Clinical & Experimental Metastasis

, Volume 19, Issue 3, pp 247–258 | Cite as

Tumors and inflammatory infiltrates: Friends or foes?

  • Claudio Brigati
  • Douglas M. Noonan
  • Adriana Albini
  • Roberto Benelli


The recognition of a role for inflammation in the natural history of a tumor has a long record, stretching from the mid-19th century. From the times of Virkow, who postulated that cancer originates from inflamed tissues, to Metchnikoff and many others, this field has continued to excite (and divide) the scientific community. The question as to whether the inflammatory infiltrate helps or hinders tumors is still open. In a sense, modern molecular biology has, if anything, worsened this dualism, and the literature on this issue shows a plethora of conflicting reports. We would like to provide another contribution to this topic, which was the subject of a recent brilliant review (Balkwill F and Mantovani A. Lancet 2001; 357: 539–45 [1]), by focussing more specifically to the relation between inflammation and tumor invasion and how this could drive rational therapeutic approaches.

angiogenesis antibody chemokine cytokine inflammation leucocyte metalloproteinase metastasis tumor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Balkwill F, Mantovani A. Inflammation and cancer: Back to Virkow? Lancet 2001; 357: 539–45.PubMedGoogle Scholar
  2. 2.
    Chomez P, De Backer O, Bertrand M et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res 2001; 61(14): 5544–51.PubMedGoogle Scholar
  3. 3.
    Wada Y, Nakashima O, Kutami R et al. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepathology 1998; 27: 407–14.Google Scholar
  4. 4.
    Darnell RB, DeAngelis L.M. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 1993; 341(8836): 21–2.PubMedGoogle Scholar
  5. 5.
    Balzar M, Winter MJ, de Boer CJ et al. The biology of the 17-1A antigen (Ep-CAM). J Mol Med 1999; 77: 699–712.PubMedGoogle Scholar
  6. 6.
    Glennie MJ, Johnson PW, Clinical trials of antibody therapy. Immunol Today 2000; 21(8): 403–10.PubMedGoogle Scholar
  7. 7.
    Chen YT, Scanlan MJ, Sahin U et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA 1997; 94(5): 1914–8.PubMedGoogle Scholar
  8. 8.
    Benelli R, Morini M, Carozzino F et al. Neutrophils as a key cellular target for angiostatin: Implications for regulation of angiogenesis and inflammation. Faseb J 2002; 16: 267–9 [online; Faseb J 2001; 10.1096/fj.01-0651fje].PubMedGoogle Scholar
  9. 9.
    Sciacca F, Stuerzl M, Bussolino F et al. Expression of adhesion molecules, platelet-activating factor, and chemokines by Kaposi's sarcoma cells. J Immunol 1994; 153: 4816–25.PubMedGoogle Scholar
  10. 10.
    Bussolati B, Biancone L, Cassoni P et al. PAF produced by human breast cancer cells promotes migration and proliferation of tumor cells and neo-angiogenesis. Am J Pathol 2000; 157: 1713–25.PubMedGoogle Scholar
  11. 11.
    Strieter R, Kasahara K, Allen R et al. Human neutrophils exhibit disparate chemotactic factor gene expression. Biochem Biophys Res Commun 1990; 173: 725–30.PubMedGoogle Scholar
  12. 12.
    Gasperini S, Marchi M, Calzetti F et al. Gene expression and production of the monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein-10 (IP-10) chemokines by human neutrophils. J Immunol 1999; 162: 4928–37.PubMedGoogle Scholar
  13. 13.
    Cassatella M, Gasperini S, Russo M, Cytokine expression and release by neutrophils. Ann NY Acad Sci 1997; 832: 233–42.PubMedGoogle Scholar
  14. 14.
    Iwasaki K, Torisu M, Fujimura T. Malignant tumor and eosinophils. Prognostic significance in gastric cancer. Cancer 1986; 58: 1321–7.PubMedGoogle Scholar
  15. 15.
