Integrin-Extracellular Matrix Interactions

  • Christie J. Avraamides
  • Judith A. Varner
Part of the The Tumor Microenvironment book series (TTME, volume 4)


The extracellular matrix is an essential component of the tumor microenvironment that promotes tumor development and metastasis. Fibroblasts, endothelial cells and other stromal cells deposit extracellular matrix and growth factors that promote the growth and spread of cancer cells. Changes in the composition or architecture of the extracellular matrix within tumors can alter integrin expression and function and promote metastatic progression, angiogenesis and lymphangiogenesis. Since integrins and extracellular matrix molecules provide tumor cells with survival signals, increased blood flow and avenues for metastatic escape, suppression of integrin or extracellular matrix protein expression or function may be useful in the treatment of cancer.


Focal Adhesion Kinase Small Cell Lung Carcinoma Lymphatic Endothelial Cell Secrete Growth Factor Tumor Lymphangiogenesis 
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.


  1. Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nature Rev Mol Cell Biol 8:464–478CrossRefGoogle Scholar
  2. Arnaout MA, Mahalingam B, Xiong JP (2005) Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 21:381–410PubMedCrossRefGoogle Scholar
  3. Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8:604–617PubMedCrossRefGoogle Scholar
  4. Ayad S, Boot-Handford RP, Humphries MJ, Kadler KE, Shuttleworth CA (1994) The extracellular matrix. Academic, San DiegoGoogle Scholar
  5. Bader BL, Rayburn H, Crowley D, Hynes RO (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all [alpha]v integrins. Cell 95:507–519PubMedCrossRefGoogle Scholar
  6. Beglova N, Blacklow SC, Takagi J, Springer TA (2002) Cysteine-rich module structure reveals a fulcrum for integrin rearrangement upon activation. Nature Struct Biol 9:282–287PubMedCrossRefGoogle Scholar
  7. Beier UH, Holtmeier C, Weise JB, Gorogh T (2007) Fibronectin suppression in head and neck cancers, inflammatory tissues and the molecular mechanisms potentially involved. Int J Oncol 30:621–629PubMedGoogle Scholar
  8. Bhaskar V, Zhang D, Fox M, Seto P, Wong MH, Wales PE, Powers D, Chao DT, Dubridge RB, Ramakrishnan V (2007) A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 5:61PubMedCrossRefGoogle Scholar
  9. Bhaskar V, Fox M, Breinberg D, Wong MH, Wales PE, Rhodes S, DuBridge RB, Ramakrishnan V (2008) Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Invest New Drugs 26:7–12PubMedCrossRefGoogle Scholar
  10. Boudreau NJ, Varner JA (2004) The homeobox transcription factor Hox D3 promotes integrin [alpha]5[beta]1 expression and function during angiogenesis. J Biol Chem 279:4862–4868PubMedCrossRefGoogle Scholar
  11. Brooks PC, Clark RA, Cheresh DA (1994a) Requirement of vascular integrin [alpha]v[beta]3 for angiogenesis. Science 264:569–571CrossRefGoogle Scholar
  12. Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA (1994b) Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164CrossRefGoogle Scholar
  13. Brooks PC, Stromblad S, Klemke R, Visscher D, Sarkar FH, Cheresh DA (1995) Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 96:1815–1822PubMedCrossRefGoogle Scholar
  14. Brooks PC, Klemke RL, Schon S, Lewis JM, Schwartz MA, Cheresh DA (1997) Insulin-like growth factor receptor cooperates with integrin alpha v beta 5 to promote tumor cell dissemination in vivo. J Clin Invest 99:1390–1398PubMedCrossRefGoogle Scholar
