Review

Role of cystatins in tumor neovascularization

† Author for correspondence

Louisiana State University Health Sciences Center, Department of Cellular Biology & Anatomy and Feist-Weiller Cancer Center, School of Medicine, Shreveport, 1501 Kings Highway, PO Box 33932, Shreveport, LA 71130, USA.

Search for more papers by this author

Email the corresponding author at dkeppl@lsuhsc.edu

Felipe Sierra

National Institutes of Health/National Institute on Aging, Biology of Aging Program, Building 31, Room 5C27, 31 Center Drive, MSC 2292, Bethesda, MD 20892, USA.

Search for more papers by this author

Email the corresponding author at sierraf@nia.nih.gov

Published Online:22 Sep 2005https://doi.org/10.2217/14796694.1.5.661

View article

Abstract

Cystatins form a large superfamily of proteins with diverse biologic activities. All members of the cystatin superfamily share the presence of one, two or three cystatin domains. Cystatins were initially believed to act mainly as inhibitors of lysosomal cysteine proteases. In recent years, however, there has been increased awareness of additional or alternate biologic functions for these proteins. In this review, the authors will discuss the most recent findings and hypotheses that suggest that some members of the cystatin superfamily may play important roles during tumor progression. Special emphasis is given to their potential role as novel anti-angiogenic agents.

Keywords:

