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Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix

Cancer and Metastasis Reviews volume 28, pages 137–149 (2009)Cite this article

Abstract

Invasive tumor–derived or transformed cells, cultured on a flat extracellular matrix substratum, extend specialized proteolytically active plasma membrane protrusions. These structures, termed invadopodia, are responsible for the focal degradation of the underlying substrate. Considerable progress has been made in recent years towards understanding the basic molecular components and regulatory circuits and the ultrastructural features of invadopodia. This has generated substantial interest in invadopodia as a paradigm to study the complex interactions between the intracellular trafficking, signal transduction and cytoskeleton regulation machineries; hopes are high that they may also represent valid biological targets to help advance the anti–cancer drug discovery process. Current knowledge will be reviewed here with an emphasis on the many open questions in invadopodia biology.

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References

  1. Adams, J. C. (2001). Cell-matrix contact structures. Cell Mol Life Sci, 58, 371–392.

    PubMed  CAS  Google Scholar 

  2. Adams, J. C. (2002). Regulation of protrusive and contractile cell-matrix contacts. J Cell Sci, 115, 257–265.

    PubMed  CAS  Google Scholar 

  3. Litjens, S. H., de Pereda, J. M., & Sonnenberg, A. (2006). Current insights into the formation and breakdown of hemidesmosomes. Trends in cell biology, 16, 376–383.

    PubMed  CAS  Google Scholar 

  4. Wehrle-Haller, B., & Imhof, B. (2002). The inner lives of focal adhesions. Trends in cell biology, 12, 382–389.

    PubMed  CAS  Google Scholar 

  5. Zaidel-Bar, R., Cohen, M., Addadi, L., & Geiger, B. (2004). Hierarchical assembly of cell-matrix adhesion complexes. Biochemical Society transactions, 32, 416–420.

    PubMed  CAS  Google Scholar 

  6. Friedl, P., Entschladen, F., Conrad, C., Niggemann, B., & Zanker, K. S. (1998). CD4+ T lymphocytes migrating in three-dimensional collagen lattices lack focal adhesions and utilize beta1 integrin-independent strategies for polarization, interaction with collagen fibers and locomotion. European Journal of Immunology, 28, 2331–2343.

    PubMed  CAS  Google Scholar 

  7. Kelly, T., Mueller, S. C., Yeh, Y., & Chen, W. T. (1994). Invadopodia promote proteolysis of a wide variety of extracellular matrix proteins. J Cell Physiol, 158, 299–308.

    PubMed  CAS  Google Scholar 

  8. Mueller, S. C., & Chen, W. T. (1991). Cellular invasion into matrix beads: localization of beta 1 integrins and fibronectin to the invadopodia. J Cell Sci, 99, 213–225.

    PubMed  CAS  Google Scholar 

  9. Chen, W. T. (1989). Proteolytic activity of specialized surface protrusions formed at rosette contact sites of transformed cells. J Exp Zool, 251, 167–185.

    PubMed  CAS  Google Scholar 

  10. Bowden, E. T., Barth, M., Thomas, D., Glazer, R. I., & Mueller, S. C. (1999). An invasion-related complex of cortactin, paxillin and PKCmu associates with invadopodia at sites of extracellular matrix degradation. Oncogene, 18, 4440–4449.

    PubMed  CAS  Google Scholar 

  11. Nakahara, H., Mueller, S. C., Nomizu, M., Yamada, Y., Yeh, Y., & Chen, W. T. (1997). Activation of beta1 integrin signaling stimulates tyrosine phosphorylation of p190RhoGAP and membrane-protrusive activities at invadopodia. J Biol Chem, 273, 9–12.

    Google Scholar 

  12. Mueller, S. C., Yeh, Y., & Chen, W. T. (1992). Tyrosine phosphorylation of membrane proteins mediates cellular invasion by transformed cells. J Cell Biol, 119, 1309–1325.

