Pulmonary Angiogenesis in Neoplastic and Nonneoplastic Disorders

  • Michael P. Keane
  • Robert M. Strieter
Part of the Molecular Pathology Library book series (MPLB, volume 1)


Angiogenesis is the process of new blood vessel growth and is a critical biologic process in both physiologic and pathologic conditions. Angiogenesis can occur in physiologic conditions, including normal wound repair and embryogenesis. In contrast, pathologic angiogenesis is associated with chronic inflammatory and fibroproliferative disorders, as well as growth of tumors. A variety of factors have been described that either promote or inhibit angiogenesis, including the CXC chemokines, endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). In the local microenvironment, net angiogenesis is determined by the balance between angiogenic and angiostatic factors.


Vascular Endothelial Growth Factor Aberrant Angiogenesis Angiostatic Activity Pulmonary Angiogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    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.PubMedCrossRefGoogle Scholar
  2. 2.
    Belperio JA, Keane MP, Arenberg DA, et al. CXC chemokines in angiogenesis. J Leuk Biol 2000;68(1):1–8.Google Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Boulday G, Haskova Z, Reinders ME, Pal S, Briscoe DM. Vascular endothelial growth factor-induced signaling pathways in endothelial cells that mediate overexpression of the chemokine IFN-{gamma}-inducible protein of 10 kDa in vitro and in vivo. J Immunol 2006;176(5):3098–3107.PubMedGoogle Scholar
  5. 5.
    Ranieri G, Patruno R, Ruggieri E, et al. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem 2006;13(16):1845–1857.PubMedCrossRefGoogle Scholar
  6. 6.
    Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 2006;3(1):24–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Giatromanolaki A, Sivridis E, Koukourakis MI. Angiogenesis in colorectal cancer: prognostic and therapeutic implications. Am J Clin Oncol 2006;29(4):408–417.PubMedCrossRefGoogle Scholar
  8. 8.
    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):27348–27357PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedGoogle Scholar
  10. 10.
    Murdoch C, Monk PN, Finn A. CXC chemokine receptor expression on human endothelial cells. Cytokine 1999;11(9):704–712.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    Richmond A, Fan GH, Dhawan P, Yang J. How do chemokine/chemokine receptor activations affect tumorigenesis? Novartis Found Symp 2004;256:74–89, 91, 106’111, 266’269.PubMedCrossRefGoogle Scholar
  14. 14.
    Devalaraja RM, Nanney LB, Du J, et al. Delayed wound healing in CXCR2 knockout mice. J Invest Dermatol 2000;115(2):234–244.PubMedCrossRefGoogle Scholar
  15. 15.
    Burger M, Burger JA, Hoch RC, et al. 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.PubMedGoogle Scholar
  16. 16.
    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(8):1469–1472.PubMedCrossRefGoogle Scholar
  17. 17.
    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.PubMedCrossRefGoogle Scholar
  18. 18.
    Pawson T, Scott JD. Signaling through scaffold, anchoring, and adaptor proteins. Science 1997;278(5346):2075–2080.PubMedCrossRefGoogle Scholar
  19. 19.
    Shyamala V, Khoja H. Interleukin-8 receptors R1 and R2 activate mitogen-activated protein kinases and induce cfos, independent of Ras and Raf-1 in Chinese hamster ovary cells. Biochemistry 1998;37(45):15918–15924.PubMedCrossRefGoogle Scholar
  20. 20.
    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.PubMedCrossRefGoogle Scholar
  21. 21.
    Arvanitakis L, Geras-Raaka E, Varma A, et al. Human herpesvirus KSHV encodes a constitutively active Gprotein-coupled receptor linked to cell proliferation. Nature 1997;385(6614):347–350.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Geras-Raaka E, Arvanitakis L, Bais C, et al. 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 1 1998;187(5):801–806.CrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 25.
    Guo HG, Sadowska M, Reid W, et al. Kaposi’s sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J Virol 2003;77(4):2631–2639.PubMedCrossRefGoogle Scholar
  26. 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 Leuk Biol 1997;62(5):588–597.Google Scholar
  27. 27.
    Maussang D, Verzijl D, van Walsum M, et al. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc Natl Acad Sci USA 2006;103:13068–13073.PubMedCrossRefGoogle Scholar
  28. 28.
    Luster AD, Cardiff RD, MacLean JA, et al. Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine. Proc Assoc Am Physicians 1998;110(3):183–196.PubMedGoogle Scholar
  29. 29.
    Rollins BJ. Chemokines. Blood 1997;90(3):909–928.PubMedGoogle Scholar
  30. 30.
    Balkwill F. The molecular and cellular biology of the chemokines. J Viral Hepat 1998;5(1):1–14.PubMedCrossRefGoogle Scholar
  31. 31.
