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Table of Contents
Vol. 75, No. 1, 2008
Issue release date: March 2008
Pathobiology 2008;75:9–21
(DOI:10.1159/000113790)

Thrombospondin 1 and Its Mimetic Peptide ABT-510 Decrease Angiogenesis and Inflammation in a Murine Model of Inflammatory Bowel Disease

Punekar S.a · Zak S.a · Kalter V.G.a · Dobransky L.a · Punekar I.a · Lawler J.W.b · Gutierrez L.S.a
aWilkes University, Wilkes-Barre, Pa., and bBeth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass., USA
email Corresponding Author

Abstract

Objective: Vascular abnormalities and expression of proangiogenic factors have been repeatedly reported in inflammatory bowel disease (IBD). Thrombospondin 1 (TSP-1) is a protein well known for its antiangiogenic and anti-inflammatory properties. Using the dextran sulfate sodium (DSS) model, the role of TSP-1 in IBD has been investigated in vivo. Methods: TSP-1-deficient mice (TSP-1–/–) and WT mice were treated with DSS for 7 days. Disease activity indices, myeloperoxidase activity (MPO) and histology were analyzed. Microvascular density (MVD) was quantified using immunohistochemistry (IMH) with CD31 antibody. TGF-β1, basic FGF, VEGF, TNF-α and MMPs protein levels were evaluated by IMH and enzyme-linked immunoabsorbent assay (ELISA). Mice were treated with ABT-510 (Abbott Laboratories), an antiangiogenic TSP peptide, using miniosmotic pumps for 7 days. Results: TSP-1–/– mice had a worse clinical outcome and exhibited severe signs of rectal bleeding compared to the WT controls. The TSP-1–/– mice showed a higher level of crypt damage and deeper lesions. The grade of inflammation and the levels of MPO activity were also significantly higher in colons of TSP-1–/– mice. TSP-1–/– mice displayed higher MVD in focal areas of the colon after only 3 days of DSS treatment. Furthermore, clinical severity of the colitis and angiogenesis was significantly diminished when mice was treated with ABT-510. Conclusions: These findings directly link TSP-1 as a protective factor in IBD and suggest antiangiogenesis treatment, including compounds such as ABT-510 as an adjuvant therapy for IBD.


 goto top of outline Key Words

  • Thrombospondin 1
  • Inflammatory bowel disease
  • Metalloproteinase 2
  • Apoptosis
  • Angiogenesis
  • VEGF
  • Basic FGF

