Cancer Microenvironment

, Volume 4, Issue 2, pp 141–154 | Cite as

Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer

  • Marco Erreni
  • Alberto Mantovani
  • Paola AllavenaEmail author
Original Paper


Experimental and epidemiological studies indicate a strong link between chronic inflammation and tumor progression. Human colorectal cancer (CRC), a major cause of cancer-related death in Western countries, represents a paradigm for this link. Key features of cancer-related inflammation in CRC are the activation of transcription factors (e.g. NF-κB, STAT3), the expression of inflammatory cytokines and chemokines (e.g. TNFα, IL-6, CCL2, CXCL8) as well as a prominent leukocyte infiltrate. While considerable evidence indicates that the presence of lymphocytes of adaptive immunity may positively influence patient survival and clinical outcome in CRC, the role of tumor-associated macrophages (TAM) and of other lymphoid populations (e.g. Th17, Treg) is still unclear. In this review we will summarize the different and controversial effects that TAM play in CRC-related inflammation and progression of disease. The characterization of the most relevant inflammatory pathways in CRC is instrumental for the identification of new target molecules that could lead to improved diagnosis and treatment.


Colorectal cancer Tumor-associated macrophages Inflammation Cytokines Chemokines 



This work was supported by Associazione Italiana Ricerca Cancro (AIRC) Italy to PA and AM; grants from the European Community FP6 Project ATTACK-018914; Ministry of Health and Istituto Superiore Sanità Italy (Project oncology 2006 and Alleanza Contro il Cancro).