    Ohashi Y, Ishibashi S, Suzuki T et al. Significance of tumor associated tissue eosinophilia and other inflammatory cell infiltrate in early esophageal squamous cell carcinoma. Anticancer Res 2000; 20: 3025–30.PubMedGoogle Scholar
  16. 16.
    Kruger-Krasagakes S, Li W, Richter G et al. Eosinophils infiltrating interleukin-5 gene-transfected tumors do not suppress tumor growth. Eur J Immunol 1993; 23: 992–5.PubMedGoogle Scholar
  17. 17.
    Jonjic N, Peri G, Bernasconi S et al. Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells. J Exp Med 1992; 176: 1165–74.PubMedGoogle Scholar
  18. 18.
    Colombo N, Peccatori F, Paganin C et al. Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy. Int J Cancer 1992; 51: 42–6.PubMedGoogle Scholar
  19. 19.
    Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor a. J Exp Med 1994; 179: 1109–18.PubMedGoogle Scholar
  20. 20.
    Sallusto F, Schaerli P, Loetscher P et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 1998; 28: 2760–9.PubMedGoogle Scholar
  21. 21.
    Sallusto F, Palermo B, Lenig D et al. Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur J Immunol 1999; 29: 1617–25.PubMedGoogle Scholar
  22. 22.
    Vissers J, Hartgers F, Lindhout E et al. Quantitative analysis of chemokine expression by dendritic cell subsets in vitro and in vivo. J Leukoc Biol 2001; 69: 785–93.PubMedGoogle Scholar
  23. 23.
    Katsenelson N, Shurin G, Bykovskaia S et al. Human small cell lung carcinoma and carcinoid tumor regulate dendritic cell maturation and function. Mol Pathol 2001; 14: 40–5.Google Scholar
  24. 24.
    Menetrier-Caux C, Thomachot MC, Alberti L, et al. IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells. Cancer Res 2001; 61: 3096–104.PubMedGoogle Scholar
  25. 25.
    Yuan D, Wilder J, Dang T et al. Activation of B lymphocytes by NK cells. Int Immunol 1992; 4: 1373–80.PubMedGoogle Scholar
  26. 26.
    Mingari MC, Moretta A, Moretta L, Regulation of KIR expression in human T cells: A safety mechanism that may impair protective T-cell responses. Immunol Today 1998; 19: 153–7.PubMedGoogle Scholar
  27. 27.
    Joshi P, Zhou X, Cuchens M et al. Prostaglandin E2 suppressed IL-15-mediated human NK cell function through down-regulation of common gamma-chain. J Immunol 2001; 166: 885–91.PubMedGoogle Scholar
  28. 28.
    Inngjerdingen M, Damaj B, Maghazachi A. Expression and regulation of chemokine receptors in human natural killer cells. Blood 2001; 97: 367–75.PubMedGoogle Scholar
  29. 29.
    Mizoguchi H, O'Shea J, Longo D et al. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 1992; 258: 1795–8.PubMedGoogle Scholar
  30. 30.
    Mortarini R, Borri A, Tragni G et al. Peripheral burst of tumor-specific cytotoxic T lymphocytes and infiltration of metastatic lesions by memory CD8+ T cells in melanoma patients receiving interleukin 12. Cancer Res 2000; 60: 3559–68.PubMedGoogle Scholar
  31. 31.
    Lasek W, Mackiewicz A, Czajka A et al. Antitumor effects of the combination therapy with TNF-alpha gene-modified tumor cells and interleukin 12 in a melanoma model in mice. Cancer Gene Ther 2000; 7: 1581–90.PubMedGoogle Scholar
  32. 32.
    Musiani P, Modesti A, Giovarelli M et al. Cytokines, tumour-cell death and immunogenicity: A question of choice. Immunol Today 1997; 18: 32–6.PubMedGoogle Scholar
  33. 33.
