• 1
    Folkman J (2006) Antiangiogenesis in cancer therapy – endostatin and its mechanisms of action. Exp Cell Res 312, 594607.
  • 2
    Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438, 932936.
  • 3
    Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148, 399408.
  • 4
    Ruch C, Skiniotis G, Steinmetz MO, Walz T & Ballmer-Hofer K (2007) Structure of a VEGF-VEGF receptor complex determined by electron microscopy. Nat Struct Mol Biol 14, 249250.
  • 5
    Olsson A-K, Dimberg A, Kreuger J & Claesson-Welsh L (2006) VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol 7, 359371.
  • 6
    Franses JW, Baker AB, Chitalia VC & Edelman RE (2011) Stromal endothelial cells directly influence cancer progression. Sci Transl Med 3, 66ra5.
  • 7
    Sitohy B, Nagy JA & Dvorak HF (2012) Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res 72, 19091914.
  • 8
    Casanovas O, Hicklin DJ, Bergers G & Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299309.
  • 9
    Kadenhe-Chiweshe A, Papa J, McCrudden KW, Frischer J, Bae J-O, Huang J, Fisher J, Lefkowitch JH, Feirt N, Rudge J et al. (2008) Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation. Mol Cancer Res 6, 19.
  • 10
    Whitelock JM, Graham LD, Melrose J, Murdoch AD, Iozzo RV & Underwood PA (1999) Human perlecan immunopurified from different endothelial cell sources has different adhesive properties for vascular cells. Matrix Biol 18, 163178.
  • 11
    Farach-Carson MC & Carson DD (2007) Perlecan – a multifunctional extracellular proteoglycan scaffold. Glycobiology 17, 897905.
  • 12
    Nugent MA, Nugent HM, Iozzo RV, Sanchack K & Edelman ER (2000) Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia. Proc Natl Acad Sci USA 97, 67226727.
  • 13
    Kinsella MG, Tran P-K, Weiser-Evens MCM, Reidy M, Majack RA & Wight TN (2003) Changes in perlecan expression during vascular injury. Role in the inhibition of smooth muscle cell proliferation in the late lesion. Arterioscler Thromb Vasc Biol 23, 608614.
  • 14
    Baker AB, Ettenson DS, Jonas M, Nugent MA, Iozzo RV & Edelman ER (2008) Endothelial cells provide feedback control for vascular remodeling through a mechanosensitive autocrine TGF-β signaling pathway. Circ Res 103, 289297.
  • 15
    Rees MD, Whitelock JM, Malle E, Chuang CY, Iozzo RV, Nilasaroya A & Davies MJ (2010) Myeloperoxidase-derived oxidants selectively disrupt the protein core of the heparan sulfate proteoglycan perlecan. Matrix Biol 29, 6373.
  • 16
    Fuki I, Iozzo RV & Williams KJ (2000) Perlecan heparan sulfate proteoglycan. A novel receptor that mediates a distinct pathway for ligand catabolism. J Biol Chem 275, 2574225750.
  • 17
    Iozzo RV, Pillarisetti J, Sharma B, Murdoch AD, Danielson KG, Uitto J & Mauviel A (1997) Structural and functional characterization of the human perlecan gene promoter. Transcriptional activation by transforming factor-β via a nuclear factor 1-binding element. J Biol Chem 272, 52195228.
  • 18
    Inomata T, Ebihara N, Funaki T, Matsuda A, Wantanabe Y, Ning L, Xu Z, Murakami A & Arikawa-Hirasawa E (2012) Perlecan-deficient mutation impairs corneal epithelial structure. Invest Ophthalmol Vis Sci 53, 12771284.
  • 19
    Sher I, Zisman-Rozen S, Eliahu L, Whitelock JM, Maas-Szabowski N, Yamada Y, Breitkreutz D, Fusenig NE, Arikawa-Hirasawa E, Iozzo RV et al. (2006) Targeting perlecan in human keratinocytes reveals novel roles for perlecan in epidermal formation. J Biol Chem 281, 51785187.
  • 20
    Sharma B, Handler M, Eichstetter I, Whitelock J, Nugent MA & Iozzo RV (1998) Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo. J Clin Invest 102, 15991608.
  • 21
    Mathiak M, Yenisey C, Grant DS, Sharma B & Iozzo RV (1997) A role for perlecan in the suppression of growth and invasion in fibrosarcoma cells. Cancer Res 57, 21302136.
  • 22
    Iozzo RV (2005) Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol 6, 646656.