    PubMed  CAS  Google Scholar 

  13. Monsky, W. L., Lin, C. Y., Aoyama, A., Kelly, T., Akiyama, S. K., Mueller, S. C., et al. (1994). A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells. Cancer research, 54, 5702–5710.

    PubMed  CAS  Google Scholar 

  14. Chen, W. T. (1996). Proteases associated with invadopodia, and their role in degradation of extracellular matrix. EnzymeProtein, 49, 59–71.

    CAS  Google Scholar 

  15. Baldassarre, M., Pompeo, A., Beznoussenko, G., Castaldi, C., Cortellino, S., McNiven, M. A., et al. (2003). Dynamin participates in focal extracellular matrix degradation by invasive cells. Mol Biol Cell, 14, 1074–1084.

    PubMed  CAS  Google Scholar 

  16. Mizutani, K., Miki, H., He, H., Maruta, H., & Takenawa, T. (2002). Essential role of neural Wiskott-Aldrich syndrome protein in podosome formation and degradation of extracellular matrix in src-transformed fibroblasts. Cancer research, 62, 669–674.

    PubMed  CAS  Google Scholar 

  17. Yamaguchi, H., Lorenz, M., Kempiak, S., Sarmiento, C., Coniglio, S., Symons, M., et al. (2005). Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol, 168, 441–452.

    PubMed  CAS  Google Scholar 

  18. Ayala, I., Baldassarre, M., Caldieri, G., & Buccione, R. (2006). Invadopodia: A guided tour. Eur J Cell Biol, 85, 159–164.

    PubMed  CAS  Google Scholar 

  19. Bowden, E. T., Onikoyi, E., Slack, R., Myoui, A., Yoneda, T., Yamada, K. M., et al. (2006). Co-localization of cortactin and phosphotyrosine identifies active invadopodia in human breast cancer cells. Exp Cell Res, 312, 1240–1253.

    PubMed  CAS  Google Scholar 

  20. Baldassarre, M., Ayala, I., Beznoussenko, G., Giacchetti, G., Machesky, L. M., Luini, A., et al. (2006). Actin dynamics at sites of extracellular matrix degradation. Eur J Cell Biol, 85, 1217–1231.

    PubMed  CAS  Google Scholar 

  21. Nakahara, H., Nomizu, M., Akiyama, S. K., Yamada, Y., Yeh, Y., & Chen, W. T. (1996). A mechanism for regulation of melanoma invasion. Ligation of alpha6beta1 integrin by laminin G peptides. J Biol Chem, 271, 27221–27224.

    PubMed  CAS  Google Scholar 

  22. Mueller, S. C., Ghersi, G., Akiyama, S. K., Sang, Q. X., Howard, L., Pineiro-Sanchez, M., et al. (1999). A novel protease-docking function of integrin at invadopodia. J Biol Chem, 274, 24947–24952.

    PubMed  CAS  Google Scholar 

  23. Artym, V. V., Kindzelskii, A. L., Chen, W. T., & Petty, H. R. (2002). Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on beta1 integrins and the cytoskeleton. Carcinogenesis, 23, 1593–1601.

    PubMed  CAS  Google Scholar 

  24. Deryugina, E. I., Ratnikov, B., Monosov, E., Postnova, T. I., DiScipio, R., Smith, J. W., et al. (2001). MT1-MMP initiates activation of pro-MMP-2 and integrin alphavbeta3 promotes maturation of MMP-2 in breast carcinoma cells. Exp Cell Res, 263, 209–223.

    PubMed  CAS  Google Scholar 

  25. Coopman, P. J., Do, M. T., Thompson, E. W., & Mueller, S. C. (1998). Phagocytosis of cross-linked gelatin matrix by human breast carcinoma cells correlates with their invasive capacity. ClinCancer research, 4, 507–515.

    CAS  Google Scholar 

  26. Wyckoff, J., Wang, W., Lin, E. Y., Wang, Y., Pixley, F., Stanley, E. R., et al. (2004). A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer research, 64, 7022–7029.

