Integrins and Cancer

  • Laurie G. Hudson
  • M. Sharon Stack
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Integrins are heterodimeric transmembrane glycoproteins that bind extracellular matrix (ECM) proteins and thereby functionally couple the cytoskeleton to the extracellular environment. The relationship between integrins and cancer has been widely studied as malignant cells alter not only integrin expression and organization, but properties of the surrounding ECM as well. Although integrin cytoplasmic tails lack direct kinase activity, interaction with multiple adaptor proteins enables the assembly of signaling complexes that result in the activation of focal adhesion kinase (FAK) or integrin-linked kinase (ILK). These phosphorylation events trigger downstream signaling pathways that activate a variety of cellular responses key to tumor progression including survival, proliferation, motility, and invasion. In addition, gene expression changes induced by integrin signaling have been implicated in epithelial-to-mesenchymal transition (EMT), most notably via downregulation of E-cadherin expression and function. Emerging evidence that integrin-mediated ECM adhesion is inherently a mechanosensory process also supports a role for integrin-mediated mechanotransduction in tumor progression and metastasis. Together these studies suggest that integrin-directed therapeutics combined with strategies designed to target the mechanical properties of the ECM and restore normal tissue architecture may provide new options as single agent or combined anticancer therapies.


Focal Adhesion Kinase Epithelial Ovarian Cancer Connective Tissue Growth Factor Integrin Signaling Epithelial Ovarian Cancer Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by National Institutes of Health/National Cancer Institutes Research Grants CA109545 (MSS, LGH), CA086984 (MSS), CA085870 (MSS), and GM079381 (LGH).


  1. Acconica F, Barnes CJ, Singh RR et al (2007) Phosphorylation dependent regulation of nuclear localization and functions of integrin linked kinase. Proc Natl Acad Sci USA 104:6782–6787Google Scholar
  2. Ahmed N, Riley C, Rice G et al (2005) Role of integrin receptors for fibronectin, collagen and laminin in the regulation of ovarian carcinoma functions in response to a matrix microenvironment. Clin Exp Metastasis 22:391–402PubMedGoogle Scholar
  3. Al-Jemal R, Harrison DJ (2008) Beta1 integrin in tissue remodeling and repair: from phenomena to concepts. Pharmacol Therapeut 120:81–101Google Scholar
  4. Alexander, NR, Tran, NL, Rekapally et al (2006). N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res 66:3365–3369Google Scholar
  5. Avvisato CL et al (2007) Mechanical force modulates global gene expression and b-catenin signaling in colon cancer cells. J Cell Sci 120:2672–2682PubMedGoogle Scholar
  6. Azzam HS, Thompson EW (1992) Collagen-induced activation of the M(r) 72,000 type IV collagenase in normal and malignant human fibroblatoid cells. Cancer Res 52:4540–4544PubMedGoogle Scholar
  7. Baker EL, Zaman MH (2010) The biomechanical integrin. J Biomech 43:38–44Google Scholar
  8. Barbolina MV, Adley BP, Ariztia EV et al (2007) Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression. J Biol Chem 282:4924–4931PubMedGoogle Scholar
  9. Barbolina MV, Stack MS (2008) Membrane type 1-matrix metalloproteinase: substrate diversity in pericellular proteolysis. Semin Cell Dev Biol 19:24–33PubMedGoogle Scholar
  10. Barbolina MV, Adley BP, Kelly DL et al (2008) Motility-related actinin alpha-4 is associated with advanced and metastatic ovarian carcinoma. Lab Invest 88:602–614PubMedGoogle Scholar
  11. Barbolina MV, Adley BP, Kelly DL et al (2009) Downregulation of connective tissue growth factor by three-dimensional matrix enhances ovarian carcinoma cell invasion. Int J Cancer 125:816–825PubMedGoogle Scholar
  12. Barbolina MV, Moss NM, Westfall SD et al (2010) Microenvironmental regulation of ovarian cancer metastasis. Cancer Treat Res 149:319–334Google Scholar
  13. Berrier AL, Yamada KM (2007) Cell-matrix adhesion. J Cell Physiol 213:563–573Google Scholar
