Cytokine & Growth Factor Reviews
Volume 21, Issue 1 , Pages 27-39 , February 2010

The chemokine system in cancer biology and therapy

  • Alberto Mantovani

      Affiliations

    • Department of Translational Medicine, University of Milan, I-20089 Rozzano, Milan, Italy
    • IRCCS Istituto Clinico Humanitas, I-20089 Rozzano, Milan, Italy
    • Corresponding Author InformationCorresponding author at: IRCCS Istituto Clinico Humanitas, Via Manzoni 56, I-20089 Rozzano, Italy, Tel.: +39 02 8224 2444; fax: +39 02 8224 5101.
  • ,
  • Benedetta Savino

      Affiliations

    • Department of Translational Medicine, University of Milan, I-20089 Rozzano, Milan, Italy
    • IRCCS Istituto Clinico Humanitas, I-20089 Rozzano, Milan, Italy
  • ,
  • Massimo Locati

      Affiliations

    • Department of Translational Medicine, University of Milan, I-20089 Rozzano, Milan, Italy
    • IRCCS Istituto Clinico Humanitas, I-20089 Rozzano, Milan, Italy
  • ,
  • Luca Zammataro

      Affiliations

    • IRCCS Istituto Clinico Humanitas, I-20089 Rozzano, Milan, Italy
  • ,
  • Paola Allavena

      Affiliations

    • IRCCS Istituto Clinico Humanitas, I-20089 Rozzano, Milan, Italy
  • ,
  • Raffaella Bonecchi

      Affiliations

    • Department of Translational Medicine, University of Milan, I-20089 Rozzano, Milan, Italy
    • IRCCS Istituto Clinico Humanitas, I-20089 Rozzano, Milan, Italy