    PubMed  CAS  Google Scholar 

  27. Yamaguchi, H., Pixley, F., & Condeelis, J. (2006). Invadopodia and podosomes in tumor invasion. Eur J Cell Biol, 85, 213–218.

    PubMed  CAS  Google Scholar 

  28. Hauck, C. R., Hsia, D. A., Ilic, D., & Schlaepfer, D. D. (2002). v-Src SH3-enhanced interaction with focal adhesion kinase at beta 1 integrin-containing invadopodia promotes cell invasion. J Biol Chem, 277, 12487–12490.

    PubMed  CAS  Google Scholar 

  29. Rykx, A., De Kimpe, L., Mikhalap, S., Vantus, T., Seufferlein, T., Vandenheede, J. R., et al. (2003). Protein kinase D: a family affair. FEBS Lett, 546, 81–86.

    PubMed  CAS  Google Scholar 

  30. Wang, Q. J. (2006). PKD at the crossroads of DAG and PKC signaling. Trends Pharmacol Sci, 27, 317–323.

    PubMed  CAS  Google Scholar 

  31. Tague, S. E., Muralidharan, V., & D'Souza-Schorey, C. (2004). ADP-ribosylation factor 6 regulates tumor cell invasion through the activation of the MEK/ERK signaling pathway. Proc Natl Acad Sci U S A, 101, 9671–9676.

    PubMed  CAS  Google Scholar 

  32. Ayala, I., Baldassarre, M., Giacchetti, G., Caldieri, G., Tete, S., Luini, A. et al. (2008). Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation. J Cell Sci.

  33. Kolch, W. (2005). Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol, 6, 827–837.

    PubMed  CAS  Google Scholar 

  34. Bokoch, G. M. (2003). Biology of the p21-activated kinases. Annual review of biochemistry, 72, 743–781.

    PubMed  CAS  Google Scholar 

  35. Kumar, R., Gururaj, A. E., & Barnes, C. J. (2006). p21-activated kinases in cancer. Nat Rev Cancer, 6, 459–471.

    PubMed  CAS  Google Scholar 

  36. Zhao, Z. S., & Manser, E. (2005). PAK and other Rho-associated kinases-effectors with surprisingly diverse mechanisms of regulation. Biochem J, 386, 201–214.

    PubMed  CAS  Google Scholar 

  37. Hall, A. (2005). Rho GTPases and the control of cell behaviour. Biochemical Society transactions, 33, 891–895.

    PubMed  CAS  Google Scholar 

  38. Heasman, S. J., & Ridley, A. J. (2008). Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol, 9, 690–701.

    PubMed  CAS  Google Scholar 

  39. Nobes, C. D., & Hall, A. (1995). Rho, rac and cdc42 GTPases: regulators of actin structures, cell adhesion and motility. Biochemical Society transactions, 23, 456–459.

    PubMed  CAS  Google Scholar 

  40. Etienne-Manneville, S. (2004). Cdc42-the centre of polarity. J Cell Sci, 117, 1291–1300.

    PubMed  CAS  Google Scholar 

  41. Nakahara, H., Otani, T., Sasaki, T., Miura, Y., Takai, Y., & Kogo, M. (2003). Involvement of Cdc42 and Rac small G proteins in invadopodia formation of RPMI7951 cells. Genes Cells, 8, 1019–1027.

    PubMed  CAS  Google Scholar 

  42. Sakurai-Yageta, M., Recchi, C., Le Dez, G., Sibarita, J. B., Daviet, L., Camonis, J., et al. (2008). The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA. J Cell Biol, 181(6), 985–988.

    PubMed  CAS  Google Scholar 

  43. Schmidt, A., & Hall, A. (2002). Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev, 16, 1587–1609.

    PubMed  CAS  Google Scholar 

  44. Zhou, K., Wang, Y., Gorski, J. L., Nomura, N., Collard, J., & Bokoch, G. M. (1998). Guanine nucleotide exchange factors regulate specificity of downstream signaling from Rac and Cdc42. J Biol Chem, 273, 16782–16786.