  14. Bershadsky AD, Balaban NQ, Geiger B (2003) Adhesion-dependent cell mechanosensitivity. Ann Rev Cell Dev Biol 19:677–695Google Scholar
  15. Bierele EA, Trujillo A, Nagaram A et al (2008) TAE226 inhibits human neuroblastoma cell survival. Cancer Invest 26:145–151Google Scholar
  16. Brabletz T, Jung A, Spaderna S et al (2005) Opinion: migrating cancer stem cells – an integrated concept of malignant tumour progression. Nat Rev Cancer 5:744–749PubMedGoogle Scholar
  17. Burleson KM, Hansen LK and Skubitz APN (2004a) Ovarian carcinoma spheroids disaggregate on type I collagen and invade live human mesothelial cell monolayers. Clin Exp Mets 21:685–697Google Scholar
  18. Burleson KM, Casey RC, Skubitz KM et al (2004b) Ovarian carcinoma ascites spheroids adhere to extracellular matrix components and mesothelial cell monolayers. Gynecol Oncol 93:170–181PubMedGoogle Scholar
  19. Burleson KM, Boente MP, Pambuccian SE et al (2006) Disaggregation and invasion of ovarian carcinoma ascites spheroids. J Transl Med 4:1–16Google Scholar
  20. Butcher DT, Alliston T, Weaver VM (2009) A tense situation: forcing tumor progression. Nat Rev Cancer 9:108–122PubMedGoogle Scholar
  21. Cance WG, Harris JE, Iacocca MV et al (2000) Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes. Clin Cancer Res 6:2417–2423PubMedGoogle Scholar
  22. Cannistra SA, Kansas GS, Niloff J et al Binding of ovarian cancer cells to peritoneal mesothelium in vitro is partly mediated by CD44H (1993) Cancer Res 53:3830–3838PubMedGoogle Scholar
  23. Castello-Cross R, Khan DR, Simons J et al (2009) Stages stromal extracellular 3D matrices differentially regulate breast cancer cell responses through PI3K and beta1-integrins. BMC Cancer 26:94Google Scholar
  24. Chicurel M, Singer RH, Meyer C et al (1998) Integrin binding and mechanical tension induce moement of mRNA and ribosomes to focal adhesions. Nature 392:730–733PubMedGoogle Scholar
  25. Christiansen JJ, Rajasekaran AK (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66:8319–8326PubMedGoogle Scholar
  26. Chunthapong J, Seftor E, Khalkhali-Ellis Z et al (2004) Dual roles of E-cadherin in prostate cancer invasion. J Cell Biochem 91:649–661PubMedGoogle Scholar
  27. Cowden Dahl KD, Symowicz J, Ning Y et al (2008) Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells. Cancer Res 68:4606–4613PubMedGoogle Scholar
  28. Delcommenne M, Tan C, Gray V et al (1998) Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 95:11211–11216PubMedGoogle Scholar
  29. Dubash AD, Menold MM, Samson T et al (2009) Focal adhesions: new angles on an old structure. Int Rev Cell Mol Biol 277:1–65PubMedGoogle Scholar
  30. Edwards LA et al (2005) Inhibition of OLK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis and delays tumor growth. Oncogene 24:3596–3605PubMedGoogle Scholar
  31. Ellerbroek SM, Fishman DA, Kearns AS et al (1999) Ovarian carcinoma regulation of matrix metalloproteinase 2 and membrane type 1 matrix metalloproteinase through beta 1 integrin. Cancer Res 59:1635–1641PubMedGoogle Scholar
  32. Ellerbroek SM, Wu YI, Overall CM et al (2001) Functional interplay between type I collagen and cell surface matrix metalloproteinase activity. J Biol Chem 276:24833–24842PubMedGoogle Scholar
  33. Fielding AB et al (2008) Integrin linked kinase localizes to the centrosome and regulates mitotic spindle organization. J Cell Biol 180:681–689PubMedGoogle Scholar
  34. Fielding AB, Dedhar S. (2009) The mitotic functions of integrin linked kinase. Cancer Mets Rev 28:99–111Google Scholar
  35. Fishman DA, Kearns AM, Chilikuri K et al (1998) Metastatic dissemination of human ovarian epithelial carcinoma is promoted by α2β1 integrin-mediated interaction with type I collagen. Invasion Mets 18:15–26Google Scholar
  36. Friedl P, Wolf K (2009) Proteolytic interstitial cell migration: a five-step process. Cancer Metastasis Rev 28:129–135PubMedGoogle Scholar
  37. Frisch SM, Vuori K, Ruoslahti E et al (1996) Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 134:793–799PubMedGoogle Scholar
  38. Gálvez BG, Matías-Román S, Yáñez-Mó M et al (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 159:509–521PubMedGoogle Scholar