 goto top of outline Abstract

Objective: Vascular abnormalities and expression of proangiogenic factors have been repeatedly reported in inflammatory bowel disease (IBD). Thrombospondin 1 (TSP-1) is a protein well known for its antiangiogenic and anti-inflammatory properties. Using the dextran sulfate sodium (DSS) model, the role of TSP-1 in IBD has been investigated in vivo. Methods: TSP-1-deficient mice (TSP-1–/–) and WT mice were treated with DSS for 7 days. Disease activity indices, myeloperoxidase activity (MPO) and histology were analyzed. Microvascular density (MVD) was quantified using immunohistochemistry (IMH) with CD31 antibody. TGF-β1, basic FGF, VEGF, TNF-α and MMPs protein levels were evaluated by IMH and enzyme-linked immunoabsorbent assay (ELISA). Mice were treated with ABT-510 (Abbott Laboratories), an antiangiogenic TSP peptide, using miniosmotic pumps for 7 days. Results: TSP-1–/– mice had a worse clinical outcome and exhibited severe signs of rectal bleeding compared to the WT controls. The TSP-1–/– mice showed a higher level of crypt damage and deeper lesions. The grade of inflammation and the levels of MPO activity were also significantly higher in colons of TSP-1–/– mice. TSP-1–/– mice displayed higher MVD in focal areas of the colon after only 3 days of DSS treatment. Furthermore, clinical severity of the colitis and angiogenesis was significantly diminished when mice was treated with ABT-510. Conclusions: These findings directly link TSP-1 as a protective factor in IBD and suggest antiangiogenesis treatment, including compounds such as ABT-510 as an adjuvant therapy for IBD.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. McLaren WJ, Anikijenko P, Thomas SG, Delaney PM, King RG: In vivo detection of morphological and microvascular changes of the colon in association with colitis using fiberoptic confocal imaging (FOCI). Dig Dis Sci 2002;47:2424–2433.
  2. Satoyoshi K, Akita Y, Nozu F, Yoshikawa N, Mitamura K: Hemodynamics in the colonic mucosa of rats with dextran sulfate-induced colitis in the early phase. J Gastroenterol 1996;31:512–517.
  3. Venkatraman A, Ramakrishna BS, Pulimood AB, Patra S, Murthy S: Increased permeability in dextran sulphate colitis in rats: time course of development and effect of butyrate. Scand J Gastroenterol 2000;35:1053–1059.
  4. Di Sabatino A, Ciccocioppo R, Armellini E, Morera R, Ricevuti L, Cazzola P, Fulle I, Corazza GR: Serum bFGF and VEGF correlate respectively with bowel wall thickness and intramural blood flow in Crohn’s disease. Inflamm Bowel Dis 2004;10:573–577.
  5. Giatromanolaki A, Sivridis E, Maltezos E, Papazoglou D, Simopoulos C, Gatter KC, Harris AL, Koukourakis MI: Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol 2003;56:209–213.
  6. Griga T, Voigt E, Gretzer B, Brasch F, May B: Increased production of vascular endothelial growth factor by intestinal mucosa of patients with inflammatory bowel disease. Hepatogastroenterology 1999;46:920–923.
  7. Griga T, Gutzeit A, Sommerkamp C, May B: Increased production of vascular endothelial growth factor by peripheral blood mononuclear cells in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 1999;11:175–179.
  8. Griga T, May B, Pfisterer O, Muller KM, Brasch F: Immunohistochemical localization of vascular endothelial growth factor in colonic mucosa of patients with inflammatory bowel disease. Hepatogastroenterology 2002;49:116–123.
  9. Kanazawa S, Tsunoda T, Onuma E, Majima T, Kagiyama M, Kikuchi K: VEGF, basic-FGF, and TGF-beta in Crohn’s disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. Am J Gastroenterol 2001;96:822–828.
  10. Kapsoritakis A, Sfiridaki A, Maltezos E, Simopoulos K, Giatromanolaki A, Sivridis E, Koukourakis MI: Vascular endothelial growth factor in inflammatory bowel disease. Int J Colorectal Dis 2003;18:418–422.
  11. Konno S, Iizuka M, Yukawa M, Sasaki K, Sato A, Horie Y, Nanjo H, Fukushima T, Watanabe S: Altered expression of angiogenic factors in the VEGF-Ets-1 cascades in inflammatory bowel disease. J Gastroenterol 2004;39:931–939.
  12. Ferrante M, Pierik M, Henckaerts L, Joossens M, Claes K, Van Schuerbeek N, Vlietinck R, Rutgeerts P, Van Assche G, Vermeire S: The role of vascular endothelial growth factor (VEGF) in inflammatory bowel disease. Inflamm Bowel Dis 2006;12:870–878.
  13. Chidlow JH Jr, Langston W, Greer JJ, Ostanin D, Abdelbaqi M, Houghton J, Senthilkumar A, Shukla D, Mazar AP, Grisham MB, Kevil CG: Differential angiogenic regulation of experimental colitis. Am J Pathol 2006;169:2014–2030.
  14. Hatoum OA, Heidemann J, Binion DG: The intestinal microvasculature as a therapeutic target in inflammatory bowel disease. Ann NY Acad Sci 2006;1072:78–97.
  15. Danese S, Sans M, Spencer DM, Beck I, Donate F, Plunkett ML, de la Motte C, Redline R, Shaw DE, Levine AD, Mazar AP, Fiocchi C: Angiogenesis blockade as a new therapeutic approach to experimental colitis. Gut 2007;56:855–862.