    PubMed  CAS  Google Scholar 

  45. Olson, M. F. (1996). Guanine nucleotide exchange factors for the Rho GTPases: a role in human disease? Journal of molecular medicine (Berlin, Germany), 74, 563–571.

    CAS  Google Scholar 

  46. Donaldson, J. G., & Honda, A. (2005). Localization and function of Arf family GTPases. Biochemical Society transactions, 33, 639–642.

    PubMed  CAS  Google Scholar 

  47. Palacios, F., Price, L., Schweitzer, J., Collard, J. G., & D'Souza-Schorey, C. (2001). An essential role for ARF6-regulated membrane traffic in adherens junction turnover and epithelial cell migration. Embo J, 20, 4973–4986.

    PubMed  CAS  Google Scholar 

  48. Hashimoto, S., Onodera, Y., Hashimoto, A., Tanaka, M., Hamaguchi, M., Yamada, A., et al. (2004). Requirement for Arf6 in breast cancer invasive activities. Proc Natl Acad Sci U S A, 101, 6647–6652.

    PubMed  CAS  Google Scholar 

  49. Buccione, R., Orth, J. D., & McNiven, M. A. (2004). Foot and mouth: podosomes, invadopodia and circular dorsal ruffles. Nat Rev Mol Cell Biol, 5, 647–657.

    PubMed  CAS  Google Scholar 

  50. Gimona, M., Buccione, R., Courtneidge, S. A., & Linder, S. (2008). Assembly and biological role of podosomes and invadopodia. Curr Opin Cell Biol, 20(2), 235–241.

    PubMed  CAS  Google Scholar 

  51. Linder, S. (2007). The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends in cell biology, 17, 107–117.

    PubMed  CAS  Google Scholar 

  52. Stylli, S. S., Kaye, A. H., & Lock, P. (2008). Invadopodia: at the cutting edge of tumour invasion. J Clin Neurosci, 15, 725–737.

    PubMed  CAS  Google Scholar 

  53. Cao, H., Weller, S., Orth, J. D., Chen, J., Huang, B., Chen, J. L., et al. (2005). Actin and Arf1-dependent recruitment of a cortactin-dynamin complex to the Golgi regulates post-Golgi transport. Nature cell biology, 7, 483–492.

    PubMed  CAS  Google Scholar 

  54. Weed, S. A., & Parsons, J. T. (2001). Cortactin: coupling membrane dynamics to cortical actin assembly. Oncogene, 20, 6418–6434.

    PubMed  CAS  Google Scholar 

  55. McNiven, M. A., Kim, L., Krueger, E. W., Orth, J. D., Cao, H., & Wong, T. W. (2000). Regulated interactions between dynamin and the actin-binding protein cortactin modulate cell shape. J Cell Biol, 151, 187–198.

    PubMed  CAS  Google Scholar 

  56. Patel, A. S., Schechter, G. L., Wasilenko, W. J., & Somers, K. D. (1998). Overexpression of EMS1/cortactin in NIH3T3 fibroblasts causes increased cell motility and invasion in vitro. Oncogene, 16, 3227–3232.

    PubMed  CAS  Google Scholar 

  57. Bringuier, P. P., Tamimi, Y., Schuuring, E., & Schalken, J. (1996). Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. Oncogene, 12, 1747–1753.

    PubMed  CAS  Google Scholar 

  58. Schuuring, E. (1995). The involvement of the chromosome 11q13 region in human malignancies: cyclin D1 and EMS1 are two new candidate oncogenes—a review. Gene, 159, 83–96.

    PubMed  CAS  Google Scholar 

  59. Hui, R., Ball, J. R., Macmillan, R. D., Kenny, F. S., Prall, O. W., Campbell, D. H., et al. (1998). EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival. Oncogene, 17, 1053–1059.

    PubMed  CAS  Google Scholar 

  60. Uruno, T., Liu, J., Zhang, P., Fan, Y., Egile, C., Li, R., et al. (2001). Activation of Arp2/3 complex-mediated actin polymerization by cortactin. Nature cell biology, 3, 259–266.