  39. Giehl K, Menke A (2008) Microenvironmental regulation of E-cadherin-mediated adherens junctions. Front Biosci 13:3975–3985PubMedGoogle Scholar
  40. Giene RS, Hendzel MJ (2008) Mechanotransduction from the ECM to the genome: are the pieces now in place? J Cell Biochem 104:1964–1987Google Scholar
  41. Gilles C, Polette M, Seiki M et al (1997) Implication of collagen type I-induced membrane-type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activaiton in the metastatic progression of breast carcinoma. Lab Invest 76:651–660PubMedGoogle Scholar
  42. Golubovskaya VM, Virnig C, Cance WG (2008) TAE226-induced apoptosis in breast cancer cells with overexpressed Src or EGFR. Mol Carcinog 47:222–234PubMedGoogle Scholar
  43. Goulioumis AK, Bravou V, Varakis J et al (2008) Integrin linked kinase cytoplasmic and nuclear expression in laryngeal carcinomas. Virchows Arch 453:511–519PubMedGoogle Scholar
  44. Grashoff C, Aszódi A, Sakai T et al (2003) Integrin-linked kinase regulates chondrocyte shape and proliferation. EMBO Rep 4:432–438PubMedGoogle Scholar
  45. Guan JL, Trevithick JE, Hynes RO (1991) Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120 kDa protein. Cell Regul 2:951–964PubMedGoogle Scholar
  46. Guan JL, Shalloway D (1992) Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 358:690–692PubMedGoogle Scholar
  47. Guarino M, Rubino B, Ballabio G (2007) The role of epithelial-mesenchymal transition in cancer pathology. Pathology 39:305–318PubMedGoogle Scholar
  48. Halder J, Lin YG, Merritt WM et al (2007) Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res 67:10976–10983PubMedGoogle Scholar
  49. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedGoogle Scholar
  50. Harburger DS, Calderwood DA (2009) Integrin signalling at a glance. J Cell Sci 122:159–163PubMedGoogle Scholar
  51. Hay ED (2005) EMT concept and examples from the vertebrate embryo. In: Savagner P (ed) Rise and fall of epithelial phenotype: concepts of epithelial-mesenchymal transition. Springer, Berlin, pp 111–134Google Scholar
  52. Holmbeck K, Bianco P, Caterina J et al (1999) MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99:81–92PubMedGoogle Scholar
  53. Huang S, Ingber DE (2005) Cell tension, matrix mechanics, and cancer development. Cancer Cell 8:175–176PubMedGoogle Scholar
  54. Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119:3901–3903PubMedGoogle Scholar
  55. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedGoogle Scholar
  56. Illic D, Furuta Y, Kanazawa S et al (1995) Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-defieicnt mice. Nature 377:539–544Google Scholar
  57. Imamichi Y, König A, Gress T et al (2007) Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer. Oncogene 26:2381–2385PubMedGoogle Scholar
  58. Ingber DE (2002) Cancer as a disease of epithelial-mesenchymal interactions and extracellular matrix regulation. Differentiation 70:547–560PubMedGoogle Scholar
  59. Ingber DE (2003a) Tensegrity I. Cell structure and hierarchical systems biology. J Cell Sci 116:1157–1173PubMedGoogle Scholar
  60. Ingber DE (2003b) Tensegrity II. How structural networks influence cellular information processing networks. J Cell Sci 116:1397–1408PubMedGoogle Scholar
  61. Ingber DE (2006) Cellular mechanotransduction: putting all the pieces together again. FASEB J 20:811–827PubMedGoogle Scholar
  62. Ingber DE (2008) Can cancer be reversed by engineering the tumor microenvironment? Semin Cancer Biol 18:356–364PubMedGoogle Scholar
  63. Jaalouk DE, Lammerding J (2009) Mechanotransduction gone awry. Nat Rev Mol Cell Biol 10:63–73PubMedGoogle Scholar
  64. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428PubMedGoogle Scholar
  65. Katsumi A, Orr AW, Tzima E et al (2004) Integrins in mechano-transduction. J Biol Chem 279:12001–12004PubMedGoogle Scholar
  66. Kenny HA, Krausz T, Yamada SD et al (2007) Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extracellular matrices on adhesion and invasion of ovarian cancer cells to the omentum. Int J Cancer 121:1463–1472PubMedGoogle Scholar
