The Extracellular Matrix of Tumors: A Focus on Fibronectin and Fibulin-5

  • Mary Topalovski
  • Rolf A. BrekkenEmail author
Part of the Biology of Extracellular Matrix book series (BEM)


The extracellular matrix (ECM) in tumors is highly dynamic and contributes to tumor evolution. Fibronectin (FN) is a key component of the ECM in tumors that ligates and stimulates integrins on tumor cells, fibroblasts and endothelial cells in the tumor microenvironment. FN induced integrin activity is reduced by fibulin-5 (Fbln5), a matricellular protein that competes with FN for integrin binding but does not stimulate integrin signaling. A consequence of FN-induced integrin activation is the generation of reactive oxygen species (ROS), which can promote cell survival or apoptosis pending the microenvironment. The tumor microenvironment Fbln5 can be viewed as a molecular rheostat that tunes FN stimulated integrin-induced ROS generation.


  1. Aguilera KY et al (2014) Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma. Cancer Res 74(4):1032–1044CrossRefPubMedGoogle Scholar
  2. Akiyama SK, Olden K, Yamada KM (1995) Fibronectin and integrins in invasion and metastasis. Cancer Metastasis Rev 14(3):173–189CrossRefPubMedGoogle Scholar
  3. Albig AR (2006) Fibulins 3 and 5 antagonize tumor angiogenesis in vivo. Cancer Res 66:2621–2629CrossRefPubMedGoogle Scholar
  4. Albig AR, Schiemann WP (2004) Fibulin-5 antagonizes vascular endothelial growth factor (VEGF) signaling and angiogenic sprouting by endothelial cells. DNA Cell Biol 23(6):367–379CrossRefPubMedGoogle Scholar
  5. Alexandre J et al (2006) Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int J Cancer 119(1):41–48CrossRefPubMedGoogle Scholar
  6. Arnold SA et al (2010) Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Model Mech 3(1–2):57–72CrossRefPubMedGoogle Scholar
  7. Bachem MG et al (2005) Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128(4):907–921CrossRefPubMedGoogle Scholar
  8. Beck K, Hunter I, Engel J (1990) Structure and function of laminin: anatomy of a multidomain glycoprotein. FASEB J 4(2):148–160PubMedGoogle Scholar
  9. Besse B et al (2012) Phase Ib safety and pharmacokinetic study of volociximab, an anti- 5 1 integrin antibody, in combination with carboplatin and paclitaxel in advanced non-small-cell lung cancer. Ann Oncol 24:90–96CrossRefPubMedGoogle Scholar
  10. Bhaskar V et al (2007) A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 5:61CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bhaskar V et al (2008) Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Investig New Drugs 26(1):7–12CrossRefGoogle Scholar
  12. Blum R, Kloog Y (2014) Metabolism addiction in pancreatic cancer. Cell Death Dis 5:e1065CrossRefPubMedPubMedCentralGoogle Scholar
  13. Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15(4):255–273CrossRefPubMedGoogle Scholar
  14. Bornstein P, Sage EH (2002) Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 14(5):608–616CrossRefPubMedGoogle Scholar
  15. Chapman SL et al (2009) Fibulin-2 and fibulin-5 cooperatively function to form the internal elastic lamina and protect from vascular injury. Arterioscler Thromb Vasc Biol 30:68–74CrossRefPubMedPubMedCentralGoogle Scholar
  16. Chen HC, Guan JL (1994) Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 91(21):10148–10152CrossRefPubMedPubMedCentralGoogle Scholar
  17. Chiarugi P et al (2003) Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J Cell Biol 161(5):933–944CrossRefPubMedPubMedCentralGoogle Scholar
  18. Chiquet-Ehrismann R et al (1988) Tenascin interferes with fibronectin action. Cell 53(3):383–390CrossRefPubMedGoogle Scholar