  15. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 42:932–936CrossRefGoogle Scholar
  16. Caswell PT, Spence HJ, Parsons M, White DP, Clark K, Cheng KW, Mills GB, Humphries MJ, Messent AJ, Anderson KI, McCaffrey MW, Ozanne BW, Norman JC (2007) Rab25 associates with alpha5beta1 integrin to promote invasive migration in 3D microenvironments. Dev Cell 13:496–510PubMedCrossRefGoogle Scholar
  17. Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, Jahnke K, Hauschild A, Hirakawa S, Mihm MC, Detmar M (2005) Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol 18:1232–1242PubMedCrossRefGoogle Scholar
  18. Desgrosellier JS, Barnes LA, Shields DJ, Huang M, Lau SK, Prevost N, Tarin D, Shattil SJ, Cheresh DA (2009) An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med (in press)Google Scholar
  19. Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S, Hemler ME, Lobb RR (1990) VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60:577–584PubMedCrossRefGoogle Scholar
  20. Ferreira M, Fujiwara H, Morita K, Watt FM (2009) An activating beta1 integrin mutation increases the conversion of benign to malignant skin tumors. Cancer Res 69:1334–1342PubMedCrossRefGoogle Scholar
  21. Figlin RA, Kondagunta GV, Yazji S, Motzer RJ, Bukowski RM (2006) Phase II study of volociximab (M200), an [alpha]5[beta]1 anti-integrin antibody in refractory metastatic clear cell renal cell cancer (RCC). J Clin Oncol ASCO Annu Meeting Proc 24:4535Google Scholar
  22. Friedl P, Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10:445–457PubMedCrossRefGoogle Scholar
  23. Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA (1995) Definition of two angiogenic pathways by distinct alpha v integrins. Science 270:1500–1502PubMedCrossRefGoogle Scholar
  24. Friedlander M, Theesfeld CL, Sugita M, Fruttiger M, Thomas MA, Chang S, Cheresh DA (1996) Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases. Proc Natl Acad Sci U S A 93:9764–9769PubMedCrossRefGoogle Scholar
  25. Fu Y, Ponce ML, Thill M, Yuan P, Wang NS, Csaky KG (2007) Angiogenesis inhibition and choroidal neovascularization suppression by sustained delivery of an integrin antagonist, EMD478761. Invest Ophthalmol Vis Sci 48:5184–5190PubMedCrossRefGoogle Scholar
  26. Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9:1392–1400PubMedCrossRefGoogle Scholar
  27. Garmy-Susini B, Jin H, Zhu Y, Sung RJ, Hwang R, Varner J (2005) Integrin [alpha]4[beta]1-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J Clin Invest 115:1542–1551PubMedCrossRefGoogle Scholar
  28. Ghajar CM, Bissell MJ (2008) Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging. Histochem Cell Biol 130:1105–1118PubMedCrossRefGoogle Scholar
  29. Gosslar U, Jonas P, Luz A, Lifka A, Naor D, Hamann A, Holzmann B (1996) Predominant role of alpha 4-integrins for distinct steps of lymphoma metastasis. Proc Natl Acad Sci U S A 93:4821–4826PubMedCrossRefGoogle Scholar
  30. Grabovsky V, Feigelson S, Chen C, Bleijs DA, Peled A, Cinamon G, Baleux F, Arenzana-Seisdedos F, Lapidot T, van Kooyk Y, Lobb RR, Alon R (2000) Subsecond induction of [alpha]4 integrin clustering by immobilized chemokines stimulates leukocyte tethering and rolling on endothelial vascular cell adhesion molecule 1 under flow conditions. J Exp Med 192:495–506PubMedCrossRefGoogle Scholar
