Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Extracellular Matrix in Tumor Biology

Part of the book series: Biology of Extracellular Matrix ((BEM))

  • 894 Accesses

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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):1032–1044

    Article  CAS  PubMed  Google Scholar 

  • Akiyama SK, Olden K, Yamada KM (1995) Fibronectin and integrins in invasion and metastasis. Cancer Metastasis Rev 14(3):173–189

    Article  CAS  PubMed  Google Scholar 

  • Albig AR (2006) Fibulins 3 and 5 antagonize tumor angiogenesis in vivo. Cancer Res 66:2621–2629

    Article  CAS  PubMed  Google Scholar 

  • 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):367–379

    Article  CAS  PubMed  Google Scholar 

  • 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):41–48

    Article  CAS  PubMed  Google Scholar 

  • 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):57–72

    Article  CAS  PubMed  Google Scholar 

  • Bachem MG et al (2005) Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128(4):907–921

    Article  CAS  PubMed  Google Scholar 

  • Beck K, Hunter I, Engel J (1990) Structure and function of laminin: anatomy of a multidomain glycoprotein. FASEB J 4(2):148–160

    CAS  PubMed  Google Scholar 

  • 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 24:90–96

    Article  PubMed  Google Scholar 

  • Bhaskar V et al (2007) A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 5:61

    Article  PubMed  PubMed Central  Google Scholar 

  • Bhaskar V et al (2008) Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Investig New Drugs 26(1):7–12

    Article  CAS  Google Scholar 

  • Blum R, Kloog Y (2014) Metabolism addiction in pancreatic cancer. Cell Death Dis 5:e1065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15(4):255–273

    Article  CAS  PubMed  Google Scholar 

  • Bornstein P, Sage EH (2002) Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 14(5):608–616

    Article  CAS  PubMed  Google Scholar 

  • 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 30:68–74

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen HC, Guan JL (1994) Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 91(21):10148–10152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):933–944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiquet-Ehrismann R et al (1988) Tenascin interferes with fibronectin action. Cell 53(3):383–390

    Article  CAS  PubMed  Google Scholar 

  • 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):269–276

    Article  CAS  PubMed  Google Scholar 

  • Costa-Silva B et al (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17:816–826

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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):721–729

    Article  PubMed  PubMed Central  Google Scholar 

  • 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–G1147

    Article  CAS  PubMed  Google Scholar 

  • Eliceiri BP (2001) Integrin and growth factor receptor crosstalk. Circ Res 89(12):1104–1110

    Article  CAS  PubMed  Google Scholar 

  • Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13(5):555–562

    Article  CAS  PubMed  Google Scholar 

  • Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • George EL et al (1993) Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119(4):1079–1091

    CAS  PubMed  Google Scholar 

  • Giancotti FG (1999) Integrin signaling. Science 285:1028–1033

    Article  CAS  PubMed  Google Scholar 

  • 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 286:7093–7103

    Article  CAS  PubMed  Google Scholar 

  • Guadamillas MC, Cerezo A, Del Pozo MA (2011) Overcoming anoikis – pathways to anchorage-independent growth in cancer. J Cell Sci 124(Pt 19):3189–3197

    Article  CAS  PubMed  Google Scholar 

  • 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):315–323

    Article  CAS  PubMed  Google Scholar 

  • Harburger DS, Calderwood DA (2009) Integrin signalling at a glance. J Cell Sci 122(Pt 2):159–163

    Article  CAS  PubMed  Google Scholar 

  • Heo JH et al (2015) Fibulin-5 is a tumour suppressor inhibiting cell migration and invasion in ovarian cancer. J Clin Pathol 69:109–116

    Article  PubMed  Google Scholar 

  • 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):1345–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holmstrom KM, Finkel T (2014) Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15(6):411–421

    Article  CAS  PubMed  Google Scholar 

  • 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):8586–8594

    CAS  PubMed  Google Scholar 

  • 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):e84218

    Article  PubMed  PubMed Central  Google Scholar 

  • Itano N, Zhuo L, Kimata K (2008) Impact of the hyaluronan-rich tumor microenvironment on cancer initiation and progression. Cancer Sci 99(9):1720–1725

    Article  CAS  PubMed  Google Scholar 

  • 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):788–798

    Article  CAS  PubMed  Google Scholar 

  • 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):1345–1362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kowal RC et al (1999) EVEC, a novel epidermal growth factor like repeat-containing protein upregulated in embryonic and diseased adult vasculature. Circ Res 84:1166–1176

    Article  CAS  PubMed  Google Scholar 

  • Krieglstein CF et al (2002) Collagen-binding integrin alpha1beta1 regulates intestinal inflammation in experimental colitis. J Clin Invest 110(12):1773–1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–C1421

    Article  CAS  PubMed  Google Scholar 

  • Kuwada SK (2007) Drug evaluation: Volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr Opin Mol Ther 9(1):92–98

    CAS  PubMed  Google Scholar 

  • Kyriakides TR, Bornstein P (2003) Matricellular proteins as modulators of wound healing and the foreign body response. Thromb Haemost 90(6):986–992

    CAS  PubMed  Google Scholar 

  • Lamalice L, Le Boeuf F, Huot J (2007) Endothelial cell migration during angiogenesis. Circ Res 100(6):782–794

    Article  CAS  PubMed  Google Scholar 

  • Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18(7):816–827

    Article  CAS  PubMed  Google Scholar 

  • 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 29:2243–2251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lipfert L et al (1992) Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets. J Cell Biol 119(4):905–912

    Article  CAS  PubMed  Google Scholar 

  • Liu X et al (2004) Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet 36(2):178–182