  16. Adams JC, Lawler J: The thrombospondins. Int J Biochem Cell Biol 2004;36:961–968.
  17. Jimenez B, Volpert O, Crawford SE, Febbraio M, Silverstein RL, Bouck N: Signal leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 2000;6:41–48.
  18. 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 1997;138:707–717.
  19. Rodriguez-Manzaneque J, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML: Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA 2001;98:12485–12490.
  20. Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO: Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 1998;101:982–992.
  21. Schultz-Cherry S, Chen H, Mosher DF, Misenheimer TM, Krutzsch HC, Roberts DD, Murphy-Ullrich JE: Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1. J Biol Chem 1995;270:7304–7310.
  22. Li Z, Sipes JM, Cashel JA, Krutzsch HC, Annis DS, Mosher DF, Roberts DD: Interactions of thrombospondins with α4β1 integrin and CD47 differentially modulate T cell behavior. J Cell Biol 2002;157:509–551.
  23. Doyen V, Rubio M, Braun D, Nakajima T, Abe J, Saito H, Delespesse G, Sarfati M: Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J Exp Med 2003;198:1277–1283.
  24. Cooper HS, Murthy S, Kido K, Yoshitake H, Flanigan A: Dysplasia and cancer in the dextran sulfate sodium mouse colitis model. Relevance to colitis-associated neoplasia in the human: a study of histopathology, B-catenin and p53 expression and the role of inflammation. Carcinogenesis 2000;21:757–768.
  25. Cooper HS, Murthy S, Shah RS, Sedergran DJ: Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 1993;69:238–249.
  26. Haviv F, Bradley MF, Kalvin DM, Schneider AJ, Davidson DJ, Majest SM, McKay LM, Haskell CJ, Bell RL, Nguyen B, Marsh KC, Surber BW, Uchic JT, Ferrero J, Wang YC, Leal J, Record RD, Hodde J, Badylak SF, Lesniewski RR, Henkin J: Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities. J Med Chem 2005;48:2838–2846.
  27. Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS: Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 2005;7:101–111.
  28. Gutierrez LS, Suckow M, Lawler J, Ploplis VA, Castellino FJ: Thrombospondin 1 – a regulator of adenoma growth and carcinoma progression in the ApcMin/+ mouse model. Carcinogenesis 2003;24:199–207.
  29. Shiraki M, Aihara H, Kinouchi Y, Takahashi S, Oki M, Noguchi M, Takahashi K, Miyazaki J, Shimosegawa T: IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice. Lab Invest 2004;84:1491–1500.
  30. Lindberg FP, Bullard DC, Caver TE, Gresham HD, Beaudet AL, Brown EJ: Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 1996;274:795–798.
  31. Narizhneva NV, Razorenova OV, Podrez EA, Chen J, Chandrasekharan UM, Dicorleto PE, Plow EF, Topol EJ, Byzova TV: Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium. FASEB J 2005;19:1158–1160.
  32. Wang S, Wu Z, Sorenson CM, Lawler J, Sheibani N: Thrombospondin-1-deficient mice exhibit increased vascular density during retinal vascular development and are less sensitive to hyperoxia-mediated vessel obliteration. Dev Dyn 2003;228:630–642.
  33. Miao WM, Seng WL, Duquette M, Lawler P, Laus C, Lawler J: Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer Res 2001;61:7830–7839.
  34. Yap R, Veliceasa D, Emmenegger U, Kerbel RS, McKay LM, Henkin J, Volpert OV: Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy. Clin Cancer Res 2005;11:6678–6685.
  35. Rusk A, McKeegan E, Haviv Majest A, Henkin J, Khanna C: Preclinical evaluation of antiangiogenic thrombospondin-1 peptide mimetics, ABT-526 and ABT-510, in companion dogs with naturally occurring cancers. Clin Cancer Res 2006;12:7444–7455.
  36. Hoekstra R, de Vos FY, Eskens FA, de Vries EG, Uges DR, Knight R, Carr RA, Humerickhouse R, Verweij J, Gietema JA: Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination. Eur J Cancer 2006;42:467–472.
  37. Yang Q, Tian Y, Liu S, Zeine R, Chlenski A, Salwen HR, Henkin J, Cohn SL: Thrombospondin-1 peptide ABT-510 combined with valproic acid is an effective antiangiogenesis strategy in neuroblastoma. Cancer Res 2007;67:1716–1724.
  38. Zak S, Treven J, Nash N, Gutierrez LS: Lack of thrombospondin-1 increases angiogenesis in a model of chronic inflammatory bowel disease. Int J Colorectal Dis 2008;23:297–304.
  39. Bein K, Simmons M: Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. J Biol Chem 2000;275:32167–32173.
  40. Emonard H, Bellon G, Troeberg L, Berton A, Robinet A, Henriet P, Marbaix E, Kirkegaard K, Patthy L, Eeckhout Y, Nagase H, Hornebeck W, Courtoy PJ: Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2.TIMP-2 complex through a thrombospondin-independent mechanism. J Biol Chem 2004;279:54944–54951.
  41. Lawler J, Duquette M, Urry L, McHenry K, Smith TF: The evolution of the thrombospondin gene family. J Mol Evol 1993;36:509–516.
  42. Gao Q, Meijer MJ, Kubben FJ, Sier CF, Kruidenier L, van Duijn W, van den Berg M, van Hogezand RA, Lamers CB, Verspaget HW: Expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel diseases. Dig Liver Dis 2005;37:584–592.