  31. Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, Cheresh DA (2000) Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin [alpha]v[beta]3. Clin Cancer Res 6:3056–3061PubMedGoogle Scholar
  32. Hersey P, Sosman J, O’Day S, Richards J, Bedikian A, Gonzalez R, Sharfman W, Weber R, Logan T, Kirkwood JM (2005) A phase II, randomized, open-label study evaluating the antitumor activity of MEDI-522, a humanized monoclonal antibody directed against the human [alpha]v[beta]3 ([alpha]v[beta]3) integrin, [plusmn] dacarbazine (DTIC) in patients with metastatic melanoma. J Clin Oncol 2005 ASCO Annu Meeting Proc 23:7507Google Scholar
  33. Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201:1089–1099PubMedCrossRefGoogle Scholar
  34. Huang XZ, Wu JF, Ferrando R, Lee JH, Wang YL, Farese RV Jr, Sheppard D (2000) Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1. Mol Cell Biol 20:5208–5215PubMedCrossRefGoogle Scholar
  35. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedCrossRefGoogle Scholar
  36. Kalluri R (2003) Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3:422–433PubMedCrossRefGoogle Scholar
  37. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401PubMedCrossRefGoogle Scholar
  38. Kaspar M, Zardi L, Neri D (2006) Fibronectin as target for tumor therapy. Int J Cancer 118:1331–1339PubMedCrossRefGoogle Scholar
  39. Kim S, Bell K, Mousa SA, Varner JA (2000) Regulation of angiogenesis in vivo by ligation of integrin [alpha]5[beta]1 with the central cell-binding domain of fibronectin. Am J Pathol 156:1345–1362PubMedCrossRefGoogle Scholar
  40. Kuwada SK (2007) Drug evaluation: volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr Opin Mol Ther 9:92–98PubMedGoogle Scholar
  41. Liao YF, Gotwals PJ, Koteliansky VE, Sheppard D, Van De Water L (2002) The EIIIA segment of fibronectin is a ligand for integrins [alpha]9[beta]1 and [alpha]4[beta]1 providing a novel mechanism for regulating cell adhesion by alternative splicing. J Biol Chem 277:14467–14474PubMedCrossRefGoogle Scholar
  42. Lin EY, Pollard JW (2007) Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res 67:5064–5066PubMedCrossRefGoogle Scholar
  43. Lu C, Takagi J, Springer TA (2001) Association of the membrane proximal regions of the [alpha] and [beta] subunit cytoplasmic domains constrains an integrin in the inactive state. J Biol Chem 276:14642–14648PubMedCrossRefGoogle Scholar
  44. Magnusson MK, Mosher DF (1998) Fibronectin: structure, assembly, and cardiovascular implications. Arterioscler Thromb Vasc Biol 18:1363–1370PubMedCrossRefGoogle Scholar
  45. Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV (2006) Integrin signaling is critical for pathological angiogenesis. J Exp Med 203:2495–2507PubMedCrossRefGoogle Scholar
  46. Manabe R, Ohe N, Maeda T, Fukuda T, Sekiguchi K (1997) Modulation of cell-adhesive activity of fibronectin by the alternatively spliced EDA segment. J Cell Biol 139:295–307PubMedCrossRefGoogle Scholar
  47. Marastoni S, Ligresti G, Lorenzon E, Colombatti A, Mongiat M (2008) Extracellular matrix: a matter of life and death. Connect Tissue Res 49:203–206PubMedCrossRefGoogle Scholar
  48. Matsuura N, Puzon-McLaughlin W, Irie A, Morikawa Y, Kakudo K, Takada Y (1996) Induction of experimental bone metastasis in mice by transfection of integrin alpha 4 beta 1 into tumor cells. Am J Pathol 148:55–61PubMedGoogle Scholar