  67. Kim YB, Yu J, lee SY et al (2005) Cell adhesion status-dependent histone acetylation is regulated through intracellular contractility-related signaling activities. J Biol Chem 280:28357–28364PubMedGoogle Scholar
  68. Koenig A, Mueller C, Hasel C et al (2006) Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. Cancer Res 66:4662–4671PubMedGoogle Scholar
  69. Kornberg LJ, Earp HS, Turner CE et al (1991) Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Nat Acad Sci USA 88:8392–8396PubMedGoogle Scholar
  70. Kumar S, Weaver VM (2009) Mechanics, malignancy and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev 28:113–127PubMedGoogle Scholar
  71. Lark AL, Livasy CA, Dressler L et al (2005) High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype. Mod Pathol 18:1289–1294PubMedGoogle Scholar
  72. Larsen M, Artym VV, Green JA et al (2006) The matrix reorganized: extracellular matrix remodeling and integrin signaling. Curr Opin Cell Biol 18:463–471PubMedGoogle Scholar
  73. Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84:359–369PubMedGoogle Scholar
  74. LeBeyec J, Xu R, Lee SY et al (2007) Cell shape regulates global histone acetylation in human mammary epithelial cells. Exp Cell Res 313:3066–3075Google Scholar
  75. Lee KH, Choi EY, Hyun MS et al (2007) Association of extracellular cleavage of E-cadherin mediated by MMP-7 with HGF-induced in vitro invasion in human stomach cancer cells. Eur Surg Res 39:208–215PubMedGoogle Scholar
  76. Legate KR, Fässler R (2009) Mechanisms that regulate adaptor binding to beta-integrin cytoplasmic tails. J Cell Sci 122:187–198PubMedGoogle Scholar
  77. Lelievre SA (2009) Contributions of extracellular matrix signaling and tissue architecture to nuclear mechanisms and spatial organization of gene expression control. Biochim Biophys Acta 1790:925–935PubMedGoogle Scholar
  78. Lim ST, Chen XL, Lim Y et al (2008a) Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell 29:9–22PubMedGoogle Scholar
  79. Lim ST, Mikolon D, Stupack DG et al (2008b) FERM control of FAK function: implications for cancer therapy. Cell Cycle 7:2306–2314PubMedGoogle Scholar
  80. Liu WF, Nelson CM, Pirone DM et al (2006) E-cadherin engagement stimulates proliferation via Rac1. J Cell Biol 173:431–441PubMedGoogle Scholar
  81. Liu TJ, LaFortune T, Honda T et al (2007) Inhibition of both focal adhesion kinase and insulin-like growth factor I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther 6:1357–1367PubMedGoogle Scholar
  82. Lorenz K, Grashoff C, Torka R et al (2007) Integrin-linked kinase is required for epidermal and hair follicle morphogenesis. J Cell Biol 177:501–513PubMedGoogle Scholar
  83. Luo BH, Springer TA (2006) Integrin structures and conformational signaling. Curr Opin Cell Biol 18:579–586PubMedGoogle Scholar
  84. Makale M (2008) Cellular mechanobiology and cancer metastasis. Birth Defects Res 81:329–343Google Scholar
  85. McDonald PC, Fielding AB, Dedhar S. (2008) Integrin linked kinase—essential roles in physiology and cancer biology. J Cell Sci 121:3121–3132PubMedGoogle Scholar
  86. McLean GW, Carragher N, Avizienyte E et al (2005) The role of focal adhesion kinase in cancer – a new therapeutic opportunity. Nat Rev Cancer 5:505–515PubMedGoogle Scholar
  87. Meyer CJ, Alenghat FJ, Rim P et al (2000) Mechanical control of cyclic AMP signaling and gene transcription through activated integrins. Nat Cell Biol 2:666–668PubMedGoogle Scholar
  88. Mitra SK, Schlaepfer DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18:516–523PubMedGoogle Scholar
  89. Miyamoto S, Teramoto H, Coso OA et al (1995) Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol 131:791–805PubMedGoogle Scholar
  90. Moreno-Bueno G, Portillo F, Cano A (2008) Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27:6958–6969PubMedGoogle Scholar
  91. Moser TL, Pizzo SV, Bafetti LM et al (1996) Evidence for preferential adhesion of ovarian epithelial carcinoma cells to type I collagen mediated by the alpha2beta1 integrin. Int J Cancer 67:695–701PubMedGoogle Scholar