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW (2005) Colorectal cancer. Lancet 365:153–165PubMedGoogle Scholar
  2. 2.
    Calvert PM, Frucht H (2002) The genetics of colorectal cancer. Ann Intern Med 137:603–612PubMedGoogle Scholar
  3. 3.
    Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932PubMedGoogle Scholar
  4. 4.
    Rustgi AK (2007) The genetics of hereditary colon cancer. Genes Dev 21:2525–2538PubMedGoogle Scholar
  5. 5.
    Soreide K, Janssen EA, Soiland H, Korner H, Baak JP (2006) Microsatellite instability in colorectal cancer. Br J Surg 93:395–406PubMedGoogle Scholar
  6. 6.
    Laghi L, Bianchi P, Malesci A (2003) Gender difference for promoter methylation pattern of hMLH1 and p16 in sporadic MSI colorectal cancer. Gastroenterology 124:1165–1166PubMedGoogle Scholar
  7. 7.
    Westra JL, Plukker JT, Buys CH, Hofstra RM (2004) Genetic alterations in locally advanced stage II/III colon cancer: a search for prognostic markers. Clin Colorectal Cancer 4:252–259PubMedGoogle Scholar
  8. 8.
    Malesci A et al. (2007) Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 13:3831–3839PubMedGoogle Scholar
  9. 9.
    Prall F et al. (2004) Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol 35:808–816PubMedGoogle Scholar
  10. 10.
    Dolcetti R et al. (1999) High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 154:1805–1813PubMedGoogle Scholar
  11. 11.
    Banerjea A et al. (2004) Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity. Mol Cancer 3:21PubMedGoogle Scholar
  12. 12.
    Muller A, Fishel R (2002) Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Cancer Invest 20:102–109PubMedGoogle Scholar
  13. 13.
    Wang D, Dubois RN, Richmond A (2009) The role of chemokines in intestinal inflammation and cancer. Curr Opin Pharmacol 9:688–696PubMedGoogle Scholar
  14. 14.
    Meira LB et al. (2008) DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest 118:2516–2525PubMedGoogle Scholar
  15. 15.
    Talmadge JE, Donkor M, Scholar E (2007) Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev 26:373–400PubMedGoogle Scholar
  16. 16.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedGoogle Scholar
  17. 17.
    Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217PubMedGoogle Scholar
  18. 18.
    DeNardo DG, Johansson M, Coussens LM (2008) Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev 27:11–18PubMedGoogle Scholar
  19. 19.
    Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444PubMedGoogle Scholar
  20. 20.
    Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–759PubMedGoogle Scholar
  21. 21.
    Witz IP (2009) The tumor microenvironment: the making of a paradigm. Cancer Microenviron 2(Suppl 1):9–17PubMedGoogle Scholar
  22. 22.
    Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131–2142PubMedGoogle Scholar
  23. 23.
    Flossmann E, Rothwell PM (2007) Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 369:1603–1613PubMedGoogle Scholar
  24. 24.
    Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458PubMedGoogle Scholar
  25. 25.
    Sumimoto H, Imabayashi F, Iwata T, Kawakami Y (2006) The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 203:1651–1656PubMedGoogle Scholar
  26. 26.
    Shchors K, Shchors E, Rostker F, Lawlor ER, Brown-Swigart L, Evan GI (2006) The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta. Genes Dev 20:2527–2538PubMedGoogle Scholar
  27. 27.
    Borrello MG et al. (2005) Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proc Natl Acad Sci U S A 102:14825–14830PubMedGoogle Scholar
  28. 28.
    Germano G et al. (2010) Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 70:2235–2244PubMedGoogle Scholar
  29. 29.
    Guerra C et al. (2007) Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11:291–302PubMedGoogle Scholar
  30. 30.
    Bierie B, Moses HL (2006) TGF-beta and cancer. Cytokine Growth Factor Rev 17:29–40PubMedGoogle Scholar
  31. 31.
    Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W (2003) Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425:307–311PubMedGoogle Scholar
  32. 32.
    Schioppa T et al. (2003) Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198:1391–1402PubMedGoogle Scholar
  33. 33.
    Gupta RB et al. (2007) Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 133:1099–1105, quiz 1340-1PubMedGoogle Scholar
  34. 34.
    Itzkowitz SH, Harpaz N (2004) Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroenterology 126:1634–1648PubMedGoogle Scholar
  35. 35.
    Bernstein CN, Blanchard JF, Kliewer E, Wajda A (2001) Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 91:854–862PubMedGoogle Scholar
  36. 36.
    Terzic J, Grivennikov S, Karin E, Karin M (2010) Inflammation and colon cancer. Gastroenterology 138:2101–2114.e5PubMedGoogle Scholar
  37. 37.