 goto top of outline Author Contacts

Dr. Linda S. Gutierrez
Department of Biology, 354 Stark Learning Center
Wilkes University, 84 W. South St.
Wilkes-Barre, PA 18766 (USA)
Tel. +1 570 408 4636, Fax +1 570 408 7862, E-Mail linda.gutierrez@wilkes.edu


 goto top of outline Article Information

Received: June 12, 2007
Accepted: September 7, 2007
Published online: March 11, 2008
Number of Print Pages : 13
Number of Figures : 6, Number of Tables : 0, Number of References : 42


 goto top of outline Publication Details

Pathobiology (Pathobiology - Exploring the basis of disease)

Vol. 75, No. 1, Year 2008 (Cover Date: March 2008)

Journal Editor: Borisch B. (Geneva), Yasui W. (Hiroshima)
ISSN: 1015–2008 (Print), eISSN: 1423–0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objective: Vascular abnormalities and expression of proangiogenic factors have been repeatedly reported in inflammatory bowel disease (IBD). Thrombospondin 1 (TSP-1) is a protein well known for its antiangiogenic and anti-inflammatory properties. Using the dextran sulfate sodium (DSS) model, the role of TSP-1 in IBD has been investigated in vivo. Methods: TSP-1-deficient mice (TSP-1–/–) and WT mice were treated with DSS for 7 days. Disease activity indices, myeloperoxidase activity (MPO) and histology were analyzed. Microvascular density (MVD) was quantified using immunohistochemistry (IMH) with CD31 antibody. TGF-β1, basic FGF, VEGF, TNF-α and MMPs protein levels were evaluated by IMH and enzyme-linked immunoabsorbent assay (ELISA). Mice were treated with ABT-510 (Abbott Laboratories), an antiangiogenic TSP peptide, using miniosmotic pumps for 7 days. Results: TSP-1–/– mice had a worse clinical outcome and exhibited severe signs of rectal bleeding compared to the WT controls. The TSP-1–/– mice showed a higher level of crypt damage and deeper lesions. The grade of inflammation and the levels of MPO activity were also significantly higher in colons of TSP-1–/– mice. TSP-1–/– mice displayed higher MVD in focal areas of the colon after only 3 days of DSS treatment. Furthermore, clinical severity of the colitis and angiogenesis was significantly diminished when mice was treated with ABT-510. Conclusions: These findings directly link TSP-1 as a protective factor in IBD and suggest antiangiogenesis treatment, including compounds such as ABT-510 as an adjuvant therapy for IBD.



 goto top of outline Author Contacts

Dr. Linda S. Gutierrez
Department of Biology, 354 Stark Learning Center
Wilkes University, 84 W. South St.
Wilkes-Barre, PA 18766 (USA)
Tel. +1 570 408 4636, Fax +1 570 408 7862, E-Mail linda.gutierrez@wilkes.edu


 goto top of outline Article Information

Received: June 12, 2007
Accepted: September 7, 2007
Published online: March 11, 2008
Number of Print Pages : 13
Number of Figures : 6, Number of Tables : 0, Number of References : 42


 goto top of outline Publication Details

Pathobiology (Pathobiology - Exploring the basis of disease)

Vol. 75, No. 1, Year 2008 (Cover Date: March 2008)