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

Bibliography

1 Anastasi A, Brown MA, Kembhavi AA et al.: Cystatin, a protein inhibitor of cysteine proteinases. Improved purification from egg white, characterization, and detection in chicken serum. Biochem. J.211, 129–138 (1983)Crossref, Medline, CAS, Google Scholar
2 Turk V, Bode W: The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett.285,213–219 (1991).Crossref, Medline, CAS, Google Scholar
3 Bromme D, Kaleta J: Thiol-dependent cathepsins: pathophysiological implications and recent advances in inhibitor design. Curr. Pharm. Des.8(18), 1639–1658 (2002).Crossref, Medline, CAS, Google Scholar
4 Rawlings ND, Barrett AJ: Evolution of proteins of the cystatin superfamily. J. Mol. Evol.30, 60–71 (1990).Crossref, Medline, CAS, Google Scholar
5 Keppler D: Towards novel anticancer strategies based on cystatin function. Cancer Lett. In Press (E-Pub ahead, May 10, 2005).Google Scholar
6 Bode W, Engh R, Musil D et al.: The 2.0 A x-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. EMBO J.7, 2593–2599 (1988).•• The first high-resolution crystal structure of a cystatin.Crossref, Medline, CAS, Google Scholar
7 Turk B, Dolenc I, Turk V, Bieth JG: Kinetics of the pH-induced inactivation of human cathepsin L. Biochemistry32, 375, (1993).Google Scholar
8 Turk B, Dolenc I, Zerovnik E, Turk D, Gubensek F, Turk V: Human cathepsin B is a metastable enzyme stabilized by specific ionic interactions associated with the active site. Biochemistry33, 14800–14806 (1994).Crossref, Medline, CAS, Google Scholar
9 Turk B, Turk D, Salvesen GS: Regulating cysteine protease activity: essential role of protease inhibitors as guardians and regulators. Curr. Pharm. Des.8(18), 1623–1637 (2002).Crossref, Medline, CAS, Google Scholar
10 Linebaugh BE, Sameni M, Day NA, Sloane BF, Keppler D: Exocytosis of active cathepsin B: enzyme activity at pH 7.0, inhibition and molecular mass. Eur. J. Biochem.264, 100–109 (1999).Crossref, Medline, CAS, Google Scholar
11 Dehrmann FM, Coetzer TH, Pike RN, Dennison C: Mature cathepsin L is substantially active in the ionic milieu of the extracellular medium. Arch. Biochem. Biophys.324, 93–98 (1995).Crossref, Medline, CAS, Google Scholar
12 Sloane BF, Rozhin J, Johnson K, Taylor H, Crissman JD, Honn KV: Cathepsin B: association with plasma membrane in metastatic tumors. Proc. Natl Acad. Sci. USA83, 2483–2487 (1986).Crossref, Medline, CAS, Google Scholar
13 Guinec N, Dalet-Fumeron V, Pagano M: Quantitative study of the binding of cysteine proteinases to basement membranes. FEBS Lett.308, 305–308 (1992).Crossref, Medline, CAS, Google Scholar
14 Selzer PM, Pingel S, Hsieh I et al.: Cysteine protease inhibitors as chemotherapy: lessons from a parasite target. Proc. Natl Acad. Sci. USA96(20), 11015–11022 (1999).Crossref, Medline, CAS, Google Scholar
15 Caffrey CR, Scory S, Steverding D: Cysteine proteinases of trypanosome parasites: novel targets for chemotherapy. Curr. Drug Targets1(2), 155–162 (2000).Crossref, Medline, CAS, Google Scholar
16 Authie E, Boulange A, Muteti D, Lalmanach G, Gauthier F, Musoke AJ: Immunisation of cattle with cysteine proteinases of Trypanosoma congolense: targeting the disease rather than the parasite. Int. J. Parasitol.31(13), 1429–1433 (2001).Crossref, Medline, CAS, Google Scholar
17 Cornwall GA, Cameron A, Lindberg I, Hardy DM, Cormier N, Hsia N: The cystatin-related epididymal spermatogenic protein inhibits the serine protease prohormone convertase 2. Endocrinology144(3), 901–908 (2003).Crossref, Medline, CAS, Google Scholar
18 Normant E, Martres MP, Schwartz JC, Gros C: Purification, cDNA cloning, functional expression, and characterization of a 26-kDa endogenous mammalian carboxypeptidase inhibitor. Proc. Natl Acad. Sci. USA92(26), 12225–12229 (1995).Crossref, Medline, CAS, Google Scholar
19 Aagaard A, Listwan P, Cowieson N et al.: An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: relationship to cystatins and the tumor suppressor TIG1. Structure13(2), 309–317 (2005).Crossref, Medline, CAS, Google Scholar
20 Yamamoto K, Sinohara H: Isolation and characterization of mouse countertrypin, a new trypsin inhibitor belonging to the mammalian fetuin family. J. Biol. Chem.268(24), 17750–17753 (1993).Crossref, Medline, CAS, Google Scholar
21 Yoshida K, Suzuki Y, Yamamoto K, Sinohara H: Cystatin-like domain of mouse countertrypin, a member of mammalian fetuin family, is responsible for the inhibition of trypsin. Evidence from site-directed mutagenesis. Biochem. Mol. Biol. Int.39, 1023–1028 (1996).Medline, CAS, Google Scholar
22 Ray S, Lukyanov P, Ochieng J: Members of the cystatin superfamily interact with MMP-9 and protect it from autolytic degradation without affecting its gelatinolytic activities. Biochim. Biophys. Acta1652(2), 91–102 (2003).Crossref, Medline, CAS, Google Scholar
23 Abrahamson M, Alvarez-Fernandez M, Nathanson CM: Cystatins. Biochem. Soc. Symp. (70), 179–199 (2003).•• Important review to understand the mechanisms of interaction of cystatins with lysosomal cysteine proteases.Crossref, Medline, Google Scholar
24 Shi GP, Sukhova GK, Kuzuya M et al.: Deficiency of the cysteine protease cathepsin S impairs microvessel growth. Circ. Res.92(5), 493–500 (2003).•• First evidence showing that a lysosomal cysteine protease is required for neovascularizationCrossref, Medline, CAS, Google Scholar
25 Knight G: Active-site titration of peptidases. Methods Enzymol 248, 85–104 (1995).•• Comprehensive overview of enzymological parameters influencing protease inhibition.Google Scholar
26 Joyce JA, Baruch A, Chehade K et al.: Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5(5), 443–453 (2004).• Convincing use of synthetic inhibitors of lysosomal cysteine proteases as novel anticancer and anti-angiogenic agents in mice.Google Scholar
27 Amamoto T, Okazaki T, Komurasaki T et al.: Immunopharmacologic profiles of a thiol protease inhibitor, L-trans-dicyclohexyl epoxysuccinate. Jpn. J. Pharmacol.34(3), 335–342 (1984).Google Scholar
28 Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin. Oncol.29(6 Suppl. 16), 15–18 (2002).Google Scholar
29 Asahara T, Masuda H, Takahashi T et al.: Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ. Res.85(3), 221–228 (1999).Crossref, Medline, CAS, Google Scholar
30 Urbich C, Heeschen C, Aicher A et al.: Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nature Med.11(2), 206–213 (2005).•• First evidence demonstrating that a lysosomal cysteine protease is required for endothelial progenitor cell-induced neovascularization.Crossref, Medline, CAS, Google Scholar
31 StCroix B, Rago C, Velculescu V et al.: Genes expressed in human tumor endothelium [see comments]. Science 289(5482), 1197–1202 (2000).• High expression of salivary-type cystatins (CST1, CST2 and/or CST4) in the tumor endothelium when compared to normal colonic endothelium.Medline, Google Scholar
32 Machein MR, Renninger S, de Lima-Hahn E, Plate KH: Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. Brain Pathol.13(4), 582–597 (2003).Crossref, Medline, CAS, Google Scholar
33 Keppler D, Sameni M, Moin K, Mikkelsen T, Diglio CA, Sloane BF: Tumor progression and angiogenesis: cathepsin B & Co. Biochem. Cell Biol.74(6), 799–810 (1996).Crossref, Medline, CAS, Google Scholar
34 Mikkelsen T, Yan PS, Ho KL et al.: Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis. J. Neurosurg.83, 285–290 (1995).Crossref, Medline, CAS, Google Scholar
35 Rempel SA, Rosenblum ML, Mikkelsen T et al.: Cathepsin B expression and localization in glioma progression and invasion. Cancer Res.54, 6027–6031 (1994).Medline, CAS, Google Scholar
36 Yanamandra N, Gumidyala KV, Waldron KGet al.: Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis. Oncogene23(12), 2224–2230 (2004).•• First evidence that a lysosomal cysteine protease expressed in glioblastoma cells plays an essential role for tumor-induced angiogenesis.Crossref, Medline, CAS, Google Scholar
37 Gondi CS, Lakka SS, Dinh DH, Olivero WC, Gujrati M, Rao JS: RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas. Oncogene23(52), 8486–8496 (2004).Crossref, Medline, CAS, Google Scholar
38 Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N: Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem.267(36), 26031–26037 (1992).Crossref, Medline, CAS, Google Scholar
39 Konduri SD, Yanamandra N, Siddique K et al.: Modulation of cystatin C expression impairs the invasive and tumorigenic potential of human glioblastoma cells. Oncogene21(57), 8705–8712 (2002).Crossref, Medline, CAS, Google Scholar
40 Taupin P, Ray J, Fischer WH et al.: FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine co-factor. Neurone28(2), 385–397 (2000).• Confirmation of an autocrine role of cystatin C on neural stem cells.Crossref, Medline, CAS, Google Scholar
41 Sokol JP, Schiemann WP: Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells. Mol. Cancer Res.2(3), 183–195 (2004).• First report to show that cystatin C can interfere with transforming growth factor (TGF)ß signaling.Medline, CAS, Google Scholar
42 Verdot L, Lalmanach G, Vercruysse V, Hoebeke J, Gauthier F, Vray B: Chicken cystatin stimulates nitric oxide release from interferon-gamma-activated mouse peritoneal macrophages via cytokine synthesis. Eur. J. Biochem.266(3), 1111–1117 (1999).•• First report showing that some cystatins have immunomodulatory function.Crossref, Medline, CAS, Google Scholar
43 Schierack P, Lucius R, Sonnenburg B, Schilling K, Hartmann S: Parasite-specific immunomodulatory functions of filarial cystatin. Infect. Immun.71(5), 2422–2429 (2003).Crossref, Medline, CAS, Google Scholar
44 Kato T, Ito T, Imatani T, Minaguchi K, Saitoh E, Okuda K: Cystatin SA, a cysteine proteinase inhibitor, induces interferon-gamma expression in CD4-positive T-cells. Biol. Chem.385(5), 419–422 (2004).Crossref, Medline, CAS, Google Scholar
45 Pedersen KO: Size relationship among similar proteins; association and dissociation reactions of protein units. Cold Spring Harbor Symposium on Quantitative Biolology14, 140–152 (1950).Crossref, Medline, CAS, Google Scholar
46 Kellermann J, Haupt H, Auerswald EA, Muller-Ester W: The arrangement of disulfide loops in human alpha 2-HS glycoprotein. Similarity to the disulfide bridge structures of cystatins and kininogens. J. Biol. Chem.264, 14121–14128 (1989).Crossref, Medline, CAS, Google Scholar
47 Olivier E, Soury E, Ruminy P et al.: Fetuin-B, a second member of the fetuin family in mammals. Biochem. J.350(Pt 2), 589–597 (2000).Crossref, Medline, CAS, Google Scholar
48 Jones AL, Hulett MD, Parish CR: Histidine-rich glycoprotein: A novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems. Immunol. Cell Biol.83(2), 106–118 (2005).Crossref, Medline, CAS, Google Scholar
49 Rizzu P, Baldini A: Three members of the human cystatin gene superfamily, AHSG, HRG, and KNG, map within one megabase of genomic DNA at 3q27. Cytogenet. Cell Genet.70, 26–28 (1995).Crossref, Medline, CAS, Google Scholar
50 Hsu SJ, Nagase H, Balmain A: Identification of Fetuin-B as a member of a cystatin-like gene family on mouse chromosome 16 with tumor suppressor activity. Genome47(5), 931–946 (2004).•• Fetuin (FET)B-mediated suppression of human skin squamous carcinoma tumor growth in nude mice.Crossref, Medline, CAS, Google Scholar
51 Muller-Esterl W, Fritz H, Kellermann J, Lottspeich F, Machleidt W, Turk V: Genealogy of mammalian cysteine proteinase inhibitors. Common evolutionary origin of stefins, cystatins and kininogens. FEBS Lett.191, 221–226 (1985).Crossref, Medline, Google Scholar
52 Elzanowski A, Barker WC, Hunt LT, Seibel-Ross E: Cystatin domains in alpha-2-HS-glycoprotein and fetuin. FEBS Lett.227, 167–170 (1988).Crossref, Medline, CAS, Google Scholar
53 Liu Q, Yu L, Gao J et al.: Cloning, tissue expression pattern and genomic organization of latexin, a human homologue of rat carboxypeptidase A inhibitor. Mol. Biol. Rep.27(4), 241–246 (2000).Crossref, Medline, CAS, Google Scholar
54 Dickson IR, Poole AR, Veis A: Localisation of plasma alpha2HS glycoprotein in mineralising human bone. Nature256(5516), 430–432 (1975).Crossref, Medline, CAS, Google Scholar
55 Triffitt JT, Gebauer U, Ashton BA, Owen ME, Reynolds JJ: Origin of plasma alpha2HS-glycoprotein and its accumulation in bone. Nature262(5565), 226–227 (1976).Crossref, Medline, CAS, Google Scholar
56 Schinke T, Amendt C, Trindl A, Poschke O, Muller-Esterl W, Jahnen-Dechent W: The serum protein alpha2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis. J.Biol. Chem.271, 20789–20796 (1996).Crossref, CAS, Google Scholar
57 Schinke T, Koide T, Jahnen-Dechent W: Human histidine-rich glycoprotein expressed in SF9 insect cells inhibits apatite formation. FEBS Lett.412, 559–562 (1997).Crossref, Medline, CAS, Google Scholar
58 Heiss A, DuChesne A, Denecke B et al.: Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J. Biol. Chem.278(15), 13333–13341 (2003).Crossref, Medline, CAS, Google Scholar
59 Jahnen-Dechent W, Schinke T, Trindl A et al.: Cloning and targeted deletion of the mouse fetuin gene. J. Biol. Chem.272, 31496–31503 (1997).Crossref, Medline, Google Scholar
60 Szweras M, Liu D, Partridge EA et al.: Alpha 2-HS glycoprotein/fetuin, a transforming growth factor-beta/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling. J. Biol. Chem.277(22), 19991–19997 (2002).Crossref, Medline, CAS, Google Scholar
61 Demetriou M, Binkert C, Sukhu B, Tenenbaum HC, Dennis JW: Fetuin/alpha2-HS glycoprotein is a transforming growth factor-beta Type II receptor mimic and cytokine antagonist. J. Biol. Chem.271, 12755–12761 (1996).• Alpha 2-HS glycoprotein (AHSG)/FETA interferes with TGFß signaling.Crossref, Medline, CAS, Google Scholar
62 Swallow CJ, Partridge EA, Macmillan JC et al.: alpha2HS-glycoprotein, an antagonist of transforming growth factor beta in vivo, inhibits intestinal tumor progression. Cancer Res.64(18), 6402–6409 (2004).•• Intestinal tumor suppression by AHSG/FETACrossref, Medline, CAS, Google Scholar
63 Leite-Browning ML, McCawley LJ, Jahnen-Dechent W et al.: Alpha 2-HS glycoprotein (fetuin-A) modulates murine skin tumorigenesis. Int. J. Oncol.25(2), 319–324 (2004).• Reduced skin tumorigenesis in AHSG/FETA knockout mice.Medline, Google Scholar
64 Kundranda MN, Henderson M, Carter KJ et al.: The serum glycoprotein fetuin-A promotes Lewis lung carcinoma tumorigenesis via adhesive-dependent and adhesive-independent mechanisms. Cancer Res.65(2), 499–506 (2005).• Reduced Lewis lung carcinoma tumorigenesis in AHSG/FETA knockout mice.Medline, CAS, Google Scholar
65 Cayatte AJ, Kumbla L, Subbiah MT: Marked acceleration of exogenous fatty acid incorporation into cellular triglycerides by fetuin. J. Biol. Chem.265, 5883–5888 (1990).Crossref, Medline, CAS, Google Scholar
66 Rohrlich ST, Rifkin DB: Isolation of the major serine protease inhibitor from the 5-day serum-free conditioned medium of human embryonic lung cells and demonstration that it is fetuin. J. Cell. Physiol.109(1), 1–15 (1981).Crossref, Medline, CAS, Google Scholar
67 Lewis JG, Andre CM: Enhancement of human monocyte phagocytic function by alpha 2HS glycoprotein. Immunology42(3), 481–487 (1981).Medline, CAS, Google Scholar
68 Wajih N, Borras T, Xue W, Hutson SM, Wallin R: Processing and transport of matrix gamma-carboxyglutamic acid protein and bone morphogenetic protein-2 in cultured human vascular smooth muscle cells: evidence for an uptake mechanism for serum fetuin. J. Biol. Chem.279(41), 43052–43060 (2004).Crossref, Medline, CAS, Google Scholar
69 Kundranda MN, Ray S, Saria M et al.: Annexins expressed on the cell surface serve as receptors for adhesion to immobilized fetuin-A. Biochim. Biophys. Acta1693(2), 211–123 (2004).Crossref, Google Scholar
70 Ochieng J, Green B: The interactions of alpha 2HS glycoprotein with metalloproteinases. Biochem. Mol. Biol. Int.40, 13–20 (1996).Medline, CAS, Google Scholar
71 Ohnishi T, Nakamura O, Arakaki N, Daikuhara Y: Effect of phosphorylated rat fetuin on the growth of hepatocytes in primary culture in the presence of human hepatocyte-growth factor. Evidence that phosphorylated fetuin is a natural modulator of hepatocyte-growth factor. Eur. J. Biochem.243, 753–761 (1997).Crossref, Medline, CAS, Google Scholar
72 Nagase H, Mao JH, Balmain A: A subset of skin tumor modifier loci determines survival time of tumor-bearing mice. Proc. Natl Acad. Sci. USA96(26), 15032–15037 (1999).Crossref, Medline, CAS, Google Scholar
73 Hajjar DP, Boyd DB, Harpel PC, Nachman RL: Histidine-rich glycoprotein inhibits the antiproliferative effect of heparin on smooth muscle cells. J. Exp. Med.165(3), 908–913 (1987).Crossref, Medline, CAS, Google Scholar
74 Brown KJ, Parish CR: Histidine-rich glycoprotein and platelet factor 4 mask heparan sulfate proteoglycans recognized by acidic and basic fibroblast growth factor. Biochemistry33(46), 13918–13927 (1994).Crossref, Medline, CAS, Google Scholar
75 Borza DB, Morgan WT: Acceleration of plasminogen activation by tissue plasminogen activator on surface-bound histidine-proline-rich glycoprotein. J. Biol. Chem.272(9), 5718–5726 (1997).Crossref, Medline, CAS, Google Scholar
76 Jones AL, Hulett MD, Altin JG, Hogg P, Parish CR: Plasminogen is tethered with high affinity to the cell surface by the plasma protein, histidine-rich glycoprotein. J. Biol. Chem.279(37), 78267–38276 (2004).Crossref, Google Scholar
77 Simantov R, Febbraio M, Crombie R, Asch AS, Nachman RL, Silverstein RL: Histidine-rich glycoprotein inhibits the anti-angiogenic effect of thrombospondin-1. J. Clin. Invest.107(1), 45–52 (2001).Crossref, Medline, CAS, Google Scholar
78 Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP: CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells. J. Cell Biol.138(3), 707–717 (1997).Crossref, Medline, CAS, Google Scholar
79 Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N: Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature Med.6(1), 41–48 (2000).Crossref, Medline, CAS, Google Scholar
80 Juarez JC, Guan X, Shipulina NV et al.: Histidine-proline-rich glycoprotein has potent anti-angiogenic activity mediated through the histidine-proline-rich domain. Cancer Res.62(18), 5344–5350 (2002).Medline, CAS, Google Scholar
81 Guan X, Juarez JC, Qi X et al.: Histidine-proline rich glycoprotein (HPRG) binds and transduces anti-angiogenic signals through cell surface tropomyosin on endothelial cells. Thromb. Haemost.92(2), 403–412 (2004).• Confirmation that histidine rich glyoprotein (HRG,) like HKa, binds to endothelial cell surface tropomyosin via its His/Pro-rich domainCrossref, Medline, CAS, Google Scholar
82 Olsson AK, Larsson H, Dixelius J et al.: A fragment of histidine-rich glycoprotein is a potent inhibitor of tumor vascularization. Cancer Res.64(2), 599–605 (2004).Crossref, Medline, CAS, Google Scholar
83 Zhang JC, Donate F, Qi X et al.: The anti-angiogenic activity of cleaved high molecular weight kininogen is mediated through binding to endothelial cell tropomyosin. Proc. Natl Acad. Sci. USA99(19), 12224–12229 (2002).• Similar to endostatin, the anti-angiogenic activity of high-molecular weight kinnogen (HK)a is dependent on Zn2+ ions and mediated through binding to cell surface exposed tropomyosin.Crossref, Medline, CAS, Google Scholar
84 Donate F, Juarez JC, Guan X et al.: Peptides derived from the histidine-proline domain of the histidine-proline-rich glycoprotein bind to tropomyosin and have anti-angiogenic and antitumor activities. Cancer Res.64(16), 5812–5817 (2004).•• First promising preclinical studies with His/Pro-rich peptides showing anti-angiogenic activity in Matrigel plugs in mice and antitumor activity in two syngeneic mouse tumor models.Crossref, Medline, CAS, Google Scholar
85 Borza DB, Tatum FM, Morgan WT: Domain structure and conformation of histidine-proline-rich glycoprotein. Biochemistry35, 1925–1934 (1996).Crossref, Medline, CAS, Google Scholar
86 Salvesen G, Parkes C, Abrahamson M, Grubb A, Barrett AJ: Human low-Mr kininogen contains three copies of a cystatin sequence that are divergent in structure and in inhibitory activity for cysteine proteinases. Biochem. J.234, 429–434 (1986).Crossref, Medline, CAS, Google Scholar
87 Kitamura N, Kitagawa H, Fukushima D, Takagaki Y, Miyata T, Nakanishi S: Structural organization of the human kininogen gene and a model for its evolution. J. Biol. Chem.260, 8610–8617 (1985).•• Study provides the first genetic basis for the occurrence of two kininogen forms in serum.Crossref, Medline, CAS, Google Scholar
88 Guo YL, Colman RW: Two faces of high-molecular-weight kininogen (HK) in angiogenesis: bradykinin turns it on and cleaved HK (HKa) turns it off. J. Thromb. Haemost.3(4), 670–676 (2005).Crossref, Medline, CAS, Google Scholar
89 Herwald H, Hasan AA, Godovac-Zimmermann J, Schmaier AH, Muller-Esterl W: Identification of an endothelial cell binding site on kininogen domain D3. J.Biol. Chem.270, 14634–14642 (1995).Crossref, CAS, Google Scholar
90 Hayashi I, Amano H, Yoshida S et al.: Suppressed angiogenesis in kininogen-deficiencies. Lab. Invest.82(7), 871–880 (2002).•• Importance of the kininogen–kinin axis in various rat in vivo models of angiogenesis.Crossref, Medline, CAS, Google Scholar
91 Colman RW, Pixley RA, Sainz IM et al.: Inhibition of angiogenesis by antibody blocking the action of proangiogenic high-molecular-weight kininogen. J. Thromb. Haemost.1(1), 164–170 (2003).• Evidence that a monoclonal antibody directed against HK domain D5 is able to neutralize the proangiogenic effect of HK in the chicken chorio-allantoic membrane assay.Crossref, Medline, CAS, Google Scholar
92 Song JS, Sainz IM, Cosenza SC et al.: Inhibition of tumor angiogenesis in vivo by a monoclonal antibody targeted to domain 5 of high molecular weight kininogen. Blood104(7), 2065–2072 (2004).Crossref, Medline, CAS, Google Scholar
93 Emanueli C, Minasi A, Zacheo A et al.: Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischaemia. Circulation103(1), 125–132 (2001).Crossref, Medline, CAS, Google Scholar
94 Emanueli C, Madeddu P: Targeting kinin receptors for the treatment of tissue ischaemia. Trends Pharmacol. Sci.22(9), 478–484 (2001).Crossref, Medline, CAS, Google Scholar
95 Regoli D, Jukic D, Gobeil F, Rhaleb NE: Receptors for bradykinin and related kinins: a critical analysis. Can. J. Physiol. Pharmacol.71(8), 556–567 (1993).Crossref, Medline, CAS, Google Scholar
96 Ikeda Y, Hayashi I, Kamoshita E et al.: Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth. Cancer Res.64(15), 5178–5185 (2004).• Evidence for the importance of the kininogen-bradykinin-B2 receptor axis in subcutaneous tumor angiogenesis and growth in the rat.Crossref, Medline, CAS, Google Scholar
97 Parenti A, Morbidelli L, Ledda F, Granger HJ, Ziche M: The bradykinin/B1 receptor promotes angiogenesis by upregulation of endogenous FGF-2 in endothelium via the nitric oxide synthase pathway. FASEB J.15(8), 1487–1489 (2001).• Predominant role of the bradykinin B1 receptor in angiogenesis of the rabbit cornea.Crossref, Medline, CAS, Google Scholar
98 Seegers HC, Hood VC, Kidd BL, Cruwys SC, Walsh DA: Enhancement of angiogenesis by endogenous substance P release and neurokinin-1 receptors during neurogenic inflammation. J. Pharmacol. Exp. Ther.306(1), 8–12 (2003).Crossref, Medline, CAS, Google Scholar
99 Thuringer D, Maulon L, Frelin C: Rapid transactivation of the vascular endothelial growth factor receptor KDR/Flk-1 by the bradykinin B2 receptor contributes to endothelial nitric-oxide synthase activation in cardiac capillary endothelial cells. J. Biol. Chem.277(3), 2028–2032 (2002).•• Novel mechanism whereby a G-protein coupled receptor (B2 receptor) transactivates a receptor tyrosine kinase to generate a biologic response.Crossref, Medline, CAS, Google Scholar
100 Browder T, Folkman J, Pirie-Shepherd S: The hemostatic system as a regulator of angiogenesis. J. Biol. Chem.275(3), 1521–1524 (2000).Crossref, Medline, CAS, Google Scholar
101 Zhang JC, Claffey K, Sakthivel R et al.: Two-chain high molecular weight kininogen induces endothelial cell apoptosis and inhibits angiogenesis: partial activity within domain 5. FASEB J.14(15), 2589–2600 (2000).•• First demonstration that HKa selectively inhibits proliferation and induces apoptosis of endothelial cells but not that of other cell types.Crossref, Medline, CAS, Google Scholar
102 Colman RW, Jameson BA, Lin Y, Johnson D, Mousa SA: Domain 5 of high molecular weight kininogen (kininostatin) downregulates endothelial cell proliferation and migration and inhibits angiogenesis. Blood95(2), 543–550 (2000).•• First evidence that the antiproliferative, antimigration and anti-angiogenic activities of HKa map to domain D5.Crossref, Medline, CAS, Google Scholar
103 Weisel JW, Nagaswami C, Woodhead JL et al.: The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interactions with prekallikrein, as determined by electron microscopy. J. Biol. Chem.269, 10100–10106 (1994).Crossref, Medline, CAS, Google Scholar
104 Joseph K, Tholanikunnel BG, Ghebrehiwet B, Kaplan AP: Interaction of high molecular weight kininogen binding proteins on endothelial cells. Thromb. Haemost.91(1), 61–70 (2004).Crossref, Medline, CAS, Google Scholar
105 Guo YL, Wang S, Cao DJ, Colman RW: Apoptotic effect of cleaved high molecular weight kininogen is regulated by extracellular matrix proteins. J. Cell. Biochem.89(3), 622–632 (2003).Crossref, Medline, CAS, Google Scholar
106 Guo YL, Wang S, Colman RW: Kininostatin, an angiogenic inhibitor, inhibits proliferation and induces apoptosis of human endothelial cells. Arterioscler. Thromb. Vasc. Biol.21(9), 1427–1433 (2001).Crossref, Medline, CAS, Google Scholar
107 Hasan AA, Cines DB, Zhang J, Schmaier AH: The carboxyl terminus of bradykinin and amino terminus of the light chain of kininogens comprise an endothelial cell binding domain. J. Biol. Chem.269, 31822–31830 (1994).Crossref, Medline, CAS, Google Scholar
108 Nakazawa Y, Joseph K, Kaplan AP: Inhibition of contact activation by a kininogen peptide (HKH20) derived from domain 5. Int. Immunopharmacol.2(13–14), 1875–1885 (2002).Crossref, Medline, CAS, Google Scholar
109 Espinola RG, Uknis A, Sainz IM et al.: A monoclonal antibody to high-molecular weight kininogen is therapeutic in a rodent model of reactive arthritis. Am. J. Pathol.165(3), 969–976 (2004).•• Successful use of a monoclonal antibody directed against HK domain D5 in the treatment of a rat model of arthritis and systemic inflammation.Crossref, Medline, CAS, Google Scholar
110 Muraoka-Cook RS, Dumont N, Arteaga CL: Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin. Cancer Res.11(2 Pt 2), S937–S943 (2005).Google Scholar
111 Somoza JR, Jiang F, Tong L, Kang CH, Cho JM, Kim SH: Two crystal structures of a potently sweet protein. Natural monellin at 2.75 A resolution and single-chain monellin at 1.7 A resolution. J. Mol. Biol.234, 390–404 (1993).Crossref, Medline, CAS, Google Scholar
201 Merops peptidase database merops.sanger.ac.uk (Accessed September 2005)Google Scholar

Vol. 1, No. 5

Metrics

Downloaded 106 times

History

Published online 22 September 2005

Published in print October 2005

Information

Keywords

Acknowledgements

The authors wish to acknowledge the assistance of Robin Walter in improving the style and grammar of this paper. Part of this study was supported by a grant from the National Cancer Institute (R21 CA91785), as well as generous startup funds from the School of Medicine, the Feist-Weiller Cancer Center, and the Department of Cellular Biology and Anatomy at LSUHSC in Shreveport.

PDF download