    Mantovani A, Bottazzi B, Colotta F et al. The origin and function of tumor-associated macrophages. Immunol Today 1992; 13: 265–70.PubMedGoogle Scholar
  34. 34.
    Moore RJ, Owens DM, Stamp G et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999; 5: 828–31.PubMedGoogle Scholar
  35. 35.
    Saren P, Welgus HG, Kovanen PT. TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol 1996; 157: 4159–65.PubMedGoogle Scholar
  36. 36.
    Boyano M, Garcia-Vazquez M, Gardeazabal J et al. Serum-soluble IL-2 receptor and IL-6 levels in patients with melanoma. Oncology 1997; 54: 400–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Wakiyaina T, Shinohara T et al. The localization of thrombospondin-1 (TSP-1), cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG) TSP receptor, and matrix metalloproteinase-9 (MMP-9) in colorectal cancer. Histol Histopathol 2001; 16: 345–51.Google Scholar
  38. 38.
    Sporn M, Roberts A, Transforming growth factor-beta: recent progress and new challenges. J Cell Biol 1992; 119: 1017–21.PubMedGoogle Scholar
  39. 39.
    Crowe M, Doetschman T, Greenhalgh D. Delayed wound healing in immunodeficient TGF-beta 1 knockout mice. J Invest Dermatol 2000; 115: 3–11.PubMedGoogle Scholar
  40. 40.
    McEarchern JA, Kobie JJ, Mack V et al. Invasion and metastasis of a mammary tumor involves TGF-beta signaling. Int J Cancer 2001; 91: 76–82.PubMedGoogle Scholar
  41. 41.
    Shah A, Lee C, TGF-beta-based immunotherapy for cancer: breaching the tumor firewall. Prostate 2000; 45: 167–72.PubMedGoogle Scholar
  42. 42.
    Fujiwara H, Hamaoka T. Antitumor and antimetastatic effects of interleukin 12. Cancer Chemother Pharmacol 1996; 38: 522–6.Google Scholar
  43. 43.
    Collison K, Saleh S, Parhar R et al. Evidence for IL-12-activated Ca2+ and tyrosine signaling pathways in human neutrophils. J Immunol 1998; 161: 3737–45.PubMedGoogle Scholar
  44. 44.
    Bussolati B, Mariano F, Cignetti A et al. Platelet-activating factor synthesized by IL-12-stimulated polymorphonuclear neutrophils and NK cells mediates chemotaxis. J Immunol 1998; 161: 1493–500.PubMedGoogle Scholar
  45. 45.
    Ito R, Kitadai Y, Kyo E et al. Interleukin 1 alpha acts as an autocrine growth stimulator for human gastric carcinoma cells. Cancer Res 1993; 53: 4102–6.PubMedGoogle Scholar
  46. 46.
    Bar-Eli M. Role of interleukin-8 in tumor growth and metastasis of human melanoma. Pathobiology 1999; 67: 12–8.PubMedGoogle Scholar
  47. 47.
    Martins-Green M, Boudreau N, Bissell M. Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res 1994; 54: 4334–41.PubMedGoogle Scholar
  48. 48.
    Mantovani A. Tumor-associated macrophages in neoplastic progression: A paradigm for the in vivo function of chemokines. Lab Invest 1994; 71: 5–16.PubMedGoogle Scholar
  49. 49.
    Rollins BJ. Chemokines. Blood 1997; 90: 909–28.PubMedGoogle Scholar
  50. 50.
    Bonecchi R, Facchetti F, Dusi S et al. Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes. J Immunol 2000; 164: 3862–9.PubMedGoogle Scholar
  51. 51.
    Coughlin C, Salhany K, Wysocka M et al. Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angigogenesis. J Clin Invest 1998; 101: 1441–52.PubMedGoogle Scholar
  52. 52.
    Gusella G, Musso T, Bosco M et al. IL-2 up-regulates but IFN-gamma suppresses IL-8 expression in human monocytes. J Immunol 1993; 151: 2725–32.PubMedGoogle Scholar
  53. 53.