  19. Clark RA et al (1982) Blood vessel fibronectin increases in conjunction with endothelial cell proliferation and capillary ingrowth during wound healing. J Invest Dermatol 79(5):269–276CrossRefPubMedGoogle Scholar
  20. Costa-Silva B et al (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17:816–826CrossRefPubMedGoogle Scholar
  21. Cranmer LD, Bedikian A, Ribas A (2005) Phase II study of volociximab (M200), an α5β1 anti-integrin antibody in metastatic melanoma. J Clin Oncol 24 (Abstr 8011)Google Scholar
  22. de Fougerolles AR et al (2000) Regulation of inflammation by collagen-binding integrins alpha1beta1 and alpha2beta1 in models of hypersensitivity and arthritis. J Clin Invest 105(6):721–729CrossRefPubMedPubMedCentralGoogle Scholar
  23. Edderkaoui M et al (2005) Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase. Am J Physiol Gastrointest Liver Physiol 289(6):G1137–G1147CrossRefPubMedGoogle Scholar
  24. Eliceiri BP (2001) Integrin and growth factor receptor crosstalk. Circ Res 89(12):1104–1110CrossRefPubMedGoogle Scholar
  25. Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13(5):555–562CrossRefPubMedGoogle Scholar
  26. Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022CrossRefPubMedPubMedCentralGoogle Scholar
  27. George EL et al (1993) Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119(4):1079–1091PubMedGoogle Scholar
  28. Giancotti FG (1999) Integrin signaling. Science 285:1028–1033CrossRefPubMedGoogle Scholar
  29. Guadall A et al (2011) Fibulin-5 Is Up-regulated by hypoxia in endothelial cells through a hypoxia-inducible factor-1 (HIF-1)-dependent mechanism. J Biol Chem 286:7093–7103CrossRefPubMedGoogle Scholar
  30. Guadamillas MC, Cerezo A, Del Pozo MA (2011) Overcoming anoikis – pathways to anchorage-independent growth in cancer. J Cell Sci 124(Pt 19):3189–3197CrossRefPubMedGoogle Scholar
  31. Han S, Khuri FR, Roman J (2006) Fibronectin stimulates non-small cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways. Cancer Res 66(1):315–323CrossRefPubMedGoogle Scholar
  32. Harburger DS, Calderwood DA (2009) Integrin signalling at a glance. J Cell Sci 122(Pt 2):159–163CrossRefPubMedGoogle Scholar
  33. Heo JH et al (2015) Fibulin-5 is a tumour suppressor inhibiting cell migration and invasion in ovarian cancer. J Clin Pathol 69:109–116CrossRefPubMedGoogle Scholar
  34. Hocevar BA, Brown TL, Howe PH (1999) TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J 18(5):1345–1356CrossRefPubMedPubMedCentralGoogle Scholar
  35. Holmstrom KM, Finkel T (2014) Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15(6):411–421CrossRefPubMedGoogle Scholar
  36. Huang W et al (2001) Interference of tenascin-C with syndecan-4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation. Cancer Res 61(23):8586–8594PubMedGoogle Scholar
  37. Hwang CF et al (2013) Oncogenic fibulin-5 promotes nasopharyngeal carcinoma cell metastasis through the FLJ10540/AKT pathway and correlates with poor prognosis. PLoS One 8(12):e84218CrossRefPubMedPubMedCentralGoogle Scholar
  38. Itano N, Zhuo L, Kimata K (2008) Impact of the hyaluronan-rich tumor microenvironment on cancer initiation and progression. Cancer Sci 99(9):1720–1725CrossRefPubMedGoogle Scholar
  39. Ju HQ et al (2015) Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. Mol Cancer Ther 14(3):788–798CrossRefPubMedGoogle Scholar
  40. Kim S et al (2000) Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 156(4):1345–1362CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kowal RC et al (1999) EVEC, a novel epidermal growth factor like repeat-containing protein upregulated in embryonic and diseased adult vasculature. Circ Res 84:1166–1176CrossRefPubMedGoogle Scholar
  42. Krieglstein CF et al (2002) Collagen-binding integrin alpha1beta1 regulates intestinal inflammation in experimental colitis. J Clin Invest 110(12):1773–1782CrossRefPubMedPubMedCentralGoogle Scholar