    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):3696–705.PubMedCrossRefGoogle Scholar
  32. 32.
    Ehlert JE, Addison CA, Burdick MD, et al. Identification and partial characterization of a variant of human CXCR3 generated by posttranscriptional exon skipping. J Immunol 2004;173(10):6234–6240.PubMedGoogle Scholar
  33. 33.
    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.PubMedCrossRefGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    Salani D, Di Castro V, Nicotra MR, et al. Role of endothelin-1 in neovascularization of ovarian carcinoma. Am J Pathol 2000;157(5):1537–1547.PubMedGoogle Scholar
  37. 37.
    Salani D, Taraboletti G, Rosano L, et al. Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol 2000;157(5):1703–1711.PubMedGoogle Scholar
  38. 38.
    Pedram A, Razandi M, Hu RM, Levin ER. Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion. J Biol Chem 1997;272(27):17097–17103.PubMedCrossRefGoogle Scholar
  39. 39.
    Venuti A, Salani D, Manni V, et al. Expression of endothelin 1 and endothelin A receptor in HPV-associated cervical carcinoma: new potential targets for anticancer therapy. FASEB J 2000;14(14):2277–2283.PubMedCrossRefGoogle Scholar
  40. 40.
    Cruz A, Parnot C, Ribatti D, et al. Endothelin-1, a regulator of angiogenesis in the chick chorioallantoic membrane. J Vasc Res 2001;38(6):536–545.PubMedCrossRefGoogle Scholar
  41. 41.
    Bek EL, McMillen MA. Endothelins are angiogenic. J Cardiovasc Pharmacol 2000;36(5 Suppl 1):S135–S139.PubMedGoogle Scholar
  42. 42.
    Akimoto M, Hashimoto H, Maeda A, et al. Roles of angiogenic factors and endothelin-1 in gastric ulcer healing. Clin Sci (Lond) 2002;103(Suppl 48):450S–454S.Google Scholar
  43. 43.
    Tsui JC, Baker DM, Biecker E, et al. Potential role of endothelin 1 in ischaemia-induced angiogenesis in critical leg ischaemia. Br J Surg 2002;89(6):741–747.PubMedCrossRefGoogle Scholar
  44. 44.
    Favier J, Plouin P-F, Corvol P, Gasc J-M. Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. Am J Pathol 2002;161(4):1235–1246.PubMedGoogle Scholar
  45. 45.
    Rosano L, Spinella F, Salani D, et al. Therapeutic targeting of the endothelin a receptor in human ovarian carcinoma. Cancer Res 2003;63(10):2447–2453.PubMedGoogle Scholar
  46. 46.
    Fagan KA, McMurtry IF, Rodman DM. Role of endothelin-1 in lung disease. Respir Res 2001;2(2):90–101.PubMedCrossRefGoogle Scholar
  47. 47.
    Hoeper MM, Galie N, Simonneau G, Rubin LJ. New treatments for pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165(9):1209–1216.PubMedCrossRefGoogle Scholar
  48. 48.
    Lee SD, Shroyer KR, Markham NE, et al. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998;101(5):927–934.PubMedCrossRefGoogle Scholar
  49. 49.
    Tuder RM, Voelkel NF. Angiogenesis and pulmonary hypertension: a unique process in a unique disease. Antioxid Redox Signal 2002;4(5):833–843.PubMedCrossRefGoogle Scholar
  50. 50.
    Tuder RM, Chacon M, Alger L, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol 2001;195(3):367–374.PubMedCrossRefGoogle Scholar
  51. 51.
    Taraseviciene-Stewart L, Kasahara Y, Alger L, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001;15(2):427–438.PubMedCrossRefGoogle Scholar
  52. 52.
    Turner-Warwick M. Precapillary systemic-pulmonary anastomoses. Thorax 1963;18:225–237.PubMedCrossRefGoogle Scholar
  53. 53.
    Peao MND, Aguas AP, DeSa CM, Grande NR. Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin. Anat Rec 1994;238:57–67.PubMedCrossRefGoogle Scholar
  54. 54.
    Mitzner W, Lee W, Georgakopoulos D, Wagner E. Angiogenesis in the mouse lung. Am J Pathol 2000;157(1):93–101.PubMedGoogle Scholar
  55. 55.
    Srisuma S, Biswal SS, Mitzner WA, et al. Identification of genes promoting angiogenesis in mouse lung by transcriptional profiling. Am J Respir Cell Mol Biol 2003;29(2):172–179.PubMedCrossRefGoogle Scholar
  56. 56.
    Keane MP, Arenberg DA, Lynch JPr, et al. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol 1997;159(3):1437–1443.PubMedGoogle Scholar
  57. 57.