    Addison C, Daniel T, Burdick M et al. The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. J Immunol 2000; 165: 5269–77.PubMedGoogle Scholar
  54. 54.
    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.PubMedGoogle Scholar
  55. 55.
    Feil C, Augustin H, Endothelial cells differentially express functional CXC-chemokine receptor-4 (CXCR-4/fusin) under the control of autocrine activity and exogenous cytokines. Biochem Biophys Res Commun 1998; 247: 38–45.PubMedGoogle Scholar
  56. 56.
    Tachibana K, Hirota S, Iizasa H et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 1998; 393: 595–9.Google Scholar
  57. 57.
    Salcedo R, Ponce ML, Young HA et al. Human endothelial cells express CCR2 and respond to MCP-1: Direct role of MCP-1 in angiogenesis and tumor progression. Blood 2000; 96(1): 34–40.PubMedGoogle Scholar
  58. 58.
    Benelli R, Barbero A, Ferrini S et al. Human immunodeficiency virus transactivator protein (Tat) stimulates chemotaxis, calcium mobilization, and activation of human polymorphonuclear leukocytes: Implications for Tat-mediated pathogenesis. J Infect Dis 2000; 182(6): 1643–51.PubMedGoogle Scholar
  59. 59.
    Youngs S, Ali S, Taub D et al. Chemokines induce migrational responses in human breast carcinoma cell lines. Int J Cancer 1997; 71: 257–66.PubMedGoogle Scholar
  60. 60.
    Muller A, Homey B, Soto H et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50–6.PubMedGoogle Scholar
  61. 61.
    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: 588–97.Google Scholar
  62. 62.
    Proost P, De Wolf-Peeters C, Conings R et al. 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(3): 1000–10.PubMedGoogle Scholar
  63. 63.
    Smith D, Polverini P, Kunkel S et al. Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma. J Exp Med 1994; 179: 1409–15.PubMedGoogle Scholar
  64. 64.
    Baggiolini M. Interleukin-8 and related chemotactic cytokines-CXC and CC chemokines. Adv Immunol 1994; 55: 99–179.Google Scholar
  65. 65.
    Bottazzi B, Polentarutti N, Acero R et al. Regulation of the macrophage content of neoplasms by chemoattractants. Science 1983; 220(4593): 210–2.PubMedGoogle Scholar
  66. 66.
    Coussens LM, Tinkle CL, Hanahan D et al. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 2000; 103: 481–90.PubMedGoogle Scholar
  67. 67.
    Zheng J, Ramirez V. Piceatannol, a stilbene phytochemical, inhibits mitochondrial F0F1-ATPase activity by targeting the F1 complex. Biochem Biophys Res Commun 1999; 261: 499–503.PubMedGoogle Scholar
  68. 68.
    Jang M, Cai L, Udeani G et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997; 275: 218–20.PubMedGoogle Scholar
  69. 69.
    Schnurr M, Then F, Galambos P et al. Extracellular ATP and TNF-alpha synergize in the activation and maturation of human dendritic cells. J Immunol 2000; 165(8): 4704–9.PubMedGoogle Scholar
  70. 70.
    Capodici C, Pillinger M, Han G et al. Integrin-dependent homotypic adhesion of neutrophils. Arachidonic acid activates Raf-1/Mek/Erk via a 5-lipoxygenase-dependent pathway. J Clin Invest 1998; 102: 165–75.PubMedCrossRefGoogle Scholar
  71. 71.
    Richard D, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem 2000; 275: 26765–71.PubMedGoogle Scholar
  72. 72.
    Ekbom A, Helmick C, Zack M et al. Ulcerative colitis and colorectal cancer. N Engl J Med 1990; 323: 1228–33.PubMedCrossRefGoogle Scholar
  73. 73.
    Roboz GJ, Dias S, Lam G et al. Arsenic trioxide induces dose-and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood 2000; 96: 1525–30.PubMedGoogle Scholar
  74. 74.
