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Chemokines and Angiogenesis

  • Chapter
The Chemokine Receptors

Part of the book series: The Receptors ((REC))

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Abstract

Angiogenesis is the process of new blood vessel growth and is a critical biological process under both physiologic and pathologic conditions. Angiogenesis can occur under physiologic conditions that include embryogenesis and the ovarian/menstrual cycle. In contrast, pathologic angiogenesis is associated with chronic inflammation/chronic fibroproliferative disorders and tumorigenesis of cancer. Similarly, aberrant angiogenesis associated with chronic inflammation/fibroproliferative disorders is analogous to neovascularization of tumorigenesis of cancer. Net angiogenesis is determined by a balance in the expression of angiogenic compared with angiostatic factors. CXC chemokines are heparin-binding proteins that display unique disparate roles in the regulation of angiogenesis. Based on their structure, CXC chemokines can be divided into two groups that either promote or inhibit angiogenesis, and they are therefore uniquely placed to regulate net angiogenesis in both physiologic and pathologic conditions.

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References

  1. Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J 1997;11(6):457–465.

    PubMed  CAS  Google Scholar 

  2. Strieter RM, Polverini PJ, Kunkel SL, et al. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 1995;270(45):27348–27357.

    Article  PubMed  CAS  Google Scholar 

  3. Belperio JA, Keane MP, Arenberg DA, et al. CXC chemokines in angiogenesis. J Leukoc Biol 2000;68(1):1–8.

    PubMed  CAS  Google Scholar 

  4. Lasagni L, Francalanci M, Annunziato F, et al. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. J Exp Med 2003;197(11):1537–1549.

    Article  PubMed  CAS  Google Scholar 

  5. Boulday G, Haskova Z, Reinders ME, Pal S, Briscoe DM. Vascular endothelial growth factor-induced signaling pathways in endothelial cells that mediate over-expression of the chemokine IFN-(gamma)-inducible protein of 10kDa in vitro and in vivo. J Immunol 2006;176(5):3098–3107.

    PubMed  CAS  Google Scholar 

  6. Strieter RM, Polverini PJ, Kunkel SL, et al. The functional role of the “ELR” motif in CXC chemokine-mediated angiogenesis. J Biol Chem 1995;270(45):27348–27357.

    Article  PubMed  CAS  Google Scholar 

  7. Addison CL, Daniel TO, Burdick MD, et al. The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR(+) CXC chemokine-induced angiogenic activity. J Immunol 2000;165(9):5269–5277.

    PubMed  CAS  Google Scholar 

  8. Murdoch C, Monk PN, Finn A. CXC chemokine receptor expression on human endothelial cells. Cytokine 1999;11(9):704–712.

    Article  PubMed  CAS  Google Scholar 

  9. Salcedo R, Resau JH, Halverson D, et al. Differential expression and responsiveness of chemokine receptors (CXCR1–3) by human microvascular endothelial cells and umbilical vein endothelial cells. FASEB J 2000;14(13):2055–2064.

    Article  PubMed  CAS  Google Scholar 

  10. Heidemann J, Ogawa H, Dwinell MB, et al. Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem 2003;278(10):8508–8515.

    Article  PubMed  CAS  Google Scholar 

  11. Richmond A, Fan GH, Dhawan P, Yang J. How do chemokine/chemokine receptor activations affect tumorigenesis? Novartis Found Symp 2004;256:74–89.

    PubMed  CAS  Google Scholar 

  12. Devalaraja RM, Nanney LB, Qian Q, et al. Delayed wound healing in CXCR2 knockout mice. J Invest Dermatol 2000;115(2):234–244.

    Article  PubMed  CAS  Google Scholar 

  13. Keane MP, Belperio JA, Xue YY, Burdick MD, Strieter RM. Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 2004;172(5):2853–2860.

    PubMed  CAS  Google Scholar 

  14. Burger M, Burger JA, Hoch RC, Oades Z, Takamori H, Schraufstatter IU. Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi’s sarcoma herpesvirus-G protein-coupled receptor. J Immunol 1999;163(4):2017–2022.