  49. McNeel DG, Eickhoff J, Lee FT, King DM, Alberti D, Thomas JP, Friedl A, Kolesar J, Marnocha R, Volkman J, Zhang J, Hammershaimb L, Zwiebel JA, Wilding G (2005) Phase I trial of a monoclonal antibody specific for [alpha]v[beta]3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion. Clin Cancer Res 11:7851–7860PubMedCrossRefGoogle Scholar
  50. Mercurio AM (2002) Lessons from the alpha2 integrin knockout mouse. Am J Pathol 161:3–6PubMedCrossRefGoogle Scholar
  51. Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R, Noonan DM, Natali PG, Albini A (2000) The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int J Cancer 87:336–42PubMedCrossRefGoogle Scholar
  52. Mosher DF (1984) Physiology of fibronectin. Annu Rev Med 35:561–575PubMedCrossRefGoogle Scholar
  53. Muether PS, Dell S, Kociok N, Zahn G, Stragies R, Vossmeyer D, Joussen AM (2007) The role of integrin [alpha]5[beta]1 in the regulation of corneal neovascularization. Exp Eye Res 85:356–365PubMedCrossRefGoogle Scholar
  54. Muro AF, Moretti FA, Moore BB, Yan M, Atrasz RG, Wilke CA, Flaherty KR, Martinez FJ, Tsui JL, Sheppard D, Baralle FE, Toews GB, White ES (2008) An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med 177:638–645PubMedCrossRefGoogle Scholar
  55. Nyberg P, Salo T, Kalluri R (2008) Tumor microenvironment and angiogenesis. Front Biosci 13:6537–6553PubMedCrossRefGoogle Scholar
  56. Okada T, Hawley RG, Kodaka M, Okuno H (1999) Significance of VLA-4-VCAM-1 interaction and CD44 for transendothelial invasion in a bone marrow metastatic myeloma model. Clin Exp Metastasis 17:623–629PubMedCrossRefGoogle Scholar
  57. Peng C, Liu X, Liu E, Xu K, Niu W, Chen R, Wang J, Zhang Z, Lin P, Wang J, Agrez M, Niu J (2009) Norcantharidin induces HT-29 colon cancer cell apoptosis through the alphavbeta6-extracellular signal-related kinase signaling pathway. Cancer Sci 100(12):2302–2308Google Scholar
  58. Perentes JY, McKee TD, Ley CD, Mathiew H, Dawson M, Padera TP, Munn LL, Jain RK, Boucher Y (2009) In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts. Nat Methods 6:143–145PubMedCrossRefGoogle Scholar
  59. Pytela R, Pierschbacher MD, Ruoslahti E (1985) Identification and isolation of a 140 kd cell surface glycoprotein with properties expected of a fibronectin receptor. Cell 40:191–198PubMedCrossRefGoogle Scholar
  60. Ramos DM, But M, Regezi J, Schmidt BL, Atakilit A, Dang D, Ellis D, Jordan R, Li X (2002) Expression of integrin beta 6 enhances invasive behavior in oral squamous cell carcinoma. Matrix Biol 21:297–307PubMedCrossRefGoogle Scholar
  61. Ritzenthaler JD, Han S, Roman J (2008) Stimulation of lung carcinoma cell growth by fibronectin-integrin signalling. Mol Biosyst 4:1160–1169PubMedCrossRefGoogle Scholar
  62. Robertson JH, Yang SY, Winslet MC, Seifalian AM (2009) Functional blocking of specific integrins inhibit colonic cancer migration. Clin Exp Metastasis (in press)Google Scholar
  63. Roma AA, Magi-Galluzzi C, Kral MA, Jin TT, Klein EA, Zhou M (2006) Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma. Mod Pathol 19:392–398PubMedCrossRefGoogle Scholar
  64. Schmid MC, Varner JA (2007) Myeloid cell trafficking and tumor angiogenesis. Cancer Lett 250:1–8PubMedCrossRefGoogle Scholar
  65. Schnapp LM, Hatch N, Ramos DM, Klimanskaya IV, Sheppard D, Pytela R (1995) The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. J Biol Chem 270:23196–23202PubMedCrossRefGoogle Scholar