References 

  1. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow?. Lancet. 2001;357:539–545
  2. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444
  3. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–867
  4. Mantovani A. Cancer: inflaming metastasis. Nature. 2009;457:36–37
  5. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540–550
  6. Bottazzi B, Polentarutti N, Acero R, et al. Regulation of the macrophage content of neoplasms by chemoattractants. Science. 1983;220:210–212
  7. Mantovani A. The chemokine system: redundancy for robust outputs. Immunol Today. 1999;20:254–257
  8. Mantovani A, Bonecchi R, Locati M. Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol. 2006;6:907–918
  9. Nibbs RJ, Gilchrist DS, King V, et al. The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors. J Clin Invest. 2007;117:1884–1892
  10. Vetrano S, Borroni EM, Sarukhan A, et al. The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6. Gut 2009; Oct 20 [Epub ahead of print].
  11. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 2006;25:315–322
  12. Markiewski MM, Lambris JD. Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol. 2009;30:286–292
  13. Proost P, Struyf S, Van Damme J. Natural post-translational modifications of chemokines. Biochem Soc Trans. 2006;34:997–1001
  14. Proost P, Loos T, Mortier A, et al. Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation. J Exp Med. 2008;205:2085–2097
  15. Grisotto MG, Garin A, Martin AP, et al. The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells. J Clin Invest. 2006;116:1264–1273
  16. 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;191:445–454
  17. Sozzani S, Luini W, Bianchi G, et al. The viral chemokine macrophage inflammatory protein-II is a selective Th2 chemoattractant. Blood. 1998;92:4036–4039
  18. Stine JT, Wood C, Hill M, et al. KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood. 2000;95:1151–1157
  19. Endres MJ, Garlisi CG, Xiao H, Shan L, Hedrick JA. The Kaposi's sarcoma-related herpesvirus (KSHV)-encoded chemokine vMIP-I is a specific agonist for the CC chemokine receptor (CCR)8. J Exp Med. 1999;189:1993–1998
  20. Borrello MG, Alberti L, Fischer A, et al. Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proc Natl Acad Sci USA. 2005;102:14825–14830
  21. Mestdagt M, Polette M, Buttice G, et al. Transactivation of MCP-1/CCL2 by beta-catenin/TCF-4 in human breast cancer cells. Int J Cancer. 2006;118:35–42
  22. Sparmann A, Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell. 2004;6:447–458
  23. Yan W, Chen X. Identification of GRO1 as a critical determinant for mutant p53 gain of function. J Biol Chem. 2009;284:12178–12187
  24. Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med. 2007;13:1211–1218
  25. Buonamici S, Trimarchi T, Ruocco MG, et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature. 2009;459:1000–1004
  26. Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol. 2002;2:664–674
  27. Schwieger M, Schuler A, Forster M, et al. Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C. Blood. 2009;
  28. Akekawatchai C, Holland JD, Kochetkova M, Wallace JC, McColl SR. Transactivation of CXCR4 by the insulin-like growth factor-1 receptor (IGF-1R) in human MDA-MB-231 breast cancer epithelial cells. J Biol Chem. 2005;280:39701–39708
  29. Mira E, Lacalle RA, Gonzalez MA, et al. A role for chemokine receptor transactivation in growth factor signaling. EMBO Rep. 2001;2:151–156
  30. Wallace AE, Sales KJ, Catalano RD, et al. Prostaglandin F2alpha-F-prostanoid receptor signaling promotes neutrophil chemotaxis via chemokine (C-X-C motif) ligand 1 in endometrial adenocarcinoma. Cancer Res. 2009;69:5726–5733
  31. Kulbe H, Hagemann T, Szlosarek PW, Balkwill FR, Wilson JL. The inflammatory cytokine tumor necrosis factor-alpha regulates chemokine receptor expression on ovarian cancer cells. Cancer Res. 2005;65:10355–10362
  32. Schioppa T, Uranchimeg B, Saccani A, et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 2003;198:1391–1402
  33. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature. 2003;425:307–311
  34. Li Y, Qiu X, Zhang S, Zhang Q, Wang E. Hypoxia induced CCR7 expression via HIF-1alpha and HIF-2alpha correlates with migration and invasion in lung cancer cells. Cancer Biol Ther. 2009;8:322–330
  35. Bierie B, Chung CH, Parker JS, et al. Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest. 2009;119:1571–1582