    PubMed  CAS  Google Scholar 

  15. Gershengorn MC, Geras-Raaka E, Varma A, Clark-Lewis I. Chemokines activate Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture. J Clin Invest 1998;102:1469–1472.

    PubMed  CAS  Google Scholar 

  16. Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal 1997;9(5):337–351.

    Article  PubMed  CAS  Google Scholar 

  17. Pawson T, Scott JD. Signaling through scaffold, anchoring, and adaptor proteins. Science 1997;278(5346):2075–2080.

    Article  PubMed  CAS  Google Scholar 

  18. Shyamala V, Khoja H. Interleukin-8 receptors R1 and R2 activate mitogen-activated protein kinases and induce c-fos, independent of Ras and Raf-1 in Chinese hamster ovary cells. Biochemistry 1998;37(45):15918–15924.

    Article  PubMed  CAS  Google Scholar 

  19. Couty JP, Gershengorn MC. Insights into the viral G protein-coupled receptor encoded by human herpesvirus type 8 (HHV-8). Biol Cell 2004;96(5):349–354.

    Article  PubMed  CAS  Google Scholar 

  20. Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 1997;385(6614):347–350.

    Article  PubMed  CAS  Google Scholar 

  21. Bais C, Santomasso B, Coso O, et al. G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 1998;391(6662):86–89.

    Article  PubMed  CAS  Google Scholar 

  22. Geras-Raaka E, Arvanitakis L, Bais C, Cesarma E, Mesri EA, Gershengorn MC. Inhibition of constitutive signaling of Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture. J Exp Med 1998;187(5):801–806.

    Article  PubMed  CAS  Google Scholar 

  23. Geras-Raaka E, Varma A, Ho H, Clark-Lewis I, Gershengorn MC. Human interferon-gamma-inducible protein 10 (IP-10) inhibits constitutive signaling of Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. J Exp Med 1998;188(2):405–408.

    Article  PubMed  CAS  Google Scholar 

  24. Yang TY, Chen SC, Leach MW, et al. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi’s sarcoma. J Exp Med 2000;191(3):445–454.

    Article  PubMed  CAS  Google Scholar 

  25. Guo HG, Sadowska M, Reid W, Tschachler E, Hayward G, Reitz M. Kaposi’s sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J Virol 2003;77(4):2631–2639.

    Article  PubMed  CAS  Google Scholar 

  26. Luan J, Shattuck-Brandt R, Haghnegahdar H, et al. Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression. J Leukoc Biol 1997;62(5):588–597.

    PubMed  CAS  Google Scholar 

  27. Owen JD, Strieter R, Burdick M, et al. Enhanced tumor-forming capacity for immortalized melanocytes expressing melanoma growth stimulatory activity/growth-regulated cytokine beta and gamma proteins. Int J Cancer 1997;73(1):94–103.

    Article  PubMed  CAS  Google Scholar 

  28. Addison CL, Belperio JA, Burdick MD, Strieter RM. Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis. BMC Cancer 2004;4(1):28.

    Article  PubMed  CAS  Google Scholar 

  29. Arenberg DA, Kunkel SL, Polverini PJ, Glass M, Burdick MD, Strieter RM. Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 1996;97(12):2792–2802.

    PubMed  CAS  Google Scholar 

  30. Arenberg DA, Keane MP, DiGiovine B, et al. Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin Invest 1998;102(3):465–472.

    PubMed  CAS  Google Scholar 

  31. Moore BB, Arenberg DA, Stoy K, et al. Distinct CXC chemokines mediate tumorigenicity of prostate cancer cells. Am J Pathol 1999;154(5):1503–1512.

    PubMed  CAS  Google Scholar 

  32. Luster AD. Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med 1998;338(7):436–445.

    Article  PubMed  CAS  Google Scholar 

  33. Rollins BJ. Chemokines. Blood 1997;90(3):909–928.

    PubMed  CAS  Google Scholar 

  34. Balkwill F. The molecular and cellular biology of the chemokines. J Viral Hepat 1998;5(1):1–14.

    Article  PubMed  CAS  Google Scholar 

  35. Loetscher M, Loetscher P, Brass N, Meese E, Moser B. Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization. Eur J Immunol 1998;28(11):3696–3705.