    PubMed  CAS  Google Scholar 

  61. van Rossum, A. G., de Graaf, J. H., Schuuring-Scholtes, E., Kluin, P. M., Fan, Y. X., Zhan, X., et al. (2003). Alternative splicing of the actin binding domain of human cortactin affects cell migration. J Biol Chem, 278, 45672–45679.

    PubMed  Google Scholar 

  62. Weaver, A. M., Karginov, A. V., Kinley, A. W., Weed, S. A., Li, Y., Parsons, J. T., et al. (2001). Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr Biol, 11, 370–374.

    PubMed  CAS  Google Scholar 

  63. Weaver, A. M., Young, M. E., Lee, W. L., & Cooper, J. A. (2003). Integration of signals to the Arp2/3 complex. Curr Opin Cell Biol, 15, 23–30.

    PubMed  CAS  Google Scholar 

  64. Martinez-Quiles, N., Ho, H. Y., Kirschner, M. W., Ramesh, N., & Geha, R. S. (2004). Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Molecular and cellular biology, 24, 5269–5280.

    PubMed  CAS  Google Scholar 

  65. Li, Y., Tondravi, M., Liu, J., Smith, E., Haudenschild, C. C., Kaczmarek, M., & Zhan, X. (2001). Cortactin potentiates bone metastasis of breast cancer cells. Cancer research, 61, 6906–6911.

    PubMed  CAS  Google Scholar 

  66. Wu, H., Reynolds, A. B., Kanner, S. B., Vines, R. R., & Parsons, J. T. (1991). Identification and characterization of a novel cytoskeleton-associated pp60src substrate. Molecular and cellular biology, 11, 5113–5124.

    PubMed  CAS  Google Scholar 

  67. Vuori, K., & Ruoslahti, E. (1995). Tyrosine phosphorylation of p130Cas and cortactin accompanies integrin-mediated cell adhesion to extracellular matrix. J Biol Chem, 270, 22259–22262.

    PubMed  CAS  Google Scholar 

  68. Zhan, X., Hu, X., Hampton, B., Burgess, W. H., Friesel, R., & Maciag, T. (1993). Murine cortactin is phosphorylated in response to fibroblast growth factor-1 on tyrosine residues late in the G1 phase of the BALB/c 3T3 cell cycle. J Biol Chem, 268, 24427–24431.

    PubMed  CAS  Google Scholar 

  69. Huang, C., Liu, J., Haudenschild, C. C., & Zhan, X. (1998). The role of tyrosine phosphorylation of cortactin in the locomotion of endothelial cells. J Biol Chem, 273, 25770–25776.

    PubMed  CAS  Google Scholar 

  70. Huang, C., Ni, Y., Wang, T., Gao, Y., Haudenschild, C. C., & Zhan, X. (1997). Down-regulation of the filamentous actin cross-linking activity of cortactin by Src-mediated tyrosine phosphorylation. J Biol Chem, 272, 13911–13915.

    PubMed  CAS  Google Scholar 

  71. Campbell, D. H., Sutherland, R. L., & Daly, R. J. (1999). Signaling pathways and structural domains required for phosphorylation of EMS1/cortactin. Cancer research, 59, 5376–5385.

    PubMed  CAS  Google Scholar 

  72. Wu, H., & Parsons, J. T. (1993). Cortactin, an 80/85-kilodalton pp60src substrate, is a filamentous actin-binding protein enriched in the cell cortex. J Cell Biol, 120, 1417–1426.

    PubMed  CAS  Google Scholar 

  73. Artym, V. V., Zhang, Y., Seillier-Moiseiwitsch, F., Yamada, K. M., & Mueller, S. C. (2006). Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer research, 66, 3034–3043.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  75. Krueger, E. W., Orth, J. D., Cao, H., & McNiven, M. A. (2003). A Dynamin-Cortactin-Arp2/3 Complex Mediates Actin Reorganization in Growth Factor-stimulated Cells. Mol Biol Cell, 14, 1085–1096.

