671–682 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Horejsí, V. & Vlcek, C. Novel structurally distinct family of leucocyte surface glycoproteins including CD9, CD37, CD53 and CD63. FEBS Lett. 288, 1–4 (1991).

    Article  PubMed  Google Scholar 

  142. Claas, C., Herrmann, K., Matzku, S., Möller, P. & Zöller, M. Developmentally regulated expression of metastasis-associated antigens in the rat. Cell Growth Differ. 7, 663–678 (1996).

    CAS  PubMed  Google Scholar 

  143. Defilippi, P., Di Stefano, P. & Cabodi, S. p130Cas: a versatile scaffold in signaling networks. Trends Cell Biol. 16, 257–263 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Zhou, Z. et al. TM4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression. Clin. Exp. Metastasis 25, 537–548 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

am most grateful to S. Levy for her suggestions and help during preparation of this article. I thank the (former) people of my laboratory, particularly Christoph Claas, for helpful comments. The work in the author's laboratory described in this article is supported by the German Research Foundation (grant ZO 40/12-1) and the Tumourzentrum Heidelberg/Mannheim.

Author information

Authors and Affiliations

  1. Department of Tumour Cell Biology, and Department of Tumour Progression and Immune Defense, University Hospital of Surgery, German Cancer Research Center, Heidelberg

    Margot Zöller

  2. Department of Applied Genetics, University of Karlsruhe, Karlsruhe, Germany

    Margot Zöller

Authors
  1. Margot Zöller
    View author publications

    You can also search for this author in PubMed Google Scholar

Supplementary information

Supplementary information S1 (table)

Diagnostic and prognostic relevance of CD9, CD151 and CO-029 expression in human cancer (PDF 206 kb)

Related links

Related links

FURTHER INFORMATION

M. Zöller's homepage

Glossary

Palmitoylation

S-Acylation of proteins with palmitate.

Gangliosides

Anionic glycosphingolipids characterized by sialic acid residues. Non-transformed cells mostly express gangliosides with complex oligosaccharides like GM1 and GD1a; tumour cells mostly express GM3 and GM2, which are characterized by a loss of complex oligosaccharides.

Type II phosphatidylinositol 4-kinase

(PI4KII). PI4KIIs generate phosphatidylinositol 4-phosphates, which are precursors of important regulatory phosphoinosites. PI4KIIs regulate a diverse array of signalling events, as well as vesicular trafficking and lipid transport.

EWI

A new class of transmembrane immunoglobulin G superfamily molecules that contain a conserved glutamic acid – phenyalanine–isoleucine (EWI) motif. Two members, EWI-F and EWI-2, can associate with tetraspanins directly.

Cable formation

Some cells grow on gelatinous matrices such as Matrigel along lines of mechanical tension, forming a pattern of intersecting cellular cables.

Ezrin–radixin–moesin proteins

(ERM proteins). ERM proteins mediate actin–membrane linkage and regulate signalling molecules. In the dormant state the N-terminal domain is masked by interactions with the C-terminal domain. Only phosphorylated ERM proteins link membrane proteins to the actin cytoskeleton.

ADAM

(A disintegrin and metalloprotease). A family of multidomain membrane proteins that combine a cytokine-rich disintegrin and a zinc metalloprotease domain in their ectodomain.

GRB2

(Growth factor receptor-bound protein 2). GRB2 is a key molecule in intracellular signal transduction, linking activated cell surface receptors to downstream targets by binding to specific phosphotyrosine-containing and proline-rich sequence motifs. GRB2 signalling is crucial for cell cycle progression and actin-based cell motility, and more complex processes such as epithelial morphogenesis, angiogenesis and vasculogenesis.

Endosomal sorting complexes required for transport

(ESCRT). ESCRT complexes deform the endosome-limiting membrane by specific protein–protein and protein–lipid interactions, thereby orchestrating the inward budding of vesicles.

CD13 or CD26

CD13 is a zinc-dependent metalloprotease. Along with CD26, a serine exopeptidase, it cleaves neutral amino acids from the amino-termini of proteins. CD13 is frequently deregulated in cancer.

FAKp–130CAS–CRKII complex

The recruitment of SRC into a focal adhesion kinase (FAK)–SRC signalling complex facilitates the phosphorylation of FAK-associated proteins. SRC recruits the docking protein p130CAS to focal adhesions in association with CRKII. Together, these proteins stimulate cell migration and invasion.

GAB1

(GRB2 associated binder 1). A member of an adaptor/scaffolding protein family. Gab adaptors are involved in multiple signalling pathways that are mediated by receptor and non-receptor protein tyrosine kinases and become phosphorylated upon stimulation.

TBX2

(T-box 2). A member of a family of genes encoding developmental transcription factors, characterized by a 200 amino acid DNA binding domain (a T-box). TBX2 has been implicated in development of a number of different tissues and in tumour development through downregulation of the tumour suppressor ARF and an associated bypass of senescence.

AP2

A transcription factor originally described as involved in the transcription of NRAS, PKC and TGFα.

NCOR1–TAB2–HDAC3 complex

A complex containing the nuclear receptor co-repressor NCOR1 and the TAK1-binding adaptor protein TAB2, which physically interacts with histone deacetylase 3 (HDAC3).

CSK

(C-terminal Src kinase). An endogenous inhibitor of the Src family protein tyrosine kinases.

WAVE2

Member of the WASP (Wiskott–Aldrich syndrome protein) family of proteins that regulate cortical actin filament reorganization in response to extracellular stimuli.

ARP2 and ARP3

(Actin-related proteins 2 and 3). ARP2 and ARP3 act as multifunctional organizers of actin filaments in all eukaryotes.

CLEC2

(C-type lectin-like receptor 2). CLEC2 is expressed on the surface of platelets and functions as a receptor for the snake venom protein rhodocytin. It displays a single carbohydrate recognition domain and a cytoplasmic tyrosine-based motif. CLEC2 signals through a single YXXL motif that requires the tandem SH2 domains of SYK.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zöller, M. Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer 9, 40–55 (2009). https://doi.org/10.1038/nrc2543

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2543

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing