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19 - Cytokines and Chemokines in Inflammation and Cancer

from PART IV - IMMUNOPHARMACOLOGY

Published online by Cambridge University Press:  05 April 2014

By
Thorsten Hagemann  and
Toby Lawrence
Edited by
Charles N. Serhan ,
Peter A. Ward  and
Derek W. Gilroy
With contributions by
Samir S. Ayoub
Thorsten Hagemann
Affiliation:
Barts and the London School of Medicine and Dentistry
Toby Lawrence
Affiliation:
Barts and The London School of Medicine and Dentistry
Charles N. Serhan
Affiliation:
Harvard Medical School
Peter A. Ward
Affiliation:
University of Michigan, Ann Arbor
Derek W. Gilroy
Affiliation:
University College London
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Summary

Cytokines and chemokines are peptide mediators that regulate a broad range of processes involved in the pathogenesis of inflammatory diseases and cancer. It is well established that an imbalance cytokine or chemokine activities can favor chronic inflammation leading to organ failure. Chemokines and cytokines are also implicated in malignant disease with links to tumor progression, angiogenesis, and invasion. Biological therapies targeting cytokines and chemokines have already improved outcomes of inflammatory disease and clinical trials are ongoing in cancer patients. Targeting tumor necrosis factor (TNF)-α represents a major success story for this approach. Anti-TNF-α was the first antibody against an inflammatory cytokine demonstrated to be efficacious in human disease and it showed over the years to be effective in a range of inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and more recently, cancer.

CANCER AND INFLAMMATION

The cells and mediators of inflammation also form a major part of the tumor microenvironment. In some cancers, inflammatory conditions precede development of malignancy; in others, oncogenic changes drive a tumor-promoting inflammatory milieu. Whatever its origin, this “smoldering” inflammation aids proliferation and survival of malignant cells, angiogenesis, and metastasis; subverts adaptive immunity, and alters response to hormones and chemotherapeutic agents [1, 2]. The cytokine (Figure 19.1) and chemokine network (Figure 19.2) is of great importance in the processes of cancer-related inflammation regulating both host and malignant cells in the tumor microenvironment [3].

Type
Chapter
Information
Fundamentals of Inflammation , pp. 244 - 252
Publisher: Cambridge University Press
Print publication year: 2010