  36. Yang L, Huang J, Ren X, et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008;13:23–35
  37. Sauve K, Lepage J, Sanchez M, Heveker N, Tremblay A. Positive feedback activation of estrogen receptors by the CXCL12-CXCR4 pathway. Cancer Res. 2009;69:5793–5800
  38. Huang J, Hu J, Bian X, et al. Transactivation of the epidermal growth factor receptor by formylpeptide receptor exacerbates the malignant behavior of human glioblastoma cells. Cancer Res. 2007;67:5906–5913
  39. Mantovani A, Allavena P, Sozzani S, Vecchi A, Locati M, Sica A. Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors. Semin Cancer Biol. 2004;14:155–160
  40. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–78
  41. Walter S, Bottazzi B, Govoni D, Colotta F, Mantovani A. Macrophage infiltration and growth of sarcoma clones expressing different amounts of monocyte chemotactic protein/JE. Int J Cancer. 1991;49:431–435
  42. Lavergne E, Combadiere C, Iga M, et al. Intratumoral CC chemokine ligand 5 overexpression delays tumor growth and increases tumor cell infiltration. J Immunol. 2004;173:3755–3762
  43. Manome Y, Wen PY, Hershowitz A, et al. Monocyte chemoattractant protein-1 (MCP-1) gene transduction: an effective tumor vaccine strategy for non-intracranial tumors. Cancer Immunol Immunother. 1995;41:227–235
  44. Rollins BJ, Sunday ME. Suppression of tumor formation in vivo by expression of the JE gene in malignant cells. Mol Cell Biol. 1991;11:3125–3131
  45. Conti I, Rollins BJ. CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol. 2004;14:149–154
  46. Sawanobori Y, Ueha S, Kurachi M, et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood. 2008;111:5457–5466
  47. Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 2008;267:271–285
  48. Okada M, Saio M, Kito Y, et al. Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int J Oncol. 2009;34:1621–1627
  49. Fujimoto H, Sangai T, Ishii G, et al. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 2009;125:1276–1284
  50. Luboshits G, Shina S, Kaplan O, et al. Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res. 1999;59:4681–4687
  51. Ueno T, Toi M, Saji H, et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res. 2000;6:3282–3289
  52. Harlin H, Meng Y, Peterson AC, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69:3077–3085
  53. Ohta M, Kitadai Y, Tanaka S, et al. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human esophageal squamous cell carcinomas. Int J Cancer. 2002;102:220–224
  54. Hu H, Sun L, Guo C, et al. Tumor Cell-Microenvironment Interaction Models Coupled with Clinical Validation Reveal CCL2 and SNCG as Two Predictors of Colorectal Cancer Hepatic Metastasis. Clin Cancer Res. 2009;
  55. Loberg RD, Ying C, Craig M, Yan L, Snyder LA, Pienta KJ. CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia. 2007;9:556–562
  56. Monti P, Leone BE, Marchesi F, et al. The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res. 2003;63:7451–7461
  57. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557–563
  58. Bailey C, Negus R, Morris A, et al. Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis. 2007;24:121–130
  59. Soria G, Yaal-Hahoshen N, Azenshtein E, et al. Concomitant expression of the chemokines RANTES and MCP-1 in human breast cancer: a basis for tumor-promoting interactions. Cytokine. 2008;44:191–200
  60. Dwyer RM, Potter-Beirne SM, Harrington KA, et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res. 2007;13:5020–5027
  61. Sugasawa H, Ichikura T, Kinoshita M, et al. Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination. Int J Cancer. 2008;122:2535–2541
  62. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–174
  63. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183–194
  64. Nozawa H, Chiu C, Hanahan D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA. 2006;103:12493–12498
  65. Bellocq A, Antoine M, Flahault A, et al. Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. Am J Pathol. 1998;152:83–92
  66. Tazzyman S, Lewis CE, Murdoch C. Neutrophils: key mediators of tumour angiogenesis. Int J Exp Pathol. 2009;90:222–231
  67. Xie K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 2001;12:375–391
  68. Cuenca RE, Azizkhan RG, Haskill S. Characterization of GRO alpha, beta and gamma expression in human colonic tumours: potential significance of cytokine involvement. Surg Oncol. 1992;1:323–329