  • 23
    San Antonio JD, Zoeller JJ, Habursky K, Turner K, Pimtong W, Burrows M, Choi S, Basra S, Bennett JS, DeGrado WF et al. (2009) A key role for the integrin α2β1 in experimental and developmental angiogenesis. Am J Pathol 175, 13381347.
  • 24
    Zoeller JJ, Whitelock J & Iozzo RV (2009) Perlecan regulates developmental angiogenesis by modulating the VEGF-VEGFR2 axis. Matrix Biol 28, 284291.
  • 25
    Ishijima M, Suzuki N, Hozumi K, Matsunobu T, Kosaki K, Kaneko H, Hassell JR, Arikawa-Hirasawa E & Yamada Y (2012) Perlecan modulates VEGF signaling and is essential for vascularization in endochondral bone formation. Matrix Biol 31, 234245.
  • 26
    Willis CD, Schaefer L & Iozzo RV (2012) The biology of perlecan and its bioactive modules. In Extracellular Matrix: Pathobiology and Signaling (Karamanos NK, ed.), pp. 171184. Walter de Gruyter, Berlin.
  • 27
    Gustafsson E, Almonte-Becerril M, Bloch W & Costell M (2013) Perlecan maintains microvessel integrity in vivo and modulates their formation in vitro. PLoS One 8, e53715.
  • 28
    Iozzo RV & Cohen I (1993) Altered proteoglycan gene expression and the tumor stroma. Cell Mol Life Sci 49, 447455.
  • 29
    Iozzo RV (1988) Proteoglycans and neoplasia. Cancer Metastasis Rev 7, 3950.
  • 30
    Whitelock JM & Iozzo RV (2005) Heparan sulfate: a complex polymer charged with biological activity. Chem Rev 105, 27452764.
  • 31
    Iozzo RV & Sanderson RD (2011) Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med 15, 10131031.
  • 32
    Aviezer D, Hecht D, Safran M, Eisinger M, David G & Yayon A (1994) Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis. Cell 79, 10051013.
  • 33
    Whitelock JM, Murdoch AD, Iozzo RV & Underwood PA (1996) The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin and heparanases. J Biol Chem 271, 1007910086.
  • 34
    Aviezer D, Iozzo RV, Noonan DM & Yayon A (1997) Suppression of autocrine and paracrine functions of basic fibroblast growth factor by stable expression of perlecan antisense cDNA. Mol Cell Biol 17, 19381946.
  • 35
    Mongiat M, Taylor K, Otto J, Aho S, Uitto J, Whitelock J & Iozzo RV (2000) The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7. J Biol Chem 275, 70957100.
  • 36
    Gonzalez EM, Mongiat M, Slater SJ, Baffa R & Iozzo RV (2003) A novel interaction between perlecan protein core and progranulin: potential effects on tumor growth. J Biol Chem 278, 3811338116.
  • 37
    Iozzo RV & Schaefer L (2010) Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans. FEBS J 277, 38643875.
  • 38
    Bix G & Iozzo RV (2008) Novel interactions of perlecan: unraveling perlecan's role in angiogenesis. Microsc Res 71, 339348.
  • 39
    Mongiat M, Otto J, Oldershaw R, Ferrer F, Sato JD & Iozzo RV (2001) Fibroblast growth factor-binding protein is a novel partner for perlecan protein core. J Biol Chem 276, 1026310271.
  • 40
    Whitelock JM, Melrose J & Iozzo RV (2008) Diverse cell signaling events modulated by perlecan. Biochemistry 47, 1117411183.
  • 41
    Chuang CY, Lord MS, Melrose J, Rees MD, Knox SM, Freeman C, Iozzo RV & Whitelock J (2010) Heparan sulfate-dependent signaling of fibroblast growth growth factor 18 by chondrocyte-derived perlecan. Biochemistry 49, 55245532.
  • 42
    Cohen IR, Murdoch AD, Naso MF, Marchetti D, Berd D & Iozzo RV (1994) Abnormal expression of perlecan proteoglycan in metastatic melanomas. Cancer Res 54, 57715774.
  • 43
    Iozzo RV & San Antonio JD (2001) Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J Clin Invest 108, 349355.
  • 44
    Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS & Iozzo RV (2005) BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J Biol Chem 280, 70807087.
  • 45
    Cailhier J-F, Sirois I, Raymond M-A, Lepage S, Laplante P, Brassard N, Prat A, Iozzo RV, Pshezhetsky AV & Hebért M-J (2008) Caspase-3 activation triggers extracellular release of cathepsin L and endorepellin proteolysis. J Biol Chem 283, 2722027229.