  92. Moss NM, Barbolina MV, Liu Y et al (2009) Ovarian cancer cell detachment and multicellular aggregate formation are regulated by membrane type 1 matrix metalloproteinase: a potential role in I.p. metastatic dissemination. Cancer Res 69:7121–7129PubMedGoogle Scholar
  93. Munshi HG, Stack MS (2006) Reciprocal interactions between adhesion receptor signaling and MMP regulation. Cancer Metastasis Rev 25:45–56PubMedGoogle Scholar
  94. Nakrieko KA, Vespa A, Mason D et al (2008) Modulation of integrin linked kinase nucleo-cytoplasmic shuttling by ILKAP and CRM1. Cell Cycle 15:2157–2166Google Scholar
  95. Nawrocki-Raby B, Gilles C, Polette M et al (2003) Upregulation of MMPs by soluble E-cadherin in human lung tumor cells. Int J Cancer 105:790–795PubMedGoogle Scholar
  96. Legate KR, Wickström SA, Fässler R (2009) Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev 23:397–418PubMedGoogle Scholar
  97. Niu, RF, Zhang L, Xi GM et al (2007) Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 26:385–394PubMedGoogle Scholar
  98. Novak A, Hus SC, Leung-Hagesteijn C et al (1998) Cell adhesion and the integrin linked kinase regulate the LEF1 and beta catenin signaling pathways. Proc Natl Acad Sci USA 95:4374–4379PubMedGoogle Scholar
  99. Oloumi A, Syam S, Dedhar S. (2006) Modulation of Wnt3a-mediated nuclear beta-catenin accumulation and activation by integrin-linked kinase in mammalian cells. Oncogene 25:7747–7757PubMedGoogle Scholar
  100. Orlichenko LS, Radisky DC (2008) Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin Exp Metastasis 25:593–600PubMedGoogle Scholar
  101. Orr AW, Helmke BP, Blackman BR et al (2006) Mechanisms of mechanotransduction. Dev Cell 10:11–20PubMedGoogle Scholar
  102. Owens LV, Xu L, Craven FJ et al (1995) Overexprssion of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res 55:2752–2755PubMedGoogle Scholar
  103. Paszek MJ, Zahir N, Johnson KR et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254PubMedGoogle Scholar
  104. Persad S, Troussard AA, McPhee TR et al (2001) Tumor suppressor PTEN inhibits nuclear accumulation of b-catenin and TCF1 mediated transcriptional activation. J Cell Biol 153:1161–1174PubMedGoogle Scholar
  105. Radisky DC, Levy DD et al (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123–127PubMedGoogle Scholar
  106. Reichelt J (2007) Mechanotransduction of keratinocytes in culture and in the epidermis. Eur J Cell Biol 86:807–816PubMedGoogle Scholar
  107. Roberts WG, Ung E, Whalen P et al (2008) Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor PF-562,271. Cancer Res 68:1935–1944PubMedGoogle Scholar
  108. Rowe RG, Weiss SJ (2008) Breaching the basement membrane: who, when and how? Trends Cell Biol 18:560–574PubMedGoogle Scholar
  109. Sakai T, Li S, Docheva D, Grashoff C et al (2003) Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation. Genes Dev 17:926–940PubMedGoogle Scholar
  110. Schaller MD, Borgman CA, Cobb BS et al (1992) pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 89:5192–5196PubMedGoogle Scholar
  111. Schwartz MA, DeSimone DW (2008) Cell adhesion receptors in mechano-transduction. Curr Opin Cell Bol 20:551–556Google Scholar
  112. Shen TL, Park AYJ, Alcaraz A et al (2005) Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol 169:941–952PubMedGoogle Scholar
  113. Shi Q, Hjelmeland AB, Keir ST (2007) A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. Mol Carcinog 46:488–496PubMedGoogle Scholar
  114. Sherwood DR (2006) Cell invasion through basement membranes: an anchor of understanding. Trends Cell Biol 16:250–256PubMedGoogle Scholar
  115. Shintani Y, Fukumoto Y, Chaika N et al (2008). Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1. J Cell Biol 180:1277–1289PubMedGoogle Scholar
  116. Shintani Y, Hollingsworth MA, Wheelock MJ et al (2006) Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res 66:11745–11753PubMedGoogle Scholar
  117. Siu LL, Burris HA, Mileshkin L et al (2007) Phase 1 study of a focal adhesion kinase (FAK) inhibitor PF-00562271 in patients with advanced solid tumors. J Clin Oncol 25:3527Google Scholar
  118. Sternlicht MsD, Bissell MJ, Werb Z (2000). The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene 19:1102–1113PubMedGoogle Scholar