  69. Eck M, Schmausser B, Scheller K, Brandlein S, Muller-Hermelink HK. Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma. Clin Exp Immunol. 2003;134:508–515
  70. Dhawan P, Richmond A. Role of CXCL1 in tumorigenesis of melanoma. J Leukoc Biol. 2002;72:9–18
  71. Wislez M, Philippe C, Antoine M, et al. Upregulation of bronchioloalveolar carcinoma-derived C-X-C chemokines by tumor infiltrating inflammatory cells. Inflamm Res. 2004;53:4–12
  72. Gijsbers K, Gouwy M, Struyf S, et al. GCP-2/CXCL6 synergizes with other endothelial cell-derived chemokines in neutrophil mobilization and is associated with angiogenesis in gastrointestinal tumors. Exp Cell Res. 2005;303:331–342
  73. Proost P, De Wolf-Peeters C, Conings R, Opdenakker G, Billiau A, Van Damme J. Identification of a novel granulocyte chemotactic protein (GCP-2) from human tumor cells. In vitro and in vivo comparison with natural forms of GRO, IP-10, and IL-8. J Immunol. 1993;150:1000–1010
  74. Fioretti F, Fradelizi D, Stoppacciaro A, et al. Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor. J Immunol. 1998;161:342–346
  75. Lee LF, Hellendall RP, Wang Y, et al. IL-8 reduced tumorigenicity of human ovarian cancer in vivo due to neutrophil infiltration. J Immunol. 2000;164:2769–2775
  76. Benelli R, Morini M, Carrozzino F, et al. Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J. 2002;16:267–269
  77. Bell D, Chomarat P, Broyles D, et al. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med. 1999;190:1417–1426
  78. Vicari AP, Treilleux I, Lebecque S. Regulation of the trafficking of tumour-infiltrating dendritic cells by chemokines. Semin Cancer Biol. 2004;14:161–169
  79. Kleeff J, Kusama T, Rossi DL, et al. Detection and localization of MIP-3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int J Cancer. 1999;81:650–657
  80. Scarpino S, Stoppacciaro A, Ballerini F, et al. Papillary carcinoma of the thyroid: hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells. Am J Pathol. 2000;156:831–837
  81. Fushimi T, Kojima A, Moore MA, Crystal RG. Macrophage inflammatory protein 3alpha transgene attracts dendritic cells to established murine tumors and suppresses tumor growth. J Clin Invest. 2000;105:1383–1393
  82. Zou W, Machelon V, Coulomb-L’Hermin A, et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med. 2001;7:1339–1346
  83. Treilleux I, Blay JY, Bendriss-Vermare N, et al. Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res. 2004;10:7466–7474
  84. Ishigami S, Natsugoe S, Tokuda K, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer. 2000;88:577–583
  85. Villegas FR, Coca S, Villarrubia VG, et al. Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer. 2002;35:23–28
  86. Hyakudomi M, Matsubara T, Hyakudomi R, et al. Increased expression of fractalkine is correlated with a better prognosis and an increased number of both CD8+ T cells and natural killer cells in gastric adenocarcinoma. Ann Surg Oncol. 2008;15:1775–1782
  87. Saudemont A, Jouy N, Hetuin D, Quesnel B. NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells. Blood. 2005;105:2428–2435
  88. Lavergne E, Combadiere B, Bonduelle O, et al. Fractalkine mediates natural killer-dependent antitumor responses in vivo. Cancer Res. 2003;63:7468–7474
  89. Wendel M, Galani IE, Suri-Payer E, Cerwenka A. Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Cancer Res. 2008;68:8437–8445
  90. Ishida T, Ueda R. CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci. 2006;97:1139–1146
  91. Liu C, Lou Y, Lizee G, et al. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest. 2008;118:1165–1175
  92. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964
  93. Finn OJ. Cancer immunology. N Engl J Med. 2008;358:2704–2715
  94. Laghi L, Bianchi P, Miranda E, et al. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol. 2009;10:877–884
  95. Oble DA, Loewe R, Yu P, Mihm MC. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 2009;9:3
  96. Pan J, Burdick MD, Belperio JA, et al. CXCR3/CXCR3 ligand biological axis impairs RENCA tumor growth by a mechanism of immunoangiostasis. J Immunol. 2006;176:1456–1464
  97. Ohtani H, Jin Z, Takegawa S, Nakayama T, Yoshie O. Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric carcinoma. J Pathol. 2009;217:21–31
  98. Musha H, Ohtani H, Mizoi T, et al. Selective infiltration of CCR5(+)CXCR3(+) T lymphocytes in human colorectal carcinoma. Int J Cancer. 2005;116:949–956