Journal Editor: Borisch B. (Geneva), Yasui W. (Hiroshima)
ISSN: 1015–2008 (Print), eISSN: 1423–0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. McLaren WJ, Anikijenko P, Thomas SG, Delaney PM, King RG: In vivo detection of morphological and microvascular changes of the colon in association with colitis using fiberoptic confocal imaging (FOCI). Dig Dis Sci 2002;47:2424–2433.
  2. Satoyoshi K, Akita Y, Nozu F, Yoshikawa N, Mitamura K: Hemodynamics in the colonic mucosa of rats with dextran sulfate-induced colitis in the early phase. J Gastroenterol 1996;31:512–517.
  3. Venkatraman A, Ramakrishna BS, Pulimood AB, Patra S, Murthy S: Increased permeability in dextran sulphate colitis in rats: time course of development and effect of butyrate. Scand J Gastroenterol 2000;35:1053–1059.
  4. Di Sabatino A, Ciccocioppo R, Armellini E, Morera R, Ricevuti L, Cazzola P, Fulle I, Corazza GR: Serum bFGF and VEGF correlate respectively with bowel wall thickness and intramural blood flow in Crohn’s disease. Inflamm Bowel Dis 2004;10:573–577.
  5. Giatromanolaki A, Sivridis E, Maltezos E, Papazoglou D, Simopoulos C, Gatter KC, Harris AL, Koukourakis MI: Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol 2003;56:209–213.
  6. Griga T, Voigt E, Gretzer B, Brasch F, May B: Increased production of vascular endothelial growth factor by intestinal mucosa of patients with inflammatory bowel disease. Hepatogastroenterology 1999;46:920–923.
  7. Griga T, Gutzeit A, Sommerkamp C, May B: Increased production of vascular endothelial growth factor by peripheral blood mononuclear cells in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 1999;11:175–179.
  8. Griga T, May B, Pfisterer O, Muller KM, Brasch F: Immunohistochemical localization of vascular endothelial growth factor in colonic mucosa of patients with inflammatory bowel disease. Hepatogastroenterology 2002;49:116–123.
  9. Kanazawa S, Tsunoda T, Onuma E, Majima T, Kagiyama M, Kikuchi K: VEGF, basic-FGF, and TGF-beta in Crohn’s disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. Am J Gastroenterol 2001;96:822–828.
  10. Kapsoritakis A, Sfiridaki A, Maltezos E, Simopoulos K, Giatromanolaki A, Sivridis E, Koukourakis MI: Vascular endothelial growth factor in inflammatory bowel disease. Int J Colorectal Dis 2003;18:418–422.
  11. Konno S, Iizuka M, Yukawa M, Sasaki K, Sato A, Horie Y, Nanjo H, Fukushima T, Watanabe S: Altered expression of angiogenic factors in the VEGF-Ets-1 cascades in inflammatory bowel disease. J Gastroenterol 2004;39:931–939.
  12. Ferrante M, Pierik M, Henckaerts L, Joossens M, Claes K, Van Schuerbeek N, Vlietinck R, Rutgeerts P, Van Assche G, Vermeire S: The role of vascular endothelial growth factor (VEGF) in inflammatory bowel disease. Inflamm Bowel Dis 2006;12:870–878.
  13. Chidlow JH Jr, Langston W, Greer JJ, Ostanin D, Abdelbaqi M, Houghton J, Senthilkumar A, Shukla D, Mazar AP, Grisham MB, Kevil CG: Differential angiogenic regulation of experimental colitis. Am J Pathol 2006;169:2014–2030.
  14. Hatoum OA, Heidemann J, Binion DG: The intestinal microvasculature as a therapeutic target in inflammatory bowel disease. Ann NY Acad Sci 2006;1072:78–97.
  15. Danese S, Sans M, Spencer DM, Beck I, Donate F, Plunkett ML, de la Motte C, Redline R, Shaw DE, Levine AD, Mazar AP, Fiocchi C: Angiogenesis blockade as a new therapeutic approach to experimental colitis. Gut 2007;56:855–862.
  16. Adams JC, Lawler J: The thrombospondins. Int J Biochem Cell Biol 2004;36:961–968.
  17. Jimenez B, Volpert O, Crawford SE, Febbraio M, Silverstein RL, Bouck N: Signal leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 2000;6:41–48.
  18. 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 1997;138:707–717.
  19. Rodriguez-Manzaneque J, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML: Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA 2001;98:12485–12490.
  20. Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO: Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 1998;101:982–992.
  21. Schultz-Cherry S, Chen H, Mosher DF, Misenheimer TM, Krutzsch HC, Roberts DD, Murphy-Ullrich JE: Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1. J Biol Chem 1995;270:7304–7310.