    Article  CAS  PubMed  Google Scholar 

  • 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):2113–2118

    Article  CAS  PubMed  Google Scholar 

  • 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):417–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196:395–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahadevan D, Von Hoff DD (2007) Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther 6:1186–1197

    Article  CAS  PubMed  Google Scholar 

  • Mao Y et al (2013) Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32(1-2):303–315

    Article  PubMed  PubMed Central  Google Scholar 

  • Masur SK et al (1995) Integrin-dependent tyrosine phosphorylation in corneal fibroblasts. Invest Ophthalmol Vis Sci 36(9):1837–1846

    CAS  PubMed  Google Scholar 

  • Mithieux SM, Weiss AS (2005) Elastin. Adv Protein Chem 70:437–461

    Article  CAS  PubMed  Google Scholar 

  • 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):38–44

    Article  CAS  PubMed  Google Scholar 

  • Murphy-Ullrich JE et al (1993) Heparin-binding peptides from thrombospondins 1 and 2 contain focal adhesion-labilizing activity. J Biol Chem 268(35):26784–26789

    CAS  PubMed  Google Scholar 

  • 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):22467–22483

    Article  Google Scholar 

  • Nakamura T et al (2002) Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 415(6868):171–175

    Article  CAS  PubMed  Google Scholar 

  • Nguyen AD et al (2004) Fibulin-5 is a novel binding protein for extracellular superoxide dismutase. Circ Res 95(11):1067–1074

    Article  CAS  PubMed  Google Scholar 

  • Nicosia RF, Bonanno E, Smith M (1993) Fibronectin promotes the elongation of microvessels during angiogenesis in vitro. J Cell Physiol 154(3):654–661

    Article  CAS  PubMed  Google Scholar 

  • Pankov R (2002) Fibronectin at a glance. J Cell Sci 115:3861–3863

    Article  CAS  PubMed  Google Scholar 

  • 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):273–286

    CAS  PubMed  Google Scholar 

  • Ramaswamy S et al (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33(1):49–54

    Article  CAS  PubMed  Google Scholar 

  • Reuter S et al (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49:1603–1616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ricart AD (2008) Volociximab, a chimeric monoclonal antibody that specifically binds α5β1 integrin: a phase I, pharmacokinetic, and biological correlative study. Clin Cancer Res 14:7924–7929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaffner F, Ray A, Dontenwill M (2013) Integrin α5β1, the fibronectin receptor, as a pertinent therapeutic target in solid tumors. Cancer 5:27–47

    Article  CAS  Google Scholar 

  • 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 277:27367–27377

    Article  CAS  PubMed  Google Scholar 

  • Schlaepfer DD et al (1994) Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372(6508):786–791

    Article  CAS  Google Scholar 

  • 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 3:333–342

    Article  CAS  Google Scholar 

  • 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 7:787–791

    Article  CAS  PubMed  Google Scholar 

  • Stenman S, Vaheri A (1981) Fibronectin in human solid tumors. Int J Cancer 27(4):427–435

    Article  CAS  PubMed  Google Scholar 

  • Sullivan KM et al (2007) Fibulin-5 functions as an endogenous angiogenesis inhibitor. Lab Invest 87:818–827

    Article  CAS  PubMed  Google Scholar 

  • 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 21:11127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Topalovski M, Brekken RA (2015) Matrix control of pancreatic cancer: new insights into fibronectin signaling. Cancer Lett 381:252–258

    Google Scholar 

  • Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8(7):579–591

    Article  CAS  PubMed  Google Scholar 

  • Vogel WF (2001) Collagen-receptor signaling in health and disease. Eur J Dermatol 11(6):506–514

    CAS  PubMed  Google Scholar 

  • Wang M et al (2015) Fibulin-5 blocks microenvironmental ROS in pancreatic cancer. Cancer Res 75(23):5058–5069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17(11):1359–1370

    Article  CAS  PubMed  Google Scholar 

  • Wong GS, Rustgi AK (2013) Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis. Br J Cancer 108(4):755–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):e35378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yanagisawa H et al (2002) Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415(6868):168–171

    Article  PubMed  Google Scholar 

  • Yanagisawa H, Schluterman MK, Brekken RA (2009) Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. J Cell Commun Signal 3:337–347

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang JT, Rayburn H, Hynes RO (1993) Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development 119(4):1093–1105

    CAS  PubMed  Google Scholar 

  • Yue W et al (2009) Fibulin-5 auppresses lung cancer invasion by inhibiting matrix metalloproteinase-7 expression. Cancer Res 69:6339–6346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao JC et al (2012) Cooperation between Polycomb and androgen receptor during oncogenic transformation. Genome Res 22(2):322–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu JW et al (2002) Upregulation of vascular endothelial growth factor by hydrogen peroxide in human colon cancer. World J Gastroenterol 8(1):153–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA

    Mary Topalovski & Rolf A. Brekken

Authors
  1. Mary Topalovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rolf A. Brekken
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rolf A. Brekken .

Editor information

Editors and Affiliations

  1. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center , Dallas, Texas, USA

    Rolf A. Brekken

  2. Department of Reproductive Medicine, University of California , La Jolla, California, USA

    Dwayne Stupack

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Topalovski, M., Brekken, R.A. (2017). The Extracellular Matrix of Tumors: A Focus on Fibronectin and Fibulin-5. In: Brekken, R., Stupack, D. (eds) Extracellular Matrix in Tumor Biology. Biology of Extracellular Matrix. Springer, Cham. https://doi.org/10.1007/978-3-319-60907-2_1

Download citation

Publish with us

Policies and ethics

Search

Navigation