    Article  PubMed  CAS  Google Scholar 

  36. Ehlert JE, Addison CA, Burdick MD, Kunkel SL, Strieter RM. Identification and partial characterization of a variant of human CXCR3 generated by posttranscriptional exon skipping. J Immunol 2004;173(10):6234–6240.

    PubMed  CAS  Google Scholar 

  37. Moser B, Loetscher P. Lymphocyte traffic control by chemokines. Nat Immunol 2001;2(2):123–128.

    Article  PubMed  CAS  Google Scholar 

  38. Beider K, Nagler A, Wald O, et al. Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice. Blood 2003;102(6):1951–1958.

    Article  PubMed  CAS  Google Scholar 

  39. Soto H, Wang W, Strieter RM, et al. The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3. Proc Natl Acad Sci U S A 1998;95(14):8205–8210.

    Article  PubMed  CAS  Google Scholar 

  40. Romagnani P, Annunziato F, Lasagni L, et al. Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. J Clin Invest 2001;107(1):53–63.

    Article  PubMed  CAS  Google Scholar 

  41. Yang J, Richmond A. The angiostatic activity of interferon-inducible protein-10/CXCL10 in human melanoma depends on binding to CXCR3 but not to glycosaminoglycan. Mol Ther 2004;9(6):846–855.

    Article  PubMed  CAS  Google Scholar 

  42. Burdick MD, Murray LA, Keane MP, et al. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med 2005;171(3):261–268.

    Article  PubMed  Google Scholar 

  43. Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP, Strieter RM. The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med 2003;167(12):1676–1686.

    Article  PubMed  Google Scholar 

  44. Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Res 2002;62(24):7203–7206.

    PubMed  CAS  Google Scholar 

  45. Salcedo R, Oppenheim JJ. Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 2003;10(3–4):359–370.

    Article  PubMed  CAS  Google Scholar 

  46. Kijowski J, Baj-Krzyworzeka M, Majka M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells 2001;19(5):453–466.

    Article  PubMed  CAS  Google Scholar 

  47. Salcedo R, Wasserman K, Young HA, et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-lalpha. Am J Pathol 1999;154(4):1125–1135.

    PubMed  CAS  Google Scholar 

  48. Schrader AJ, Lechner O, Templin M, et al. CXCR4/CXCL12 expression and signalling in kidney cancer. Br J Cancer 2002;86(8):1250–1256.

    Article  PubMed  CAS  Google Scholar 

  49. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410(6824):50–56.

    Article  PubMed  CAS  Google Scholar 

  50. Smith DR, Polverini PJ, Kunkel SL, et al. Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma. J Exp Med 1994;179(5):1409–1415.

    Article  PubMed  CAS  Google Scholar 

  51. Belperio JA, Keane MP, Arenberg DA, et al. CXC chemokines in angiogenesis. J Leukoc Biol 2000;68(1):1–8.

    PubMed  CAS  Google Scholar 

  52. Arenberg DA, Kunkel SL, Polverini PJ, et al. Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. J Exp Med 1996;184(3):981–992.

    Article  PubMed  CAS  Google Scholar 

  53. Maione TE, Gray GS, Petro J, et al. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 1990;247(4938):77–79.

    Article  PubMed  CAS  Google Scholar 

  54. Bikfalvi A, Gimenez-Gallego G. The control of angiogenesis and tumor invasion by platelet factor-4 and platelet factor-4-derived molecules. Semin Thromb Hemost 2004;30(1):137–144.

    Article  PubMed  CAS  Google Scholar 

  55. Eisman R, Surrey S, Ramachandran B, Schwartz E, Poncz M. Structural and functional comparison of the genes for human platelet factor 4 and PF4alt. Blood 1990;76(2):336–344.