  • 46
    Mongiat M, Sweeney S, San Antonio JD, Fu J & Iozzo RV (2003) Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan. J Biol Chem 278, 42384249.
  • 47
    Bix G & Iozzo RV (2005) Matrix revolutions: ‘tails’ of basement-membrane components with angiostatic functions. Trends Cell Biol 15, 5260.
  • 48
    Iozzo RV, Zoeller JJ & Nyström A (2009) Basement membrane proteoglycans: modulators par excellence of cancer growth and angiogenesis. Mol Cells 27, 503513.
  • 49
    Laplante P, Raymond M-A, Labelle A, Abe J-I, Iozzo RV & Hebért M-J (2006) Perlecan proteolysis induces α2β1 integrin and src-family kinases dependent anti-apoptotic pathway in fibroblasts in the absence of focal adhesion kinase activation. J Biol Chem 281, 3038330392.
  • 50
    Bix G, Fu J, Gonzalez E, Macro L, Barker A, Campbell S, Zutter MM, Santoro SA, Kim JK, Höök M et al. (2004) Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through the α2β1 integrin. J Cell Biol 166, 97109.
  • 51
    Bix G, Castello R, Burrows M, Zoeller JJ, Weech M, Iozzo RA, Cardi C, Thakur MT, Barker CA, Camphausen KC et al. (2006) Endorepellin in vivo: targeting the tumor vasculature and retarding cancer growth and metabolism. J Natl Cancer Inst 98, 16341646.
  • 52
    Bix G, Iozzo RA, Woodall B, Burrows M, McQuillan A, Campbell S, Fields GB & Iozzo RV (2007) Endorepellin, the C-terminal angiostatic module of perlecan, enhances collagen-platelet responses via the α2β1 integrin receptor. Blood 109, 37453748.
  • 53
    Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR & Detmar M (2002) The α1β1 and α2β1 integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol 160, 195204.
  • 54
    Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP & Detmar M (1997) Angiogenesis promoted by vascular endothelial growth factor: regulation through α1β1 and α2β1 integrins. Proc Natl Acad Sci USA 94, 1361213617.
  • 55
    Sweeney SM, DiLullo G, Slater SJ, Martinez J, Iozzo RV, Lauer-Fields JL, Fields GB & San Antonio JD (2003) Angiogenesis in collagen I requires α2β1 ligation of a GFP*GER sequence and possible p38 MAPK activation and focal adhesion disassembly. J Biol Chem 278, 3051630524.
  • 56
    Nyström A, Shaik ZP, Gullberg D, Krieg T, Eckes B, Zent R, Pozzi A & Iozzo RV (2009) Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity. Blood 114, 48974906.
  • 57
    Goyal A, Pal N, Concannon M, Paulk M, Doran M, Poluzzi C, Sekiguchi K, Whitelock JM, Neill T & Iozzo RV (2011) Endorepellin, the angiostatic module of perlecan, interacts with both the α2β1 integrin and vascular endothelial growth factor receptor 2 (VEGFR2). J Biol Chem 286, 2594725962.
  • 58
    Goyal A, Poluzzi C, Willis AC, Smythies J, Shellard A, Neill T & Iozzo RV (2012) Endorepellin affects angiogenesis by antagonizing diverse VEGFR2-evoked signaling pathways: transcriptional repression of HIF-1α and VEGFA and concurrent inhibition of NFAT1 activation. J Biol Chem 287, 4354343556.
  • 59
    Papo N, Silverman AP, Lahti JL & Cochran JR (2011) Antagonistic VEGF variants engineered to simultaneously bind to and inhibit VEGFR2 and αvβ3 integrin. Proc Natl Acad Sci USA 108, 1406714072.
  • 60
    Waltenberger J, Claesson-Welsh L, Siegbhan A, Shibuya M & Heldin C-H (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269, 2698826995.
  • 61
    Kroll J & Waltenberger J (1997) The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem 272, 3252132527.
  • 62
    Ito N & Claesson-Welsh L (1999) Dual effects of heparin on VEGF binding to VEGF receptor-1 and transduction of biological responses. Angiogenesis 3, 159166.
  • 63
    Gluzman-Poltorak Z, Cohen T, Shibuya M & Neufeld G (2001) Vascular endothelial growth factor receptor-1 and neuropilin-2 form complexes. J Biol Chem 276, 1868818694.
  • 64
    Holmes K, Roberts OL, Thomas AM & Cross MJ (2007) Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signalling 19, 20032012.