    PubMed  CAS  Google Scholar 

  76. Schafer, D. A. (2002). Coupling actin dynamics and membrane dynamics during endocytosis. Curr Opin Cell Biol, 14, 76–81.

    PubMed  CAS  Google Scholar 

  77. Abram, C. L., Seals, D. F., Pass, I., Salinsky, D., Maurer, L., Roth, T. M., & Courtneidge, S. A. (2003). The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells. J Biol Chem, 278, 16844–16851.

    PubMed  CAS  Google Scholar 

  78. Seals, D. F., Azucena Jr., E. F., Pass, I., Tesfay, L., Gordon, R., Woodrow, M., Resau, J. H., et al. (2005). The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell, 7, 155–165.

    PubMed  CAS  Google Scholar 

  79. Oikawa, T., Itoh, T., & Takenawa, T. (2008). Sequential signals toward podosome formation in NIH-src cells. J Cell Biol, 182, 157–169.

    PubMed  CAS  Google Scholar 

  80. Blouw, B., Seals, D. F., Pass, I., Diaz, B., & Courtneidge, S. A. (2008). A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo. Eur J Cell Biol, 87, 555–567.

    PubMed  CAS  Google Scholar 

  81. Danino, D., & Hinshaw, J. E. (2001). Dynamin family of mechanoenzymes. Curr Opin Cell Biol, 13, 454–460.

    PubMed  CAS  Google Scholar 

  82. McNiven, M. A., Cao, H., Pitts, K. R., & Yoon, Y. (2000). The dynamin family of mechanoenzymes: pinching in new places. Trends Biochem Sci, 25, 115–120.

    PubMed  CAS  Google Scholar 

  83. Hinshaw, J. E. (2000). Dynamin and Its Role in Membrane Fission. Annu Rev Cell Dev Biol, 16, 483–519.

    PubMed  CAS  Google Scholar 

  84. Schmid, S. L., McNiven, M. A., & De Camilli, P. (1998). Dynamin and its partners: a progress report. Curr Opin Cell Biol, 10, 504–512.

    PubMed  CAS  Google Scholar 

  85. Lee, E., & De Camilli, P. (2002). From the Cover: Dynamin at actin tails. Proc Natl Acad Sci U S A, 99, 161–166.

    PubMed  CAS  Google Scholar 

  86. Orth, J. D., Krueger, E. W., Cao, H., & McNiven, M. A. (2002). From the Cover: The large GTPase dynamin regulates actin comet formation and movement in living cells. Proc Natl Acad Sci U S A, 99, 167–172.

    PubMed  CAS  Google Scholar 

  87. Ochoa, G. C., Slepnev, V. I., Neff, L., Ringstad, N., Takei, K., Daniell, L., et al. (2000). A functional link between dynamin and the actin cytoskeleton at podosomes. J Cell Biol, 150, 377–389.

    PubMed  CAS  Google Scholar 

  88. McNiven, M. A., Baldassarre, M., & Buccione, R. (2004). The role of dynamin in the assembly and function of podosomes and invadopodia. Front Biosci, 9, 1944–1953.

    PubMed  CAS  Google Scholar 

  89. Shajahan, A. N., Timblin, B. K., Sandoval, R., Tiruppathi, C., Malik, A. B., & Minshall, R. D. (2004). Role of Src-induced dynamin-2 phosphorylation in caveolae-mediated endocytosis in endothelial cells. J Biol Chem, 279, 20392–20400.

    PubMed  CAS  Google Scholar 

  90. Weaver, A. M. (2006). Invadopodia: Specialized Cell Structures for Cancer Invasion. Clin Exp Metastasis, 23(2), 97–105.

    PubMed  Google Scholar 

  91. Vignjevic, D., & Montagnac, G. (2008). Reorganisation of the dendritic actin network during cancer cell migration and invasion. Semin Cancer Biol, 18, 12–22.