  99. Zeng Y, Huebener N, Fest S, et al. Fractalkine (CX3CL1)- and interleukin-2-enriched neuroblastoma microenvironment induces eradication of metastases mediated by T cells and natural killer cells. Cancer Res. 2007;67:2331–2338
  100. Ludwig A, Schulte A, Schnack C, et al. Enhanced expression and shedding of the transmembrane chemokine CXCL16 by reactive astrocytes and glioma cells. J Neurochem. 2005;93:1293–1303
  101. Wente MN, Gaida MM, Mayer C, et al. Expression and potential function of the CXC chemokine CXCL16 in pancreatic ductal adenocarcinoma. Int J Oncol. 2008;33:297–308
  102. Meijer J, Ogink J, Kreike B, Nuyten D, de Visser KE, Roos E. The chemokine receptor CXCR6 and its ligand CXCL16 are expressed in carcinomas and inhibit proliferation. Cancer Res. 2008;68:4701–4708
  103. Matsumura S, Wang B, Kawashima N, et al. Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol. 2008;181:3099–3107
  104. Gutwein P, Schramme A, Sinke N, et al. Tumoural CXCL16 expression is a novel prognostic marker of longer survival times in renal cell cancer patients. Eur J Cancer. 2009;45:478–489
  105. Hojo S, Koizumi K, Tsuneyama K, et al. High-level expression of chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. Cancer Res. 2007;67:4725–4731
  106. Darash-Yahana M, Gillespie JW, Hewitt SM, et al. The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers. PLoS One. 2009;4:e6695
  107. Gobert M, Treilleux I, Bendriss-Vermare N, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 2009;69:2000–2009
  108. Olkhanud PB, Baatar D, Bodogai M, et al. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res. 2009;69:5996–6004
  109. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–949
  110. Miller AM, Lundberg K, Ozenci V, et al. CD4+CD25 high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol. 2006;177:7398–7405
  111. Mizukami Y, Kono K, Kawaguchi Y, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer. 2008;122:2286–2293
  112. Mailloux AW, Young MR. NK-dependent increases in CCL22 secretion selectively recruits regulatory T cells to the tumor microenvironment. J Immunol. 2009;182:2753–2765
  113. Strieter RM, Burdick MD, Mestas J, Gomperts B, Keane MP, Belperio JA. Cancer CXC chemokine networks and tumour angiogenesis. Eur J Cancer. 2006;42:768–778
  114. Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK. Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis. 2005;8:63–71
  115. Aalinkeel R, Nair MP, Sufrin G, et al. Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells. Cancer Res. 2004;64:5311–5321
  116. Mestas J, Burdick MD, Reckamp K, Pantuck A, Figlin RA, Strieter RM. The role of CXCR2/CXCR2 ligand biological axis in renal cell carcinoma. J Immunol. 2005;175:5351–5357
  117. Strieter RM, Belperio JA, Burdick MD, Sharma S, Dubinett SM, Keane MP. CXC chemokines: angiogenesis, immunoangiostasis, and metastases in lung cancer. Ann N Y Acad Sci. 2004;1028:351–360
  118. Kryczek I, Lange A, Mottram P, et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 2005;65:465–472
  119. Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–348
  120. Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci USA. 2007;104:15735–15740
  121. 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;107:53–63
  122. Naschberger E, Croner RS, Merkel S, et al. Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy. Int J Cancer. 2008;123:2120–2129
  123. Sato E, Fujimoto J, Toyoki H, et al. Expression of IP-10 related to angiogenesis in uterine cervical cancers. Br J Cancer. 2007;96:1735–1739
  124. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–612
  125. Sozzani S, Rusnati M, Riboldi E, Mitola S, Presta M. Dendritic cell-endothelial cell cross-talk in angiogenesis. Trends Immunol. 2007;28:385–392
  126. Chen H, Campbell RA, Chang Y, et al. Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis. Blood. 2009;113:1992–2002
  127. Iba O, Matsubara H, Nozawa Y, et al. Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs. Circulation. 2002;106:2019–2025
  128. Balentien E, Mufson BE, Shattuck RL, Derynck R, Richmond A. Effects of MGSA/GRO alpha on melanocyte transformation. Oncogene. 1991;6:1115–1124
  129. Norgauer J, Metzner B, Schraufstatter I. Expression and growth-promoting function of the IL-8 receptor beta in human melanoma cells. J Immunol. 1996;156:1132–1137