    Bottazzi B et al. (1983) Regulation of the macrophage content of neoplasms by chemoattractants. Science 220:210–212PubMedGoogle Scholar
  38. 38.
    Rollins BJ, Sunday ME (1991) Suppression of tumor formation in vivo by expression of the JE gene in malignant cells. Mol Cell Biol 11:3125–3131PubMedGoogle Scholar
  39. 39.
    Negus RP et al. (1995) The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer. J Clin Invest 95:2391–2396PubMedGoogle Scholar
  40. 40.
    Opdenakker G, Van Damme J (1992) Chemotactic factors, passive invasion and metastasis of cancer cells. Immunol Today 13:463–464PubMedGoogle Scholar
  41. 41.
    Mantovani A, Bonecchi R, Locati M (2006) Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol 6:907–918PubMedGoogle Scholar
  42. 42.
    McConnell BB, Yang VW (2009) The role of inflammation in the pathogenesis of colorectal cancer. Curr Colorectal Cancer Rep 5:69–74PubMedGoogle Scholar
  43. 43.
    Popivanova BK et al. (2009) Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. Cancer Res 69:7884–7892PubMedGoogle Scholar
  44. 44.
    Erreni M et al. (2009) Expression of chemokines and chemokine receptors in human colon cancer. Methods Enzymol 460:105–121PubMedGoogle Scholar
  45. 45.
    Kim J et al. (2005) Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J Clin Oncol 23:2744–2753PubMedGoogle Scholar
  46. 46.
    Schimanski CC et al. (2005) Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer. Clin Cancer Res 11:1743–1750PubMedGoogle Scholar
  47. 47.
    Gunther K et al. (2005) Prediction of lymph node metastasis in colorectal carcinoma by expressionof chemokine receptor CCR7. Int J Cancer 116:726–733PubMedGoogle Scholar
  48. 48.
    Kawada K et al. (2007) Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. Oncogene 26:4679–4688PubMedGoogle Scholar
  49. 49.
    Sturm A, Baumgart DC, d’Heureuse JH, Hotz A, Wiedenmann B, Dignass AU (2005) CXCL8 modulates human intestinal epithelial cells through a CXCR1 dependent pathway. Cytokine 29:42–48PubMedGoogle Scholar
  50. 50.
    Zipin-Roitman A et al. (2007) CXCL10 promotes invasion-related properties in human colorectal carcinoma cells. Cancer Res 67:3396–3405PubMedGoogle Scholar
  51. 51.
    Vetrano S et al. (2010) The lymphatic system controls intestinal inflammation and inflammation-associated Colon Cancer through the chemokine decoy receptor D6. Gut 59:197–206PubMedGoogle Scholar
  52. 52.
    Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9:361–371PubMedGoogle Scholar
  53. 53.
    Popivanova BK et al. (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 118:560–570PubMedGoogle Scholar
  54. 54.
    Greten FR et al. (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296PubMedGoogle Scholar
  55. 55.
    Pikarsky E et al. (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466PubMedGoogle Scholar
  56. 56.
    Fukata M, Abreu MT (2008) Role of Toll-like receptors in gastrointestinal malignancies. Oncogene 27:234–243PubMedGoogle Scholar
  57. 57.
    Rakoff-Nahoum S, Medzhitov R (2007) Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317:124–127PubMedGoogle Scholar
  58. 58.
    Huang B et al. (2005) Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 65:5009–5014PubMedGoogle Scholar
  59. 59.
    Thomassen E, Renshaw BR, Sims JE (1999) Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 11:389–399PubMedGoogle Scholar
  60. 60.
    Mantovani A, Locati M, Polentarutti N, Vecchi A, Garlanda C (2004) Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR. J Leukoc Biol 75:738–742PubMedGoogle Scholar
  61. 61.
    Polentarutti N et al. (2003) Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR. Eur Cytokine Netw 14:211–218PubMedGoogle Scholar
  62. 62.
    Wald D et al. (2003) SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 4:920–927PubMedGoogle Scholar
  63. 63.
    Garlanda C et al. (2004) Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci U S A 101:3522–3526PubMedGoogle Scholar
  64. 64.
    Garlanda C et al. (2007) Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer Res 67:6017–6021PubMedGoogle Scholar
  65. 65.
    Iglesias D, Nejda N, Azcoita MM, Schwartz SJ, Gonzalez-Aguilera JJ, Fernandez-Peralta AM (2009) Effect of COX2-765G>C and c.3618A>G polymorphisms on the risk and survival of sporadic colorectal cancer. Cancer Causes Control 20:1421–1429PubMedGoogle Scholar
  66. 66.
    Arber N et al. (2006) Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355:885–895PubMedGoogle Scholar
  67. 67.
    Benelli R (2007) Aspirin, COX-2, and the risk of colorectal cancer. N Engl J Med 357:824–825, author reply 824-5PubMedGoogle Scholar
  68. 68.
    Pereira C, Medeiros RM, Dinis-Ribeiro MJ (2009) Cyclooxygenase polymorphisms in gastric and colorectal carcinogenesis: are conclusive results available? Eur J Gastroenterol Hepatol 21:76–91PubMedGoogle Scholar
  69. 69.