    PubMed  CAS  Google Scholar 

  92. Kindzelskii, A. L., Amhadk, I., Keller, D., Zhou, M. J., Haugland, R. P., Garni-Wagner, B. A., et al. (2004). Pericellular proteolysis by leukocytes and tumor cells on substrates: focal activation and the role of urokinase-type plasminogen activator. Histochem Cell Biol, 121, 299–310.

    PubMed  CAS  Google Scholar 

  93. Nozaki, S., Endo, Y., Nakahara, H., Yoshizawa, K., Ohara, T., & Yamamoto, E. (2006). Targeting urokinase-type plasminogen activator and its receptor for cancer therapy. Anticancer Drugs, 17, 1109–1117.

    PubMed  CAS  Google Scholar 

  94. Dano, K., Behrendt, N., Hoyer-Hansen, G., Johnsen, M., Lund, L. R., Ploug, M., et al. (2005). Plasminogen activation and cancer. Thromb Haemost, 93, 676–681.

    PubMed  CAS  Google Scholar 

  95. Egeblad, M., & Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer, 2, 161–174.

    PubMed  CAS  Google Scholar 

  96. Seiki, M. (2003). Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion. Cancer Lett, 194, 1–11.

    PubMed  CAS  Google Scholar 

  97. Sounni, N. E., Janssen, M., Foidart, J. M., & Noel, A. (2003). Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis. Matrix Biol, 22, 55–61.

    PubMed  CAS  Google Scholar 

  98. Holmbeck, K., Bianco, P., Yamada, S., & Birkedal-Hansen, H. (2004). MT1-MMP: a tethered collagenase. J Cell Physiol, 200, 11–19.

    PubMed  CAS  Google Scholar 

  99. Seiki, M., & Yana, I. (2003). Roles of pericellular proteolysis by membrane type-1 matrix metalloproteinase in cancer invasion and angiogenesis. Cancer Sci, 94, 569–574.

    PubMed  CAS  Google Scholar 

  100. Nakahara, H., Howard, L., Thompson, E. W., Sato, H., Seiki, M., Yeh, Y., et al. (1997). Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc Natl Acad Sci USA, 94, 7959–7964.

    PubMed  CAS  Google Scholar 

  101. Galvez, B. G., Matias-Roman, S., Yanez-Mo, M., Sanchez-Madrid, F., & Arroyo, A. G. (2002). ECM regulates MT1-MMP localization with beta1 or alphavbeta3 integrins at distinct cell compartments modulating its internalization and activity on human endothelial cells. J Cell Biol, 159, 509–521.

    PubMed  CAS  Google Scholar 

  102. Baciu, P. C., Suleiman, E. A., Deryugina, E. I., & Strongin, A. Y. (2003). Membrane type-1 matrix metalloproteinase (MT1-MMP) processing of pro-alphav integrin regulates cross-talk between alphavbeta3 and alpha2beta1 integrins in breast carcinoma cells. Exp Cell Res, 291, 167–175.

    PubMed  CAS  Google Scholar 

  103. Fujiwara, T., Oda, K., Yokota, S., Takatsuki, A., & Ikehara, Y. (1988). Brefeldin A causes disassembly of the Golgi complex and accumulation of secretory proteins in the endoplasmic reticulum. J Biol Chem, 263, 18545–18552.

    PubMed  CAS  Google Scholar 

  104. Steffen, A., Le Dez, G., Poincloux, R., Recchi, C., Nassoy, P., Rottner, K., et al. (2008). MT1-MMP-Dependent Invasion Is Regulated by TI-VAMP/VAMP7. Curr Biol, 18, 926–931.

    PubMed  CAS  Google Scholar 

  105. Gimona, M., & Buccione, R. (2006). Adhesions that mediate invasion. Int J Biochem Cell Biol, 38, 1875–1892.

    PubMed  CAS  Google Scholar 

  106. Linder, S., & Aepfelbacher, M. (2003). Podosomes: adhesion hot-spots of invasive cells. Trends in cell biology, 13, 376–385.