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References

1. Balkwill, F. 2005. Immunology for the next generation. Nat Rev Immunol 5:509–512.CrossRefGoogle ScholarPubMed
2. Bonecchi, R., Borroni, E.M., Anselmo, A., et al. 2008. Regulation of D6 chemokine scavenging activity by ligand- and Rab11-dependent surface up-regulation. Blood 112:493–503.CrossRefGoogle ScholarPubMed
3. Balkwill, F., and Coussens, L.M. 2004. Cancer: an inflammatory link. Nature 431:405–406.CrossRefGoogle Scholar
4. Feldmann, M., and Maini, S.R. 2008. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol Rev 223:7–19.CrossRefGoogle ScholarPubMed
5. Moore, R.J., Owens, D.M., Stamp, G., et al. 1999. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5:828–831.CrossRefGoogle ScholarPubMed
6. Kulbe, H., Thompson, R., Wilson, J.L., et al. 2007. The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res 67:585–592.CrossRefGoogle ScholarPubMed
7. Yang, H., Bocchetta, M., Kroczynska, B., et al. 2006. TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proc Natl Acad Sci USA 103:10397–10402.CrossRefGoogle Scholar
8. Hussain, S.P., Hofseth, L.J., and Harris, C.C. 2003. Radical causes of cancer. Nat Rev Cancer 3:276–285.CrossRefGoogle Scholar
9. Mocellin, S., Rossi, C.R., Pilati, P., and Nitti, D. 2005. Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev 16:35–53.CrossRefGoogle ScholarPubMed
10. Elgert, K.D., Alleva, D.G., and Mullins, D.W. 1998. Tumor-induced immune dysfunction: the macrophage connection. J Leukoc Biol 64:275–290.CrossRefGoogle ScholarPubMed
11. Arnott, C.H., Scott, K.A., Moore, R.J., Robinson, S.C., Thompson, R.G., and Balkwill, F.R. 2004. Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development. Oncogene 23:1902–1910.CrossRefGoogle ScholarPubMed
12. Tomita, Y., Y. X., , Ishida, Y., et al. 2004. Spontaneous regression of lung metastasis in the absence of tumour necrosis factor p55. Int J Cancer 112:927–933.CrossRefGoogle Scholar
13. Kitakata, H., Nemoto-Sasaki, Y., Takahashi, Y., Kondo, T., Mai, M., and Mukaida, N. 2002. Essential roles of tumor necrosis factor receptor p55 in liver metastasis of intrasplenic administration of colon 26 cells. Cancer Res 62:6682–6687.Google ScholarPubMed
14. Popivanova, B.K., Kitamura, K., Wu, Y., et al. 2008. Blocking TNF-alpha in mice reduces colorectal car-cinogenesis associated with chronic colitis. J Clin Invest 118:560–570.Google Scholar
15. Pikarsky, E., Porat, R.M., Stein, I., et al. 2004. NF-kappaB functions as a tumour promoter in inlammation-associated cancer. Nature 431:461–466.CrossRefGoogle ScholarPubMed
16. Maeda, S., Kamata, H., Luo, J.L., Leffert, H., and Karin, M. 2005. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977–990.CrossRefGoogle ScholarPubMed
17. Rao, V.P., Poutahidis, T., Ge, Z., et al. 2006. Proinflammatory CD4+CD45RBhi lymphocytes promote mammary and intestinal carcinogenesis in ApcMin/+ mice. Cancer Res 66:57–61.CrossRefGoogle Scholar
18. Egberts, J.-H., Cloosters, V., Noack, A., et al. 2008. Antitumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res 68:1443–1450.CrossRefGoogle Scholar
19. Naylor, M.S., Stamp, G. W. H., Foulkes, W.D., Eccles, D., and Balkwill, F.R. 1993. Tumor necrosis factor and its receptors in human ovarian cancer. J Clin Invest 91:2194–2206.CrossRefGoogle ScholarPubMed
20. Harrison, M.L., Obermueller, E., Maisey, N.R., et al. 2007. Tumour necrosis factor (TNF-a) as a new target for renal cell carcinoma: two sequential phase II trials of inliximab at standard and high dose. J Clin Oncol 25(29):4542–4549.CrossRefGoogle Scholar
21. Galban, S., Fan, J., Martindale, J.L., et al. 2003. von Hippel-Lindau protein-mediated repression of tumor necrosis factor alpha translation revealed through use of cDNA arrays. Mol Cell Biol 23:2316–2328.CrossRefGoogle ScholarPubMed
22. Stathopoulos, G.T., Kollintza, A., Moschos, C., et al. 2007. Tumor necrosis factor-a promotes malignant pleural effusion. Cancer Res 67:9825–9834.CrossRefGoogle ScholarPubMed
23. Petersen, S.L., Wang, L., Yalcin-Chin, A., et al. 2007. Autocrine TNFa signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12:445–456.CrossRefGoogle ScholarPubMed
24. Zins, K., Abraham, D., Sioud, M., and Aharinejad, S. 2007. Colon cancer cell-derived tumor necrosis factor-a mediates the tumor growth-promoting response in macrophages by up-regulating the colony-stimulating factor-1 pathway. Cancer Res 67:1038–1045.CrossRefGoogle ScholarPubMed
25. Madhusudan, S., Foster, M., Muthuramalingam, S.R., et al. 2004. A phase II study of Etanercept (Enbrel), a tumour necrosis factor-a inhibitor in patients with meta-static breast cancer. Clinical Cancer Res 10:6528–6534.CrossRefGoogle Scholar