  119. Suresh S (2007) Biomechanics and biophysics of cancer cells. Acta Biomater 3:413–438PubMedGoogle Scholar
  120. Symowicz J, Adley BP, Gleason KJ et al (2007) Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res 67:2030–2039PubMedGoogle Scholar
  121. Terpstra L, Prud’homme J, Arabian A et al (2003) Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes. J Cell Biol 162:139–148PubMedGoogle Scholar
  122. Thiery JP, Acloque H, Huang RY et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890PubMedGoogle Scholar
  123. Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101:816–829PubMedGoogle Scholar
  124. van Nimwegen MJ, van de Water B (2007) Focal adhesion kinase: a potential target in cancer therapy. Biochem Pharmacol 73:597–609PubMedGoogle Scholar
  125. Wang N, Tytell JD, Ingber DE (2009) Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat Rev Mol Cell Biol 10:75–83PubMedGoogle Scholar
  126. Watanabe N, Takaoka M, Sakurama K et al (2008) Dual tyrosine kinase inhibitor for focal adhesion kinase and insulin-like growth factor I receptor exhibits anticancer effect in esophageal adenocarcinoma in vitro and in vivo. Clin Cancer Res 14:4631–4639PubMedGoogle Scholar
  127. Weiner TM, Liu ET, Craven RJ et al (1993) Expression of focal adhesion kinase gene in invasive cancer. Lancet 342:1024–1025PubMedGoogle Scholar
  128. Wells A, Yates C, Shepard CR (2008) E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 25:621–628PubMedGoogle Scholar
  129. Wheelock MJ, Buck CA, Bechtol KB et al (1987) Soluble 80-kd fragment of cell-CAM 120/80 disrupts cell:cell adhesion. J Cell Biochem 34:187–202PubMedGoogle Scholar
  130. Wheelock MJ, Shintani Y, Maeda M et al (2008) Cadherin switching. J Cell Sci 121:727–735PubMedGoogle Scholar
  131. Wolf K, Friedl P (2009) Mapping proteolytic cancer cell-extracellular matrix interfaces. Clin Exp Metastasis 26:289–298PubMedGoogle Scholar
  132. Wolf K, Mazo I, Leung H et al (2003) Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol 160:267–277PubMedGoogle Scholar
  133. Wolf K et al (2007) Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9:893–904PubMedGoogle Scholar
  134. Wong RPC et al (2007) The role of integrin-linked kinase in melanoma cell migration, invasion and tumor growth. Mol Cancer Ther 6:1692–1700PubMedGoogle Scholar
  135. Wu C, Dedhar S (2001) Integrin linked kinase and its interactors: a new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes. J Cell Biol 12:505–510Google Scholar
  136. Yamada KM, Cukierman E (2007) Modeling tissue morphogenesis and cancer in 3D. Cell 130:601–610PubMedGoogle Scholar
  137. Yan C, Boyd DD (2007) Regulation of matrix metalloproteinase gene expression. J Cell Physiol 211:19–26PubMedGoogle Scholar
  138. Yang Z, Zhang X, Gang H et al (2007) Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun 358:925–930PubMedGoogle Scholar
  139. Yau CY, Wheeler JJ, Sutton KL et al (2005) Inhibition of integrin linked kinase by a selective small molecule inhibitor QLT0254 inhibits the PI3K/PKB/mRTOR, Stat3 and FKHR pathways and tumor growth, and enhances gemcitabine-induec apoptosis in human orthotopic primary pancreatic cell exnografts. Cancer Res 654:1497–1504Google Scholar
  140. Yilmaz M, Christofori G (2009) EMT, the cytoskeleton and cancer cell invasion. Cancer Metastasis Rev 28:15–33PubMedGoogle Scholar
  141. Younes MN, Yigitbasi OG, Yazici YD et al (2007) Effects of the integrin-linked kinase inhibitor ZLT0267 on squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 133:15–23PubMedGoogle Scholar
  142. Zeisberg M, Neilson EG (2009). Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119:1429–1437PubMedGoogle Scholar
  143. Zhao J, Guan JL (2009) Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev 28:35–49PubMedGoogle Scholar
  144. Zutter MM (2007) Integrin-mediated adhesion: tipping the balance between chemosensitivity and chemoresistance. Adv Exp Med Biol 608:87–100PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Pathology & Anatomical Sciences, Medical Physiology and PharmacologyUniversity of Missouri School of MedicineColumbiaUSA

Personalised recommendations