    Hu G. Limited proteolysis of angiogenin by elastase is regulated by plasminogen. J Protein Chem 1997; 16: 669–79.PubMedGoogle Scholar
  75. 75.
    Di Carlo E, Comes A, Basso S et al. The combined action of IL-15 and IL-12 gene transfer can induce tumor cell rejection without T and NK cell involvement. J Immunol 2000; 165(6): 3111–8.PubMedGoogle Scholar
  76. 76.
    Di Carlo E, Forni G, Lollini P et al. The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood 2001; 97(2): 339–45.PubMedGoogle Scholar
  77. 77.
    Nesbit M, Schaider H, Miller TH et al. Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in nontumorigenic melanoma cells. J Immunol 2001; 166(11): 6483–90.PubMedGoogle Scholar
  78. 78.
    Riker A, Kammula U, Panelli M et al. Threshold levels of gene expression of the melanoma antigen gp100 correlate with tumor cell recognition by cytotoxic T lymphocytes. Int J Cancer 2000; 86: 818–26.PubMedGoogle Scholar
  79. 79.
    Hadden J. The immunology and immunotherapy of breast cancer: An update. Int J Immunopharmacol 1999; 21: 79–101.PubMedGoogle Scholar
  80. 80.
    Hwang I, Nahm D, Cho S et al. Anti-T autibodies and peanut-agglutinin-binding glycoproteins in sera of patients with gastric cancer. J Cancer Res Clin Oncol 1999; 125: 582–7.PubMedGoogle Scholar
  81. 81.
    Nagoshi M, Sadanaga N, Joo H et al. Tumor-specific cytokine release by donor T cells induces an effective host anti-tumor response through recruitment of host naive antigen presenting cells. Int J Cancer 1999; 80: 308–14.PubMedGoogle Scholar
  82. 82.
    Yoong K, Afford S, Randhawa S, Hubscher S et al. Fas/Fas ligand interaction in human colorectal hepatic metastases: A mechanism of hepatocyte destruction to facilitate local tumor invasion. Am J Pathol 1999; 154: 693–703.PubMedGoogle Scholar
  83. 83.
    Yang S, Vervaert C, Seigler H et al. Tumor cells cotransduced with B7.1 and gamma-IFN induce effective rejection of established parental tumor. Gene Ther 1999; 6: 253–62.PubMedGoogle Scholar
  84. 84.
    Porgador A, Gilboa E. Bone marrow-generated dendritic cells pulsed with a class I-restricted peptide are potent inducers of cytotoxic T lymphocytes. J Exp Med 1995; 182: 255–60.PubMedGoogle Scholar
  85. 85.
    Baselga J. Herceptin((R)) Alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: Pivotal trials. Oncology 2001; 61(Suppl S2): 14–21.PubMedGoogle Scholar
  86. 86.
    James ND, Atherton PJ, Jones J et al. A phase II study of the bispecific antibody MDX-H210 (anti-HER2 × CD64) with GM-CSF in HER2+ advanced prostate cancer. Br J Cancer 2001; 85(2): 152–6.PubMedGoogle Scholar
  87. 87.
    Nakashima E, Oya A, Kubota Y et al. A candidate for cancer gene therapy: MIP-1 alpha gene transfer to an adenocarcinoma cell line reduced tumorigenicity and induced protective immunity in immunocompetent mice. Pharm Res 1996; 13: 1896–901.PubMedGoogle Scholar
  88. 88.
    Tannenbaum C, Tubbs R, Armstrong D et al. The CXC chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor. J Immunol 1998; 161: 927–32.PubMedGoogle Scholar
  89. 89.
    Dilloo D, Bacon K, Holden W et al. Combined chemokine and cytokine gene transfer enhances antitumor immunity. Nat Med 1996; 2: 1090–5.PubMedGoogle Scholar
  90. 90.