  130. 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;73:94–103
  131. Takamori H, Oades ZG, Hoch OC, Burger M, Schraufstatter IU. Autocrine growth effect of IL-8 and GROalpha on a human pancreatic cancer cell line, Capan-1. Pancreas. 2000;21:52–56
  132. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–56
  133. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761–1767
  134. Ehtesham M, Mapara KY, Stevenson CB, Thompson RC. CXCR4 mediates the proliferation of glioblastoma progenitor cells. Cancer Lett. 2009;274:305–312
  135. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–323
  136. Varney ML, Johansson SL, Singh RK. Distinct expression of CXCL8 and its receptors CXCR1 and CXCR2 and their association with vessel density and aggressiveness in malignant melanoma. Am J Clin Pathol. 2006;125:209–216
  137. Murphy C, McGurk M, Pettigrew J, et al. Nonapical and cytoplasmic expression of interleukin-8, CXCR1, and CXCR2 correlates with cell proliferation and microvessel density in prostate cancer. Clin Cancer Res. 2005;11:4117–4127
  138. Bajetto A, Barbieri F, Dorcaratto A, et al. Expression of CXC chemokine receptors 1-5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int. 2006;49:423–432
  139. Rempel SA, Dudas S, Ge S, Gutierrez JA. Identification and localization of the cytokine SDF1 and its receptor. CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res. 2000;6:102–111
  140. Zhou Y, Larsen PH, Hao C, Yong VW. CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem. 2002;277:49481–49487
  141. Ma X, Norsworthy K, Kundu N, et al. CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model. Mol Cancer Ther. 2009;8:490–498
  142. Walser TC, Rifat S, Ma X, et al. Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res. 2006;66:7701–7707
  143. Kawada K, Sonoshita M, Sakashita H, et al. Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes. Cancer Res. 2004;64:4010–4017
  144. Kawada K, Hosogi H, Sonoshita M, et al. Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. Oncogene. 2007;26:4679–4688
  145. Jones D, Benjamin RJ, Shahsafaei A, Dorfman DM. The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia. Blood. 2000;95:627–632
  146. Ghadjar P, Coupland SE, Na IK, et al. Chemokine receptor CCR6 expression level and liver metastases in colorectal cancer. J Clin Oncol. 2006;24:1910–1916
  147. Meijer J, Zeelenberg IS, Sipos B, Roos E. The CXCR5 chemokine receptor is expressed by carcinoma cells and promotes growth of colon carcinoma in the liver. Cancer Res. 2006;66:9576–9582
  148. Ding Y, Shimada Y, Maeda M, et al. Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma. Clin Cancer Res. 2003;9:3406–3412
  149. Gunther K, Leier J, Henning G, et al. Prediction of lymph node metastasis in colorectal carcinoma by expressionof chemokine receptor CCR7. Int J Cancer. 2005;116:726–733
  150. Mashino K, Sadanaga N, Yamaguchi H, et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res. 2002;62:2937–2941
  151. Takanami I. Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. Int J Cancer. 2003;105:186–189
  152. Takeuchi H, Fujimoto A, Tanaka M, Yamano T, Hsueh E, Hoon DS. CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clin Cancer Res. 2004;10:2351–2358
  153. Wiley HE, Gonzalez EB, Maki W, Wu MT, Hwang ST. Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst. 2001;93:1638–1643
  154. Cabioglu N, Yazici MS, Arun B, et al. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin Cancer Res. 2005;11:5686–5693
  155. Ghadjar P, Rubie C, Aebersold DM, Keilholz U. The chemokine CCL20 and its receptor CCR6 in human malignancy with focus on colorectal cancer. Int J Cancer. 2009;125:741–745
  156. Harasawa H, Yamada Y, Hieshima K, et al. Survey of chemokine receptor expression reveals frequent co-expression of skin-homing CCR4 and CCR10 in adult T-cell leukemia/lymphoma. Leuk Lymphoma. 2006;47:2163–2173
  157. Ishida T, Utsunomiya A, Iida S, et al. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res. 2003;9:3625–3634
  158. Kleinhans M, Tun-Kyi A, Gilliet M, et al. Functional expression of the eotaxin receptor CCR3 in CD30+ cutaneous T-cell lymphoma. Blood. 2003;101:1487–1493
  159. Letsch A, Keilholz U, Schadendorf D, et al. Functional CCR9 expression is associated with small intestinal metastasis. J Invest Dermatol. 2004;122:685–690