26. Madhusudan, S., Muthuramalingam, S.R., Braybrooke, J.P., et al. 2005. A phase II study of Ethanercept (ENBREL) a tumour necrosis factor-a inhibitor in recurrent ovarian cancer. J Clin Oncol 10:6528–6534.Google Scholar
27. Harrison, M.L., Obermueller, E., Maisey, N.R., et al. 2007. Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose. J Clin Oncol 25:4542–4549.CrossRefGoogle ScholarPubMed
28. Brown, E.R., Charles, K.A., Hoare, S.A., et al. 2008. A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer. Ann Oncol 19(7):1340–1346.CrossRefGoogle ScholarPubMed
29. Screpanti, I., Musiani, P., Bellavia, D., et al. 1996. Inactivation of the IL-6 gene prevents development of multicentric Castleman's disease in C/EBP beta-deficient mice. J Exp Med 184:1561–1566.CrossRefGoogle ScholarPubMed
30. Bommert, K., Bargou, R.C., and Stuhmer, T. 2006. Signalling and survival pathways in multiple myeloma. Eur J Cancer 42:1574–1580.CrossRefGoogle ScholarPubMed
31. Mudter, J., Amoussina, L., Schenk, M., et al. 2008. The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6. J Clin Invest 118:2415–2426.Google ScholarPubMed
32. Greten, F.R., Eckmann, L., Greten, T.E., et al. 2004. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296.CrossRefGoogle Scholar
33. Weigmann, B., Lehr, H.A., Yancopoulos, G., et al. 2008. The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. J Exp Med 205:2099–2110.CrossRefGoogle ScholarPubMed
34. Naugler, W.E., Sakurai, T., Kim, S., et al. 2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–124.CrossRefGoogle ScholarPubMed
35. Mantovani, A., Allavena, P., Sica, A., and Balkwill, F. 2008. Cancer-related inflammation. Nature 454:436–444.CrossRefGoogle ScholarPubMed
36. Ogden, C.A., Pound, J.D., Batth, B.K., et al. 2005. Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt's lymphoma. J Immunol 174:3015–3023.CrossRefGoogle Scholar
37. Lech-Maranda, E., Bienvenu, J., Michallet, A-S., et al. 2006. Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma. Eur Cytokine Netw 17:60–66.Google ScholarPubMed
38. Mocellin, S., Marincola, F.M., and Young, H.A. 2005. Interleukin-10 and the immune response against cancer: a counterpoint. J Leukoc Biol 78:1043–1051.CrossRefGoogle ScholarPubMed
39. Mangan, P.R., Harrington, L.E., O'Quinn, D.B., et al. 2006. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234.CrossRefGoogle Scholar
40. Park, H., Li, Z., O'Yang, X., et al. 2005. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141.CrossRefGoogle ScholarPubMed
41. Moseley, T.A., Haudenschild, D.R., Rose, L., and Reddi, A.H. 2003. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14:155–174.CrossRefGoogle ScholarPubMed
42. Numasaki, M., Watanabe, M., Suzuki, T., et al. 2005. IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol 175:6177–6189.CrossRefGoogle ScholarPubMed
43. Tartour, E., Fossiez, F., Joyeux, I., et al. 1999. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res 59:3698–3704.Google ScholarPubMed
44. Numasaki, M., Fukushi, J., Ono, M., et al. 2003. Interleukin-17 promotes angiogenesis and tumor growth. Blood 101:2620–2627.CrossRefGoogle ScholarPubMed
45. Benchetrit, F., Ciree, A., Vives, V., et al. 2002. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 99:2114–2121.CrossRefGoogle ScholarPubMed
46. Dranoff, G. 2004. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4:11–22.CrossRefGoogle ScholarPubMed
47. Lawrence, T., Hageman, T., and Balkwill, F. 2007. Cancer. Sex, cytokines, and cancer. Science 317:51–52.CrossRefGoogle Scholar
48. Yang, G., Rosen, D.G., Zhang, Z., et al. 2006. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci USA 103:16472–16477.CrossRefGoogle ScholarPubMed
49. Soucek, L., Lawlor, E.R., Soto, D., Shchors, K., Swigart, L.B., and Evan, G.I.. 2007. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13:1211–1218.CrossRefGoogle ScholarPubMed
50. Borrello, M.G., Alberti, L., Fischer, A., et al. 2005. Induction of a proinlammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proc Natl Acad Sci USA 102:14825–14830.CrossRefGoogle Scholar
51. Mantovani, A., Sozzani, S., Locati, M., Allavena, P., and Sica, A. 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549–555.CrossRefGoogle ScholarPubMed
52. Bingle, L., Brown, N.J., and Lewis, C.E. 2002. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254–265.CrossRefGoogle ScholarPubMed
53. Condeelis, J., and Pollard, J.W. 2006. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266.CrossRefGoogle ScholarPubMed
54. Kassiotis, G., and Kollias, G. 2001. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J Exp Med 193:427–434.CrossRefGoogle ScholarPubMed
55. Hagemann, T., Lawrence, T., McNeish, I., et al. 2008. “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268.CrossRefGoogle ScholarPubMed