    Fujisawa N, Hayashi S, Miller E. A synthetic peptide inhibitor for alpha-chemokines inhibits the tumour growth and pulmonary metastasis of human melanoma cells in nude mice. Melanoma Res 1999; 9: 105–14.PubMedGoogle Scholar
  91. 91.
    Vane J. Suppression of intestinal polyposis by inhibition of COX-2 in Apc knockout mice. Jpn J Cancer Res 1997; 88(11): inside front cover.Google Scholar
  92. 92.
    Williams CS, Luongo C, Radhika A et al. Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology 1996; 111(4): 1134–40.PubMedGoogle Scholar
  93. 93.
    Johnson W, Anderson K, Lazovich D et al. Association of aspirin and other NSAID use with incidence of postmenopausal breast cancer. In Proceedings of AACR, New Orleans 2001; 763.Google Scholar
  94. 94.
    Mamytbekova A, Rezabek K, Kacerovska H et al. Antimetastatic effect of flurbiprofen and other platelet aggregation inhibitors. Neoplasma 1986; 33: 417–21.PubMedGoogle Scholar
  95. 95.
    Elder D, Halton D, Hague A et al. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: Independence from COX-2 protein expression. Clin Cancer Res 1997; 3: 1679–83.PubMedGoogle Scholar
  96. 96.
    Li M, Wu X, Xu X. Induction of apoptosis in colon cancer cells by cyclooxygenase-2 inhibitor NS398 through a cytochrome c-dependent pathway. Clin Cancer Res 2001; 7: 1010–6.PubMedGoogle Scholar
  97. 97.
    Cao Y, Prescott S. Fatty acid CoA-ligase 4 and cyclooxygenase 2 promote carcinogenesis by lowering the intracellular level of free arachidonic acid. In Proceedings of AACR, New Orleans 2001; 591.Google Scholar
  98. 98.
    Tsujii M, Kawano S, DuBois R. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997; 94: 3336–40.PubMedGoogle Scholar
  99. 99.
    Jiang C, Ting A, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391: 82–6.PubMedGoogle Scholar
  100. 100.
    Lefebvre A, Chen I, Desreumaux P et al. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med 1998; 4: 1053–7.PubMedGoogle Scholar
  101. 101.
    He T, Chan T, Vogelstin B. PPAR delta is an APC-regulated target of nonsteroidal anti-indlammatory drugs. Cell 1999; 99: 335–45.PubMedGoogle Scholar
  102. 102.
    Yoshimura R, Sano H, Masuda C et al. Expression of cyclooxygenase-2 in prostate carcinoma. Cancer 2000; 89: 589–96.PubMedGoogle Scholar
  103. 103.
    Jones MK, Wang H, Peskar BM et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 1999; 5(12): 1418–23.PubMedGoogle Scholar
  104. 104.
    Terris B, Baldin V, Dubois S et al. PML nuclear bodies are general targets for inflammation and cell proliferation. Cancer Res 1995; 55: 1590–7.PubMedGoogle Scholar
  105. 105.
    Nakamoto T, Inagawa H, Takagi K et al. A new method of antitumor therapy with a high dose of TNF perfusion for unresectable liver tumors. Anticancer Res 2000; 20(6A): 4087–96.PubMedGoogle Scholar
  106. 106.
    Vukanovic J, Isaacs J. Linomide inhibits angiogenesis, growth, metastasis, and macrophage infiltration within rat prostatic cancers. Cancer Res 1995; 55: 1499–504.PubMedGoogle Scholar
  107. 107.
    Joseph I, Isaacs J. The antiangiogenic agent linomide inhibits tumor necrosis factor-alpha secretion via inhibition of its synthesis. Prostate 1996; 29: 183–90.PubMedGoogle Scholar
  108. 108.
    Kenyon B, Browne F, D'Amato R. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997; 64: 971–8.PubMedGoogle Scholar
  109. 109.
    Eisen T, Boshoff C, Mak I et al. Continuous low dose Thalidomide: A phase II study in advanced mclanoma, renal cell, ovarian and breast cancer. Br J Cancer 2000; 82: 812–7.PubMedGoogle Scholar
  110. 110.