  • 65
    Murdoch AD, Liu B, Schwarting R, Tuan RS & Iozzo RV (1994) Widespread expression of perlecan proteoglycan in basement membranes and extracellular matrices of human tissues as detected by a novel monoclonal antibody against domain III and by in situ hybridization. J Histochem Cytochem 42, 239249.
  • 66
    Couchman JR, Ljubimov AV, Sthanam M, Horchar T & Hassell JR (1995) Antibody mapping and tissue localization of globular and cysteine-rich regions of perlecan domain III. J Histochem Cytochem 43, 955963.
  • 67
    Handler M, Yurchenco PD & Iozzo RV (1997) Developmental expression of perlecan during murine embryogenesis. Dev Dyn 210, 130145.
  • 68
    Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, Addicks K, Timpl R & Fässler R (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147, 11091122.
  • 69
    Costell M, Carmona R, Gustafsson E, González-Iriarte M, Fässler R & Munoz-Chápuli R (2002) Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice. Circ Res 91, 158164.
  • 70
    Muthusamy A, Cooper CR & Gomes RR Jr (2010) Soluble perlecan domain I enhances vascular endothelial growth factor-165 activity and receptor phosphorylation in human bone marrow endothelial cells. BMC Biochem 11, 43.
  • 71
    Serini G, Napione L & Bussolino F (2008) Integrins team up with tyrosine kinase receptors and plexins to control angiogenesis. Curr Opin Hematol 15, 235242.
  • 72
    Seo D-W, Li H, Guedez L, Windgield PT, Diaz T, Salloum R, Wei B-Y & Stetler-Stevenson WG (2003) TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114, 171180.
  • 73
    Lee S-J, Tsang PS, Diaz TM, Wei B & Stetler-Stevenson WG (2010) TIMP-2 modulates VEGFR-2 phosphorylation and enhances phosphodiesterase activity in endothelial cells. Lab Invest 90, 374382.
  • 74
    Seo D-W, Li H, Qu C-K, Oh J, Kim Y-S, Diaz T, Wei B, Han J-W & Stetler-Stevenson WG (2006) Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells. J Biol Chem 281, 37113721.
  • 75
    Zoeller JJ, McQuillan A, Whitelock J, Ho S-Y & Iozzo RV (2008) A central function for perlecan in skeletal muscle and cardiovascular development. J Cell Biol 181, 381394.
  • 76
    Kim Y-M, Hwang S, Kim Y-M, Pyun B-J, Kim T-Y, Lee S-T, Gho YS & Kwon Y-G (2002) Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1. J Biol Chem 277, 2787227879.
  • 77
    Sakurai Y, Ohgimoto K, Kataoka Y, Yoshida N & Shibuya M (2005) Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc Natl Acad Sci USA 102, 10761081.
  • 78
    Koch S, Tugues S, Li X, Gualandi L & Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437, 169183.
  • 79
    Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA & De Vos AM (1997) Crystal structure at 1.7 Á resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91, 695704.
  • 80
    Xie L, Duncan MB, Pahler J, Sugimoto H, Martino M, Lively J, Mundel T, Soubasakos M, Rubin K, Takeda T et al. (2011) Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner. Proc Natl Acad Sci USA 108, 99399944.
  • 81
    Zhang X, Kazerounian S, Duquette M, Peruzzi C, Nagy JA, Dvorak HF, Parangi S & Lawler J (2009) Thrombospondin-1 modulates vascular endothelial growth factor activity at the receptor level. FASEB J 23, 33683376.
  • 82
    Wickström SA, Alitalo K & Keski-Oja J (2002) Endostatin associates with integrin α5β1 and caveolin-1, and activates src via a tyrosyl phosphatase-dependent pathway in human endothelial cells. Cancer Res 62, 55805589.
  • 83
    Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J et al. (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968972.
  • 84
    Goldoni S, Humphries A, Nyström A, Sattar S, Owens RT, McQuillan DJ, Ireton K & Iozzo RV (2009) Decorin is a novel antagonistic ligand of the Met receptor. J Cell Biol 185, 743754.
  • 85
    Seidler DG, Goldoni S, Agnew C, Cardi C, Thakur ML, Owens RA, McQuillan DJ & Iozzo RV (2006) Decorin protein core inhibits in vivo cancer growth and metabolism by hindering epidermal growth factor receptor function and triggering apoptosis via caspase-3 activation. J Biol Chem 281, 2640826418.
  • 86
    Ryynänen M, Ryynänen J, Solberg S, Iozzo RV, Knowlton RG & Uitto J (1992) Genetic linkage of Type VII collagen (COL7A1) to dominant dystrophic epidermolysis bullosa in families with abnormal anchoring fibrils. J Clin Invest 89, 974980.