  22. Li Z, Sipes JM, Cashel JA, Krutzsch HC, Annis DS, Mosher DF, Roberts DD: Interactions of thrombospondins with α4β1 integrin and CD47 differentially modulate T cell behavior. J Cell Biol 2002;157:509–551.
  23. Doyen V, Rubio M, Braun D, Nakajima T, Abe J, Saito H, Delespesse G, Sarfati M: Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J Exp Med 2003;198:1277–1283.
  24. Cooper HS, Murthy S, Kido K, Yoshitake H, Flanigan A: Dysplasia and cancer in the dextran sulfate sodium mouse colitis model. Relevance to colitis-associated neoplasia in the human: a study of histopathology, B-catenin and p53 expression and the role of inflammation. Carcinogenesis 2000;21:757–768.
  25. Cooper HS, Murthy S, Shah RS, Sedergran DJ: Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 1993;69:238–249.
  26. Haviv F, Bradley MF, Kalvin DM, Schneider AJ, Davidson DJ, Majest SM, McKay LM, Haskell CJ, Bell RL, Nguyen B, Marsh KC, Surber BW, Uchic JT, Ferrero J, Wang YC, Leal J, Record RD, Hodde J, Badylak SF, Lesniewski RR, Henkin J: Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities. J Med Chem 2005;48:2838–2846.
  27. Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS: Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 2005;7:101–111.
  28. Gutierrez LS, Suckow M, Lawler J, Ploplis VA, Castellino FJ: Thrombospondin 1 – a regulator of adenoma growth and carcinoma progression in the ApcMin/+ mouse model. Carcinogenesis 2003;24:199–207.
  29. Shiraki M, Aihara H, Kinouchi Y, Takahashi S, Oki M, Noguchi M, Takahashi K, Miyazaki J, Shimosegawa T: IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice. Lab Invest 2004;84:1491–1500.
  30. Lindberg FP, Bullard DC, Caver TE, Gresham HD, Beaudet AL, Brown EJ: Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 1996;274:795–798.
  31. Narizhneva NV, Razorenova OV, Podrez EA, Chen J, Chandrasekharan UM, Dicorleto PE, Plow EF, Topol EJ, Byzova TV: Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium. FASEB J 2005;19:1158–1160.
  32. Wang S, Wu Z, Sorenson CM, Lawler J, Sheibani N: Thrombospondin-1-deficient mice exhibit increased vascular density during retinal vascular development and are less sensitive to hyperoxia-mediated vessel obliteration. Dev Dyn 2003;228:630–642.
  33. Miao WM, Seng WL, Duquette M, Lawler P, Laus C, Lawler J: Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer Res 2001;61:7830–7839.
  34. Yap R, Veliceasa D, Emmenegger U, Kerbel RS, McKay LM, Henkin J, Volpert OV: Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy. Clin Cancer Res 2005;11:6678–6685.
  35. Rusk A, McKeegan E, Haviv Majest A, Henkin J, Khanna C: Preclinical evaluation of antiangiogenic thrombospondin-1 peptide mimetics, ABT-526 and ABT-510, in companion dogs with naturally occurring cancers. Clin Cancer Res 2006;12:7444–7455.
  36. Hoekstra R, de Vos FY, Eskens FA, de Vries EG, Uges DR, Knight R, Carr RA, Humerickhouse R, Verweij J, Gietema JA: Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination. Eur J Cancer 2006;42:467–472.
  37. Yang Q, Tian Y, Liu S, Zeine R, Chlenski A, Salwen HR, Henkin J, Cohn SL: Thrombospondin-1 peptide ABT-510 combined with valproic acid is an effective antiangiogenesis strategy in neuroblastoma. Cancer Res 2007;67:1716–1724.
  38. Zak S, Treven J, Nash N, Gutierrez LS: Lack of thrombospondin-1 increases angiogenesis in a model of chronic inflammatory bowel disease. Int J Colorectal Dis 2008;23:297–304.
  39. Bein K, Simmons M: Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. J Biol Chem 2000;275:32167–32173.
  40. Emonard H, Bellon G, Troeberg L, Berton A, Robinet A, Henriet P, Marbaix E, Kirkegaard K, Patthy L, Eeckhout Y, Nagase H, Hornebeck W, Courtoy PJ: Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2.TIMP-2 complex through a thrombospondin-independent mechanism. J Biol Chem 2004;279:54944–54951.
  41. Lawler J, Duquette M, Urry L, McHenry K, Smith TF: The evolution of the thrombospondin gene family. J Mol Evol 1993;36:509–516.
  42. Gao Q, Meijer MJ, Kubben FJ, Sier CF, Kruidenier L, van Duijn W, van den Berg M, van Hogezand RA, Lamers CB, Verspaget HW: Expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel diseases. Dig Liver Dis 2005;37:584–592.