    Keane MP, Belperio JA, Arenberg DA, et al. IFNgamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol 1999;163(10):5686–5692.PubMedGoogle Scholar
  58. 58.
    Keane MP, Belperio JA, Moore TA, et al. Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis [In Process Citation]. J Immunol 1999;162(9):5511–5518.PubMedGoogle Scholar
  59. 59.
    Keane MP, Belperio JA, Burdick M, et al. ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;164:2239–2242.PubMedGoogle Scholar
  60. 60.
    Renzoni EA, Walsh DA, Salmon M, et al. Interstitial vascularity in fibrosing alveolitis. Am J Respir Crit Care Med 2003;167(3):438–443.PubMedCrossRefGoogle Scholar
  61. 61.
    Cosgrove GP, Brown KK, Schiemann WP, et al. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med 2004;170:242–251.PubMedCrossRefGoogle Scholar
  62. 62.
    Hyde DM, Henderson TS, Giri SN, et al. Effect of murine gamma interferon on the cellular responses to bleomycin in mice. Exp Lung Res 1988;14:687–704.PubMedCrossRefGoogle Scholar
  63. 63.
    Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350(2):125–133.PubMedCrossRefGoogle Scholar
  64. 64.
    Strieter RM, Starko KM, Enelow RI, et al. Effects of interferon gamma-1b on biomarker expression in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004;170:133–140.PubMedCrossRefGoogle Scholar
  65. 65.
    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.PubMedCrossRefGoogle Scholar
  66. 66.
    Hamada N, Kuwano K, Yamada M, et al. Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice. J Immunol 2005;175(2):1224–1231.PubMedGoogle Scholar
  67. 67.
    Miller LJ, Kurtzman SH, Wang Y, et al. Expression of interleukin-8 receptors on tumor cells and vascular endothelial cells in human breast cancer tissue. Anticancer Res 1998;18(1A):77–81.PubMedGoogle Scholar
  68. 68.
    Richards BL, Eisma RJ, Spiro JD, et al. Coexpression of interleukin-8 receptors in head and neck squamous cell carcinoma. Am J Surg 1997;174(5):507–512.PubMedCrossRefGoogle Scholar
  69. 69.
    Kitadai Y, Haruma K, Sumii K, et al. Expression of interleukin-8 correlates with vascularity in human gastric carcinomas. Am J Pathol 1998;152(1):93–100.PubMedGoogle Scholar
  70. 70.
    Singh RK, Gutman M, Radinsky R, et al. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res 1994;54(12):3242–3247.PubMedGoogle Scholar
  71. 71.
    Cohen RF, Contrino J, Spiro JD, et al. Interleukin-8 expression by head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1995;121(2):202–209.PubMedGoogle Scholar
  72. 72.
    Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res 1999;5(6):1369–1379.PubMedGoogle Scholar
  73. 73.
    Smith DR, Polverini PJ, Kunkel SL, et al. IL-8 mediated angiogenesis in human bronchogenic carcinoma. J Exp Med 1994;179:1409–1415.PubMedCrossRefGoogle Scholar
  74. 74.
    Arenberg DA, Kunkel SL, Burdick MD, et al. Treatment with anti-IL-8 inhibits non-small cell lung cancer tumor growth [abstr]. J Invest Med 1995;43(Suppl 3):479A.Google Scholar
  75. 75.
    Yatsunami J, Tsuruta N, Ogata K, et al. Interleukin-8 participates in angiogenesis in non-small cell, but not small cell carcinoma of the lung. Cancer Lett 1997;120(1):101–108.PubMedCrossRefGoogle Scholar
  76. 76.
    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.PubMedCrossRefGoogle Scholar
  77. 77.
    White ES, Flaherty KR, Carskadon S, et al. Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis. Clin Cancer Res 2003;9(2):853–860.PubMedGoogle Scholar
  78. 78.
    Chen JJ, Yao PL, Yuan A, et al. Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clin Cancer Res 2003;9(2):729–737.PubMedGoogle Scholar
  79. 79.
    Keane MP, Belperio JA, Xue YY, et al. Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 2004;172(5):2853–2860.PubMedGoogle Scholar
  80. 80.
    Gurtsevitch VE, O’Conor GT, Lenoir GM. Burkitt’s lymphoma cell lines reveal different degrees of tumorigenicity in nude mice. Int J Cancer 1988;41(1):87–95PubMedCrossRefGoogle Scholar
  81. 81.
    Sgadari C, Angiolillo AL, Cherney BW, et al. Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo. Proc Natl Acad Sci USA 1996;93(24):13791–13796.PubMedCrossRefGoogle Scholar
  82. 82.
    Arenberg DA, Kunkel SL, Polverini PJ, et al. Interferong-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.PubMedCrossRefGoogle Scholar
  83. 83.