    Couriel D, Hicks K, Giralt S et al. Role of tumor necrosis factor-alpha inhibition with inflixiMAB in cancer therapy and hematopoietic stem cell transplantation. Curr Opin Oncol 2000; 12: 582–7.PubMedGoogle Scholar
  111. 111.
    Ueda M, Ueki M, Terai Y et al. Biological implications of growth factors on the mechanism of invasion in gynecological tumor cells. Gynecol Obstet Invest 1999; 48: 221–8.PubMedGoogle Scholar
  112. 112.
    Ye J, Ding M, Zhang X et al. On the role of hydroxyl radical and the effect of tetrandrine on nuclear factor-kappaB activation by phorbol 12-myristate 13-acetate. Ann Clin Lab Sci 2000; 30: 65–71.PubMedGoogle Scholar
  113. 113.
    Ahmad N, Gupta S, Husain MM et al. Differential antiproliferative and apoptotic response of sanguinarine for cancer cells versus normal cells. Clin Cancer Res 2000; 6: 1524–8.PubMedGoogle Scholar
  114. 114.
    Yang L, Lee C, Yen K. Induction of apoptosis by hydrolyzable tannins from Eugenia jambos L. on human leukemia cells. Cancer Lett 2000; 157: 65–75.PubMedGoogle Scholar
  115. 115.
    Dirsch V, Vollmar A. Ajoene, a natural product with non-steroidal anti-inflammatory drug (NSAID)-like properties? Biochem Pharmacol 2001; 61: 587–93.PubMedGoogle Scholar
  116. 116.
    Iizuka N, Miyamoto K, Hazama S et al. Anticachectic effects of Coptidis rhizoma, an anti-inflammatory herb, on esophageal cancer cells that produce interleukin 6. Cancer Lett 2000; 158: 35–41.PubMedGoogle Scholar
  117. 117.
    Ju D, Zheng Q, Cao X et al. Esculentoside A inhibits tumor necrosis factor, interleukin-1, and interleukin-6 production induced by lipopolysaccharide in mice. Pharmacology 1998; 56: 187–95.PubMedGoogle Scholar
  118. 118.
    Fujiki H. Two stages of cancer prevention with green tea. J Cancer Res Clin Oncol 1999; 125(11): 589–97.PubMedGoogle Scholar
  119. 119.
    Garbisa S, Biggin S, Cavallarin N et al. Tumor invasion: Molecular shears blunted by green tea. Nat Med 1999; 5(11): 1216.PubMedGoogle Scholar
  120. 120.
    Chan M, Mattiacci J, Hwang H et al. Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. Biochem Pharmacol 2000; 60: 1539–48.PubMedGoogle Scholar
  121. 121.
    Canali R, Vignolini F, Nobili F et al. Reduction of oxidative stress and cytokine-induced neutrophil chemoattractant (CINC) expression by red wine polyphenols in zinc deficiency induced intestinal damage of rat. Free Radic Biol Med 2000; 28: 1661–70.PubMedGoogle Scholar
  122. 122.
    Damianaki A, Bakogeorgou E, Kampa M et al. Potent inhibitory action of red wine polyphenols on human breast cancer cells. J Cell Biochem 2000; 78: 429–41.PubMedGoogle Scholar
  123. 123.
    Tosetti F, Ferrari N, De Flora S et al. Angioprevention: Angiogenesis is a common and key target for cancer chemopreventive agents. Faseb J 2002; 16: 2–14.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Claudio Brigati
    • 1
  • Douglas M. Noonan
    • 2
  • Adriana Albini
    • 1
  • Roberto Benelli
    • 1
  1. 1.Molecular Biology LaboratoryIstituto Nazionale per la Ricerca sul CancroGenoaItaly
  2. 2.Tumor Progression SectionIstituto Nazionale per la Ricerca sul CancroGenoaItaly

Personalised recommendations