56. Jamieson, T., Cook, D.N., Nibbs, R.J.B., et al. 2005. The chemokine receptor D6 limits the inlammatory response in vivo. Nat Immunol 6:403–411.CrossRefGoogle Scholar
57. Nibbs, R.J., Gilchrist, D.S., King, V., et al. 2007. The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumours. J Clin Invest 117:1752–1755.CrossRefGoogle Scholar
58. Rot, A., and von Andrian, U. H. 2004. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 22:891–928.CrossRefGoogle ScholarPubMed
59. Mantovani, A. 1999. The chemokine system: redundancy for robust outputs. Immunol Today 20:254–257.CrossRefGoogle ScholarPubMed
60. Murphy, C.A., Hoek, R.M., Wiekowski, M.T., Lira, S.A., and Sedgwick, J.D. 2002. Interactions between hemopoietically derived TNF and central nervous system-resident glial chemokines underlie initiation of autoimmune inflammation of the brain. J Immunol 169:7054–7062.CrossRefGoogle Scholar
61. Allen, S.J., Crown, S.E., and Handel, T.M. 2006. Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25:787–820.Google Scholar
62. Graham, G.J., and McKimmie, C.S. 2006. Chemokine scavenging by D6: a movable feast?Trends Immunol 27:381–386.CrossRefGoogle ScholarPubMed
63. Alcami, A. 2007. New insights into the subversion of the chemokine system by poxviruses. Eur J Immunol 37:880–883.CrossRefGoogle ScholarPubMed
64. Robinson, S.C., Scott, K.A., Wilson, J.L., Thompson, R.G., Proudfoot, A.E.I., and Balkwill, F.R. 2003. A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res 63:8360–8365.Google ScholarPubMed
65. Loberg, R.D., Ying, C., Craig, M., et al. 2007. Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res 67:9417–9424.CrossRefGoogle ScholarPubMed
66. Bertolini, F., Ying, C., Craig, M., et al. 2002. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin's lymphoma. Cancer Res 62:3106–3112.Google ScholarPubMed
67. Rubin, J.B., Kung, A.L., Klein, R.S., et al. 2003. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 100:13513–13518.CrossRefGoogle ScholarPubMed
68. Merritt, W.M., Lin, Y.G., Spannuth, W.A., et al. 2008. Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth. J Natl Cancer Inst 100:359–372.CrossRefGoogle ScholarPubMed
69. Miao, Z., Luker, K.E., Summers, B.C., et al. 2007. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci USA 104:15735–15740.CrossRefGoogle ScholarPubMed
70. Strand, V., Kimberly, R., and Isaacs, J.D. 2007. Biologic therapies in rheumatology: lessons learned, future directions. Nat Rev 6:75–91.Google ScholarPubMed
71. Feldmann, M. 2002. Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol 2:364–371.CrossRefGoogle ScholarPubMed
72. Sands, B.E., Anderson, F.H., Bernstein, C.N., et al. 2004. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 350:876–885.CrossRefGoogle ScholarPubMed
73. Scheinecker, C., Redlich, K., and Smolen, J.S. 2008. Cytokines as therapeutic targets: advances and limitations. Immunity 28:440–444.CrossRefGoogle ScholarPubMed
74. Rao, V.P., Poutahidis, T., Ge, Z., et al. 2006. Innate immune inflammatory response against enteric bacteria helicobacter hepaticus induces mammary adenocarcinoma in mice. Cancer Res 66:7395–7400.CrossRefGoogle ScholarPubMed
75. Scott, K.A., Moore, R.J., Arnott, C.H., et al. 2003. An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors. Mol Cancer Ther 2:445–451.Google ScholarPubMed
76. Smolen, J.S., Aletaha, D., Koeller, M., Weisman, M.H., and Emery, P. 2007. New therapies for treatment of rheumatoid arthritis. Lancet 370:1861–1874.CrossRefGoogle ScholarPubMed
77. Smolen, J.S., Beaulieu, A., Rubbert-Roth, A., et al. 2008. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371:987–997.CrossRefGoogle ScholarPubMed
78. Nagabhushanam, V., Solache, A., Ting, L-M., Escaron, C.J., Zhang, J.Y., and Ernst, J.D. 2003. Innate inhibition of adaptive immunity: mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J Immunol 171:4750–4757.CrossRefGoogle ScholarPubMed
79. Charles, P., Elliott, M.J., Davis, D., et al. 1999. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol 163:1521–1528.Google ScholarPubMed
Egberts, J.-H., Cloosters, V., Noack, A., et al. 2008. Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res 68:1443–1450.CrossRefGoogle ScholarPubMed
Mantovani, A. 1999. The chemokine system: redundancy for robust outputs. Immunol Today 20:254–257.CrossRefGoogle ScholarPubMed
Nibbs, R.J., Gilchrist, D., King, V., et al. 2007. The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumours. J Clin Invest 117:1752–1755.CrossRefGoogle Scholar
Rot, A., and von Andrian, U.H. 2004. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 22:891–928.CrossRefGoogle ScholarPubMed
Tomita, Y., Yang, X., Ishida, Y., et al. 2004. Spontaneous regression of lung metastasis in the absence of tumour necrosis factor p55. Int J Cancer 112:927–933.CrossRefGoogle Scholar

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