    Feldman AL, Friedl J, Lans TE, et al. Retroviral gene transfer of interferon-inducible protein 10 inhibits growth of human melanoma xenografts. Int J Cancer 2002;99(1):149–153.PubMedCrossRefGoogle Scholar
  84. 84.
    Addison CL, Arenberg DA, Morris SB, et al. The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis. Hum Gene Ther 2000;11(2):247–261.PubMedCrossRefGoogle Scholar
  85. 85.
    Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 2002;64(5–6):993–998.PubMedCrossRefGoogle Scholar
  86. 86.
    Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 2001;7(8):345–350.PubMedCrossRefGoogle Scholar
  87. 87.
    Phillips RJ, Mestas J, Gharaee-Kermani M, et al. Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. J Biol Chem 2005;280(23):22473–22481.PubMedCrossRefGoogle Scholar
  88. 88.
    Minet E, Michel G, Mottet D, et al. Transduction pathways involved in hypoxia-inducible factor-1 phosphorylation and activation. Free Radic Biol Med 2001;31(7):847–855.PubMedCrossRefGoogle Scholar
  89. 89.
    Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 2003;112(5):645–657.PubMedCrossRefGoogle Scholar
  90. 90.
    Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 2004;25(6):280–288.PubMedCrossRefGoogle Scholar
  91. 91.
    Nakanishi C, Toi M. Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 2005;5(4):297–309.PubMedCrossRefGoogle Scholar
  92. 92.
    Mizukami Y, Jo WS, Duerr EM, et al. Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 2005;11(9):992–927.PubMedGoogle Scholar
  93. 93.
    Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol 2002;2(9):664–674.PubMedCrossRefGoogle Scholar
  94. 94.
    Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349(5):427–434.PubMedCrossRefGoogle Scholar
  95. 95.
    Strieter RM. Masters of angiogenesis. Nat Med 2005;11(9):925–927.PubMedCrossRefGoogle Scholar
  96. 96.
    Garkavtsev I, Kozin SV, Chernova O, et al. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 2004;428(6980):328–332.PubMedCrossRefGoogle Scholar
  97. 97.
    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.PubMedCrossRefGoogle Scholar
  98. 98.
    Arenberg DA, Kunkel SL, Polverini PJ, et al. Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 1996;97(12):2792–2802.PubMedCrossRefGoogle Scholar
  99. 99.
    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.PubMedGoogle Scholar
  100. 100.
    Shen H, Schuster R, Stringer KF, et al. The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. FASEB J 2006;20(1):59–64.PubMedCrossRefGoogle Scholar
  101. 101.
    Maione TE, Gray GS, Petro J, et al. Inhibition of angiogenesis by recombinant human platelet factor-4. Science 1990;247:77–79.PubMedCrossRefGoogle Scholar
  102. 102.
    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.PubMedCrossRefGoogle Scholar
  103. 103.
    Eisman R, Surrey S, Ramachandran B, et al. Structural and functional comparison of the genes for human platelet factor 4 and PF4alt. Blood 1990;76(2):336–344.PubMedGoogle Scholar
  104. 104.
    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.PubMedGoogle Scholar
  105. 105.
    Struyf S, Burdick MD, Proost P, et al. 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.PubMedCrossRefGoogle Scholar
  106. 106.
    Brandt E, Petersen F, Ludwig A, et al. The beta-thromboglobulins and platelet factor 4: blood platelet-derived CXC chemokines with divergent roles in early neutrophil regulation. J Leuk Biol 2000;67(4):471–478.Google Scholar
  107. 107.
    Gentilini G, Kirschbaum NE, Augustine JA, et al. 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.PubMedGoogle Scholar
  108. 108.
    Sulpice E, Bryckaert M, Lacour J, et al. 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.PubMedCrossRefGoogle Scholar
  109. 109.
    Perollet C, Han ZC, Savona C, et al. Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization. Blood 1998;91(9):3289–3299.PubMedGoogle Scholar
  110. 110.
    Dudek AZ, Nesmelova I, Mayo K, et al. 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.PubMedCrossRefGoogle Scholar
  111. 111.
    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.PubMedCrossRefGoogle Scholar
  112. 112.
    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.PubMedGoogle Scholar
  113. 113.
    Schwarze SR, Luo J, Isaacs WB, Jarrard DF. Modulation of CXCL14 (BRAK) expression in prostate cancer. Prostate 2005;13:13.Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Michael P. Keane
    • 1
  • Robert M. Strieter
    • 2
  1. 1.Department of Pulmonary and Critical Care MedicineDavid Geffen School of Medicine at UCLALos AngelesUSA
  2. 2.Department of MedicineUniversity of Virginia School of MedicineCharlottesvilleUSA

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