    PubMed  CAS  Google Scholar 

  56. Green CJ, Charles RS, Edwards BF, Johnson PH. Identification and characterization of PF4varl, a human gene variant of platelet factor 4. Mol Cell Biol 1989;9(4):1445–1451.

    PubMed  CAS  Google Scholar 

  57. Struyf S, Burdick MD, Proost P, Van Damme J, Strieter RM. Platelets release CXCL4L1, a nonallelic variant of the chemokine platelet factor-4/CXCL4 and potent inhibitor of angiogenesis. Circ Res 2004;95(9):855–857.

    Article  PubMed  CAS  Google Scholar 

  58. Strieter RM, Belperio JA, Phillips RJ, Keane MP. CXC chemokines in angiogenesis of cancer. Semin Cancer Biol 2004;14(3):195–200.

    Article  PubMed  CAS  Google Scholar 

  59. Strieter RM, Belperio JA, Phillips RJ, Keane MP. Chemokines: angiogenesis and metastases in lung cancer. Novartis Found Symp 2004;256:173–84.

    PubMed  CAS  Google Scholar 

  60. Brandt E, Petersen F, Ludwig A, Ehlert JE, Bock L, Flad HD. The beta-thromboglobulins and platelet factor 4: blood platelet-derived CXC chemokines with divergent roles in early neutrophil regulation. J Leukoc Biol 2000;67(4):471–478.

    PubMed  CAS  Google Scholar 

  61. Gentilini G, Kirschbaum NE, Augustine JA, Aster RH, Visentin GP. Inhibition of human umbilical vein endothelial cell proliferation by the CXC chemokine, platelet factor 4 (PF4), is associated with impaired downregulation of p21(Cip1/WAF1). Blood 1999;93(1):25–33.

    PubMed  CAS  Google Scholar 

  62. Sulpice E, Bryckaert M, Lacour J, Contreres JO, Tobelem G. Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway. Blood 2002;100(9):3087–3094.

    Article  PubMed  CAS  Google Scholar 

  63. Perollet C, Han ZC, Savona C, Caen JP, Bikfalvi A. Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization. Blood 1998;91(9):3289–3299.

    PubMed  CAS  Google Scholar 

  64. Dudek AZ, Nesmelova I, Mayo K, Verfaillie CM, Pitchford S, Slungaard A. Platelet factor 4 promotes adhesion of hematopoietic progenitor cells and binds IL-8: novel mechanisms for modulation of hematopoiesis. Blood 2003;101(12):4687–4694.

    Article  PubMed  CAS  Google Scholar 

  65. Shellenberger TD, Wang M, Gujrati M, et al. BRAK/CXCL14 is a potent inhibitor of angiogenesis and is a chemotactic factor for immature dendritic cells. Cancer Res 2004;64:8262–8270.

    Article  PubMed  CAS  Google Scholar 

  66. Frederick MJ, Henderson Y, Xu X, et al. In vivo expression of the novel CXC chemokine BRAK in normal and cancerous human tissue. Am J Pathol 2000;156(6):1937–1950.

    PubMed  CAS  Google Scholar 

  67. Schwarze SR, Luo J, Isaacs WB, Jarrard DF. Modulation of CXCL14 (BRAK) expression in prostate cancer. Prostate 2005;13:13.

    Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA

    Michael P. Keane & John A. Belperio

  2. Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA

    Robert M. Strieter

Authors
  1. Michael P. Keane
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  2. John A. Belperio
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  3. Robert M. Strieter
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Editors and Affiliations

  1. Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL

    Jeffrey K. Harrison PhD

  2. Department of Pathology and Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI

    Nicholas W. Lukacs PhD

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© 2007 Humana Press Inc., Totowa, NJ

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Keane, M.P., Belperio, J.A., Strieter, R.M. (2007). Chemokines and Angiogenesis. In: Harrison, J.K., Lukacs, N.W. (eds) The Chemokine Receptors. The Receptors. Humana Press. https://doi.org/10.1007/978-1-59745-020-1_15

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