  160. Simonetti O, Goteri G, Lucarini G, et al. Potential role of CCL27 and CCR10 expression in melanoma progression and immune escape. Eur J Cancer. 2006;42:1181–1187
  161. Buri C, Korner M, Scharli P, et al. CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease. Blood. 2001;97:1543–1548
  162. Shulby SA, Dolloff NG, Stearns ME, Meucci O, Fatatis A. CX3CR1-fractalkine expression regulates cellular mechanisms involved in adhesion, migration, and survival of human prostate cancer cells. Cancer Res. 2004;64:4693–4698
  163. Marchesi F, Piemonti L, Fedele G, et al. The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res. 2008;68:9060–9069
  164. Darash-Yahana M, Pikarsky E, Abramovitch R, et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J. 2004;18:1240–1242
  165. Singh S, Nannuru KC, Sadanandam A, Varney ML, Singh RK. CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion. Br J Cancer. 2009;100:1638–1646
  166. Wang B, Hendricks DT, Wamunyokoli F, Parker MI. A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer. Cancer Res. 2006;66:3071–3077
  167. Wang J, Seethala RR, Zhang Q, et al. Autocrine and paracrine chemokine receptor 7 activation in head and neck cancer: implications for therapy. J Natl Cancer Inst. 2008;100:502–512
  168. Murakami T, Cardones AR, Finkelstein SE, et al. Immune evasion by murine melanoma mediated through CC chemokine receptor-10. J Exp Med. 2003;198:1337–1347
  169. Manes S, Mira E, Colomer R, et al. CCR5 expression influences the progression of human breast cancer in a p53-dependent manner. J Exp Med. 2003;198:1381–1389
  170. Mooi WJ, Peeper DS. Oncogene-induced cell senescence—halting on the road to cancer. N Engl J Med. 2006;355:1037–1046
  171. d’Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8:512–522
  172. Coppe JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853–2868
  173. Acosta JC, O’Loghlen A, Banito A, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133:1006–1018
  174. Kuilman T, Michaloglou C, Vredeveld LC, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133:1019–1031
  175. Acosta JC, Gil J. A role for CXCR2 in senescence, but what about in cancer?. Cancer Res. 2009;69:2167–2170
  176. Mangalmurti NS, Xiong Z, Hulver M, et al. Loss of red cell chemokine scavenging promotes transfusion-related lung inflammation. Blood. 2009;113:1158–1166
  177. Pruenster M, Mudde L, Bombosi P, et al. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nat Immunol. 2009;10:101–108
  178. 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;4:28
  179. Horton LW, Yu Y, Zaja-Milatovic S, Strieter RM, Richmond A. Opposing roles of murine Duffy antigen receptor for chemokine and murine CXC chemokine receptor-2 receptors in murine melanoma tumor growth. Cancer Res. 2007;67:9791–9799
  180. Lentsch AB. The Duffy antigen/receptor for chemokines (DARC) and prostate cancer. A role as clear as black and white?. FASEB J. 2002;16:1093–1095
  181. Waugh DJ, Wilson C, Seaton A, Maxwell PJ. Multi-faceted roles for CXC-chemokines in prostate cancer progression. Front Biosci. 2008;13:4595–4604
  182. Shen H, Schuster R, Stringer KF, Waltz SE, Lentsch AB. The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. Faseb J. 2006;20:59–64
  183. Bandyopadhyay S, Zhan R, Chaudhuri A, et al. Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med. 2006;12:933–938
  184. Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol. 2005;6:801–811
  185. Horuk R, Wang ZX, Peiper SC, Hesselgesser J. Identification and characterization of a promiscuous chemokine-binding protein in a human erythroleukemic cell line. J Biol Chem. 1994;269:17730–17733
  186. Desbaillets I, Diserens AC, Tribolet N, Hamou MF, Van Meir EG. Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. J Exp Med. 1997;186:1201–1212
  187. Tang T, Owen JD, Du J, Walker CL, Richmond A. Molecular cloning and characterization of a mouse gene with homology to the Duffy-antigen receptor for chemokines. DNA Seq. 1998;9:129–143
  188. Wang J, Ou ZL, Hou YF, et al. Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential. Oncogene. 2006;25:7201–7211
  189. Martinez de la Torre Y, Buracchi C, Borroni EM, et al. Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. Proc Natl Acad Sci USA. 2007;104:2319–2324
  190. Nibbs RJ, Kriehuber E, Ponath PD, et al. The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. Am J Pathol. 2001;158:867–877