  43. Kuang PP et al (2006) Fibulin-5 gene expression in human lung fibroblasts is regulated by TGF-beta and phosphatidylinositol 3-kinase activity. Am J Physiol Cell Physiol 291:C1412–C1421CrossRefPubMedGoogle Scholar
  44. Kuwada SK (2007) Drug evaluation: Volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr Opin Mol Ther 9(1):92–98PubMedGoogle Scholar
  45. Kyriakides TR, Bornstein P (2003) Matricellular proteins as modulators of wound healing and the foreign body response. Thromb Haemost 90(6):986–992PubMedGoogle Scholar
  46. Lamalice L, Le Boeuf F, Huot J (2007) Endothelial cell migration during angiogenesis. Circ Res 100(6):782–794CrossRefPubMedGoogle Scholar
  47. Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18(7):816–827CrossRefPubMedGoogle Scholar
  48. Lee YH et al (2008) Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF- in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis 29:2243–2251CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lipfert L et al (1992) Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets. J Cell Biol 119(4):905–912CrossRefPubMedGoogle Scholar
  50. Liu X et al (2004) Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet 36(2):178–182CrossRefPubMedGoogle Scholar
  51. Loeys B et al (2002) Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet 11(18):2113–2118CrossRefPubMedGoogle Scholar
  52. Lomas AC et al (2007) Fibulin-5 binds human smooth-muscle cells through alpha5beta1 and alpha4beta1 integrins, but does not support receptor activation. Biochem J 405(3):417–428CrossRefPubMedPubMedCentralGoogle Scholar
  53. Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196:395–406CrossRefPubMedPubMedCentralGoogle Scholar
  54. Mahadevan D, Von Hoff DD (2007) Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther 6:1186–1197CrossRefPubMedGoogle Scholar
  55. Mao Y et al (2013) Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32(1-2):303–315CrossRefPubMedPubMedCentralGoogle Scholar
  56. Masur SK et al (1995) Integrin-dependent tyrosine phosphorylation in corneal fibroblasts. Invest Ophthalmol Vis Sci 36(9):1837–1846PubMedGoogle Scholar
  57. Mithieux SM, Weiss AS (2005) Elastin. Adv Protein Chem 70:437–461CrossRefPubMedGoogle Scholar
  58. Miyamoto H et al (2004) Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 28(1):38–44CrossRefPubMedGoogle Scholar
  59. Murphy-Ullrich JE et al (1993) Heparin-binding peptides from thrombospondins 1 and 2 contain focal adhesion-labilizing activity. J Biol Chem 268(35):26784–26789PubMedGoogle Scholar
  60. Nakamura T, Ruiz-Lozano P, Lindner V, Yabe D, Furukawa Y, Taniwaki M, Kobuke K, Tashiro K, Lu Z, Andon NL, Schaub R, Matsumori A, Sasayama S, Chien KR, Honjoa T (1999) DANCE, a novel secreted RGD protein expressed in developing atherosclerotic, and balloon-injured arteries. J Biol Chem 274(32):22467–22483CrossRefGoogle Scholar
  61. Nakamura T et al (2002) Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 415(6868):171–175CrossRefPubMedGoogle Scholar
  62. Nguyen AD et al (2004) Fibulin-5 is a novel binding protein for extracellular superoxide dismutase. Circ Res 95(11):1067–1074CrossRefPubMedGoogle Scholar
  63. Nicosia RF, Bonanno E, Smith M (1993) Fibronectin promotes the elongation of microvessels during angiogenesis in vitro. J Cell Physiol 154(3):654–661CrossRefPubMedGoogle Scholar
  64. Pankov R (2002) Fibronectin at a glance. J Cell Sci 115:3861–3863CrossRefPubMedGoogle Scholar
  65. Ramakrishnan V et al (2006) Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent. J Exp Ther Oncol 5(4):273–286PubMedGoogle Scholar
  66. Ramaswamy S et al (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33(1):49–54CrossRefPubMedGoogle Scholar