  66. Shibue T, Weinberg RA (2009) Integrin beta1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc Natl Acad Sci U S A 106:10290–10295PubMedCrossRefGoogle Scholar
  67. Shoulders MD, Raines RT et al (2009) Collagen structure and stability. Annu Rev Biochem 78:929–958PubMedCrossRefGoogle Scholar
  68. Staniszewska I, Zaveri S, Del Valle L, Oliva I, Rothman VL, Croul SE, Roberts DD, Mosher DF, Tuszynski GP, Marcinkiewicz C (2007) Interaction of [alpha]9[beta]1 integrin with thrombospondin-1 promotes angiogenesis. Circ Res 100:1308–1316PubMedCrossRefGoogle Scholar
  69. Stupack DG (2005) Integrins as a distinct subtype of dependence receptors. Cell Death Differ 12:1021–1030PubMedCrossRefGoogle Scholar
  70. Takada Y, Wayner EA, Carter WG, Hemler ME (1988) Extracellular matrix receptors, ECMRII and ECMRI, for collagen and fibronectin correspond to VLA-2 and VLA-3 in the VLA family of heterodimers. J Cell Biochem 37:385–393PubMedCrossRefGoogle Scholar
  71. Tang J, Wu YM, Zhao P, Yang XM, Jiang JL, Chen ZN (2008) Overexpression of HAb18G/CD147 promotes invasion and metastasis via alpha3beta1 integrin mediated FAK-paxillin and FAK-PI3K-Ca2+ pathways. Cell Mol Life Sci 65:2933–2942PubMedCrossRefGoogle Scholar
  72. Tanjore H, Zeisberg EM, Gerami-Naini B, Kalluri R (2007) [beta]1 integrin expression on endothelial cells is required for angiogenesis but not for vasculogenesis. Dev Dyn 237:75–82CrossRefGoogle Scholar
  73. Umeda N, Kachi S, Akiyama H, Zahn G, Vossmeyer D, Stragies R, Campochiaro PA (2006) Suppression and regression of choroidal neovascularization by systemic administration of an [alpha]5[beta]1 integrin antagonist. Mol Pharmacol 69:1820–1828PubMedCrossRefGoogle Scholar
  74. Villa A, Trachsel E, Kaspar M, Schliemann C, Sommavilla R, Rybak JN, Rosli C, Borsi L, Neri D (2008) A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo-vasculature in vivo. Int J Cancer 122:2405–2413PubMedCrossRefGoogle Scholar
  75. Vinogradova O, Velyvis A, Velyviene A, Hu B, Haas T, Plow E, Qin J (2002) A structural mechanism of integrin [alpha]IIb[beta]3 [ldquo]inside-out[rdquo] activation as regulated by its cytoplasmic face. Cell 110:587–597PubMedCrossRefGoogle Scholar
  76. Vlahakis NE, Young BA, Atakilit A, Sheppard D (2005) The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin [alpha]9[beta]1. J Biol Chem 280:4544–4552PubMedCrossRefGoogle Scholar
  77. Vlahakis NE, Young BA, Atakilit A, Sheppard D (2007) Integrin [alpha]9[beta]1 directly binds to vascular endothelial growth factor (VEGF)-A and contributes to VEGF-A-induced angiogenesis. J Biol Chem 282:15187–15196PubMedCrossRefGoogle Scholar
  78. Vogel BE, Tarone G, Giancotti FG, Gailit J, Ruoslahti E (1990) A novel fibronectin receptor with an unexpected subunit composition (alpha v beta 1). J Biol Chem 265:5934–5937PubMedGoogle Scholar
  79. Weinacker A, Ferrando R, Elliott M, Hogg J, Balmes J, Sheppard D (1995) Distribution of integrins alpha v beta 6 and alpha 9 beta 1 and their known ligands, fibronectin and tenascin, in human airways. Am J Respir Cell Mol Biol 12:547–556PubMedGoogle Scholar
  80. Yao ES, Zhang H, Chen YY, Lee B, Chew K, Moore D, Park C (2007) Increased beta1 integrin is associated with decreased survival in invasive breast cancer. Cancer Res 67:659–664PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Moores UCSD Cancer CenterUniversity of California, San DiegoLa JollaUSA
  2. 2.Department of MedicineUniversity of California, San DiegoLa JollaUSA

Personalised recommendations