  191. McKimmie CS, Fraser AR, Hansell C, et al. Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1. J Immunol. 2008;181:8171–8181
  192. Daibata M, Matsuo Y, Machida H, Taguchi T, Ohtsuki Y, Taguchi H. Differential gene-expression profiling in the leukemia cell lines derived from indolent and aggressive phases of CD56+ T-cell large granular lymphocyte leukemia. Int J Cancer. 2004;108:845–851
  193. Wu FY, Ou ZL, Feng LY, et al. Chemokine decoy receptor d6 plays a negative role in human breast cancer. Mol Cancer Res. 2008;6:1276–1288
  194. Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem. 2008;283:4283–4294
  195. Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203:2201–2213
  196. Raggo C, Ruhl R, McAllister S, et al. Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. Cancer Res. 2005;65:5084–5095
  197. Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer. 2009;115:2580–2593
  198. Broberg K, Zhang M, Strombeck B, et al. Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15. Int J Oncol. 2002;21:321–326
  199. van Rechem C, Rood BR, Touka M, et al. The scavenger chemokine (C-X-C motif)receptor7 CXCR7 is a direct target gene of hypermethylated in cancer 1 HIC1. J Biol Chem. 2009;
  200. Takenaga M, Tamamura H, Hiramatsu K, et al. A single treatment with microcapsules containing a CXCR4 antagonist suppresses pulmonary metastasis of murine melanoma. Biochem Biophys Res Commun. 2004;320:226–232
  201. Tamamura H, Hori A, Kanzaki N, et al. T140 analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer. FEBS Lett. 2003;550:79–83
  202. Kim SY, Lee CH, Midura BV, et al. Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin Exp Metastasis. 2008;25:201–211
  203. Porvasnik S, Sakamoto N, Kusmartsev S, et al. Effects of CXCR4 antagonist CTCE-9908 on prostate tumor growth. Prostate. 2009;
  204. Richert MM, Vaidya KS, Mills CN, et al. Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone. Oncol Rep. 2009;21:761–767
  205. Kwong J, Kulbe H, Wong D, Chakravarty P, Balkwill F. An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells. Mol Cancer Ther. 2009;8:1893–1905
  206. Liles WC, Broxmeyer HE, Rodger E, et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003;102:2728–2730
  207. De Clercq E. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil). Biochem Pharmacol. 2009;77:1655–1664
  208. Perissinotto E, Cavalloni G, Leone F, et al. Involvement of chemokine receptor 4/stromal cell-derived factor 1 system during osteosarcoma tumor progression. Clin Cancer Res. 2005;11:490–497
  209. Li X, Loberg R, Liao J, et al. A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Res. 2009;69:1685–1692
  210. Rozel S, Galban CJ, Nicolay K, et al. Synergy between anti-CCL2 and docetaxel as determined by DW-MRI in a metastatic bone cancer model. J Cell Biochem. 2009;107:58–64
  211. Ito A, Ishida T, Yano H, et al. Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid. IL-2Rgamma(null) mouse model. Cancer Immunol Immunother. 2009;58:1195–1206
  212. Huang S, Mills L, Mian B, et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol. 2002;161:125–134
  213. Melnikova VO, Bar-Eli M. Bioimmunotherapy for melanoma using fully human antibodies targeting MCAM/MUC18 and IL-8. Pigment Cell Res. 2006;19:395–405
  214. Mian BM, Dinney CP, Bermejo CE, et al. Fully human anti-interleukin 8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metalloproteases and nuclear factor-kappaB. Clin Cancer Res. 2003;9:3167–3175
  215. Zigler M, Villares GJ, Lev DC, Melnikova VO, Bar-Eli M. Tumor immunotherapy in melanoma: strategies for overcoming mechanisms of resistance and escape. Am J Clin Dermatol. 2008;9:307–311
  216. DeNardo DG, Barreto JB, Andreu P, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16:91–102
  217. Ohta M, Tanaka F, Yamaguchi H, Sadanaga N, Inoue H, Mori M. The high expression of Fractalkine results in a better prognosis for colorectal cancer patients. Int J Oncol. 2005;26(1):41–47
  218. Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc Natl Acad Sci USA. 2009;106(40):17031–17036
  219. Popivanova BK, Kostadinova FI, Furuichi K, Shamekh MM, Kondo T, Wada T, et al. Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. Cancer Res. 2009;69(19):7884–7892

PII: S1359-6101(09)00114-2

doi: 10.1016/j.cytogfr.2009.11.007

Cytokine & Growth Factor Reviews
Volume 21, Issue 1 , Pages 27-39 , February 2010