    PubMed  CAS  Google Scholar 

  107. Hai, C. M., Hahne, P., Harrington, E. O., & Gimona, M. (2002). Conventional protein kinase C mediates phorbol-dibutyrate-induced cytoskeletal remodeling in a7r5 smooth muscle cells. Exp Cell Res, 280, 64–74.

    PubMed  CAS  Google Scholar 

  108. Osiak, A. E., Zenner, G., & Linder, S. (2005). Subconfluent endothelial cells form podosomes downstream of cytokine and RhoGTPase signaling. Exp Cell Res, 307, 342–353.

    PubMed  CAS  Google Scholar 

  109. Spinardi, L., Rietdorf, J., Nitsch, L., Bono, M., Tacchetti, C., Way, M., et al. (2004). A dynamic podosome-like structure of epithelial cells. Exp Cell Res, 295, 360–374.

    PubMed  CAS  Google Scholar 

  110. Wolf, K., Friedl, P. (2008). Mapping proteolytic cancer cell-extracellular matrix interfaces. Clin Exp Metastasis.

  111. Wolf, K., Wu, Y. I., Liu, Y., Geiger, J., Tam, E., Overall, C., Stack, M. S., & Friedl, P. (2007). Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nature cell biology, 9, 893–904.

    PubMed  CAS  Google Scholar 

  112. Wolf, K., & Friedl, P. (2005). Functional imaging of pericellular proteolysis in cancer cell invasion. Biochimie, 87, 315–320.

    PubMed  CAS  Google Scholar 

  113. Jurdic, P., Saltel, F., Chabadel, A., & Destaing, O. (2006). Podosome and sealing zone: specificity of the osteoclast model. Eur J Cell Biol, 85, 195–202.

    PubMed  CAS  Google Scholar 

  114. Burgstaller, G., & Gimona, M. (2005). Podosome-mediated matrix resorption and cell motility in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol, 288, H3001–3005.

    PubMed  CAS  Google Scholar 

  115. Saltel, F., Destaing, O., Bard, F., Eichert, D., & Jurdic, P. (2004). Apatite-mediated actin dynamics in resorbing osteoclasts. Mol Biol Cell, 15, 5231–5241.

    PubMed  CAS  Google Scholar 

  116. Alexander, N. R., Branch, K. M., Parekh, A., Clark, E. S., Iwueke, I. C., Guelcher, S. A., et al. (2008). Extracellular Matrix Rigidity Promotes Invadopodia Activity. Curr Biol, 18(17), 1295–1299.

    PubMed  CAS  Google Scholar 

  117. Beningo, K. A., Dembo, M., & Wang, Y. L. (2004). Responses of fibroblasts to anchorage of dorsal extracellular matrix receptors. Proc Natl Acad Sci U S A, 101, 18024–18029.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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Acknowledgements

Work from the Authors’ laboratory was supported by grants to RB from the Italian Association for Cancer Research (AIRC, Milano, Italy), the European Commission (contract LSHC-CT-2004-503049), the Ministero della Salute (Ricerca finalizzata (Art. 12 bis D.Lvo 502/92) and the Fondazione Cassa di Risparmio della Provincia di Teramo. GC was supported by a fellowship from the “Calogero Musarra” Foundation.

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  1. Department of Cell Biology and Oncology, Tumor Cell Invasion Laboratory, Consorzio Mario Negri Sud, S. Maria Imbaro, (, Chieti, ), 66030, Italy

    Roberto Buccione, Giusi Caldieri & Inmaculada Ayala

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  1. Roberto Buccione
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  2. Giusi Caldieri
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  3. Inmaculada Ayala
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Correspondence to Roberto Buccione.

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Buccione, R., Caldieri, G. & Ayala, I. Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev 28, 137–149 (2009). https://doi.org/10.1007/s10555-008-9176-1

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Keywords

  • Invadopodia
  • Cell adhesion
  • Cell invasion
  • Extracellular matrix degradation