  67. Reuter S et al (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49:1603–1616CrossRefPubMedPubMedCentralGoogle Scholar
  68. Ricart AD (2008) Volociximab, a chimeric monoclonal antibody that specifically binds α5β1 integrin: a phase I, pharmacokinetic, and biological correlative study. Clin Cancer Res 14:7924–7929CrossRefPubMedPubMedCentralGoogle Scholar
  69. Schaffner F, Ray A, Dontenwill M (2013) Integrin α5β1, the fibronectin receptor, as a pertinent therapeutic target in solid tumors. Cancer 5:27–47CrossRefGoogle Scholar
  70. Schiemann WP (2002) Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades. J Biol Chem 277:27367–27377CrossRefPubMedGoogle Scholar
  71. Schlaepfer DD et al (1994) Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372(6508):786–791CrossRefGoogle Scholar
  72. Schluterman MK et al (2010) Loss of fibulin-5 binding to 1 integrins inhibits tumor growth by increasing the level of ROS. Dis Models Mech 3:333–342CrossRefGoogle Scholar
  73. Shi X-Y et al (2014) Effect of Fibulin-5 on cell proliferation and invasion in human gastric cancer patients. Asian Pac J Trop Med 7:787–791CrossRefPubMedGoogle Scholar
  74. Stenman S, Vaheri A (1981) Fibronectin in human solid tumors. Int J Cancer 27(4):427–435CrossRefPubMedGoogle Scholar
  75. Sullivan KM et al (2007) Fibulin-5 functions as an endogenous angiogenesis inhibitor. Lab Invest 87:818–827CrossRefPubMedGoogle Scholar
  76. Tang J-C (2015) Effect of fibulin-5 on adhesion, migration and invasion of hepatocellular carcinoma cells via an integrin-dependent mechanism. World J Gastroenterol 21:11127CrossRefPubMedPubMedCentralGoogle Scholar
  77. Topalovski M, Brekken RA (2015) Matrix control of pancreatic cancer: new insights into fibronectin signaling. Cancer Lett 381:252–258Google Scholar
  78. Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8(7):579–591CrossRefPubMedGoogle Scholar
  79. Vogel WF (2001) Collagen-receptor signaling in health and disease. Eur J Dermatol 11(6):506–514PubMedGoogle Scholar
  80. Wang M et al (2015) Fibulin-5 blocks microenvironmental ROS in pancreatic cancer. Cancer Res 75(23):5058–5069CrossRefPubMedPubMedCentralGoogle Scholar
  81. Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17(11):1359–1370CrossRefPubMedGoogle Scholar
  82. Wong GS, Rustgi AK (2013) Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis. Br J Cancer 108(4):755–761CrossRefPubMedPubMedCentralGoogle Scholar
  83. Xiang L et al (2012) The extra domain A of fibronectin increases VEGF-C expression in colorectal carcinoma involving the PI3K/AKT signaling pathway. PLoS One 7(4):e35378CrossRefPubMedPubMedCentralGoogle Scholar
  84. Yanagisawa H et al (2002) Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415(6868):168–171CrossRefPubMedGoogle Scholar
  85. Yanagisawa H, Schluterman MK, Brekken RA (2009) Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. J Cell Commun Signal 3:337–347CrossRefPubMedPubMedCentralGoogle Scholar
  86. Yang JT, Rayburn H, Hynes RO (1993) Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development 119(4):1093–1105PubMedGoogle Scholar
  87. Yue W et al (2009) Fibulin-5 auppresses lung cancer invasion by inhibiting matrix metalloproteinase-7 expression. Cancer Res 69:6339–6346CrossRefPubMedPubMedCentralGoogle Scholar
  88. Zhao JC et al (2012) Cooperation between Polycomb and androgen receptor during oncogenic transformation. Genome Res 22(2):322–331CrossRefPubMedPubMedCentralGoogle Scholar
  89. Zhu JW et al (2002) Upregulation of vascular endothelial growth factor by hydrogen peroxide in human colon cancer. World J Gastroenterol 8(1):153–157CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Hamon Center for Therapeutic Oncology ResearchUT Southwestern Medical CenterDallasUSA

Personalised recommendations