    Cross JT, Poole EM, Ulrich CM (2008) A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia. Pharmacogenomics J 8:237–247PubMedGoogle Scholar
  70. 70.
    Hoebe K, Janssen E, Beutler B (2004) The interface between innate and adaptive immunity. Nat Immunol 5:971–974PubMedGoogle Scholar
  71. 71.
    Kishimoto T (2005) Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol 23:1–21PubMedGoogle Scholar
  72. 72.
    McLoughlin RM et al. (2003) Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation. J Clin Invest 112:598–607PubMedGoogle Scholar
  73. 73.
    Mantovani A, Sica A, Locati M (2005) Macrophage polarization comes of age. Immunity 23:344–346PubMedGoogle Scholar
  74. 74.
    Atreya R et al. (2000) Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med 6:583–588PubMedGoogle Scholar
  75. 75.
    Schneider MR, Hoeflich A, Fischer JR, Wolf E, Sordat B, Lahm H (2000) Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon carcinoma cells. Cancer Lett 151:31–38PubMedGoogle Scholar
  76. 76.
    Hsu CP, Chung YC (2006) Influence of interleukin-6 on the invasiveness of human colorectal carcinoma. Anticancer Res 26:4607–4614PubMedGoogle Scholar
  77. 77.
    Brozek W, Bises G, Girsch T, Cross HS, Kaiser HE, Peterlik M (2005) Differentiation-dependent expression and mitogenic action of interleukin-6 in human colon carcinoma cells: relevance for tumour progression. Eur J Cancer 41:2347–2354PubMedGoogle Scholar
  78. 78.
    Knupfer H, Preiss R (2010) Serum interleukin-6 levels in colorectal cancer patients—a summary of published results. Int J Colorectal Dis 25:135–140PubMedGoogle Scholar
  79. 79.
    Naugler WE et al. (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–124PubMedGoogle Scholar
  80. 80.
    Grivennikov S et al. (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113PubMedGoogle Scholar
  81. 81.
    Bollrath J et al. (2009) gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15:91–102PubMedGoogle Scholar
  82. 82.
    Bromberg J, Wang TC (2009) Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15:79–80PubMedGoogle Scholar
  83. 83.
    Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181PubMedGoogle Scholar
  84. 84.
    Sandel MH et al. (2005) Natural killer cells infiltrating colorectal cancer and MHC class I expression. Mol Immunol 42:541–546PubMedGoogle Scholar
  85. 85.
    Coca S et al. (1997) The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 79:2320–2328PubMedGoogle Scholar
  86. 86.
    Fernandez-Acenero MJ, Galindo-Gallego M, Sanz J, Aljama A (2000) Prognostic influence of tumor-associated eosinophilic infiltrate in colorectal carcinoma. Cancer 88:1544–1548PubMedGoogle Scholar
  87. 87.
    Nagtegaal ID et al. (2001) Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect—a histopathological and immunohistochemical study. BMC Cancer 1:7PubMedGoogle Scholar
  88. 88.
    Gounaris E et al. (2007) Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci U S A 104:19977–19982PubMedGoogle Scholar
  89. 89.
    Canna K et al. (2005) The relationship between tumour T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer 92:651–654PubMedGoogle Scholar
  90. 90.
    Chiba T et al. (2004) Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 91:1711–1717PubMedGoogle Scholar
  91. 91.
    Naito Y et al. (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494PubMedGoogle Scholar
  92. 92.
    Galon J et al. (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964PubMedGoogle Scholar
  93. 93.
    Pages F et al. (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666PubMedGoogle Scholar
  94. 94.
    Laghi L et al. (2009) CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol 10:877–884PubMedGoogle Scholar
  95. 95.
    Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L (1992) The origin and function of tumor-associated macrophages. Immunol Today 13:265–270PubMedGoogle Scholar
  96. 96.
    Allavena P, Sica A, Solinas G, Porta C, Mantovani A (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66:1–9PubMedGoogle Scholar
  97. 97.
    Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78PubMedGoogle Scholar
  98. 98.
    Dinapoli MR, Calderon CL, Lopez DM (1996) The altered tumoricidal capacity of macrophages isolated from tumor-bearing mice is related to reduce expression of the inducible nitric oxide synthase gene. J Exp Med 183:1323–1329PubMedGoogle Scholar
  99. 99.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555PubMedGoogle Scholar
  100. 100.
    Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727PubMedGoogle Scholar
  101. 101.
    Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266PubMedGoogle Scholar
  102. 102.
    Fu YX, Cai JP, Chin YH, Watson GA, Lopez DM (1992) Regulation of leukocyte binding to endothelial tissues by tumor-derived GM-CSF. Int J Cancer 50:585–588PubMedGoogle Scholar
  103. 103.
    Yaal-Hahoshen N et al. (2006) The chemokine CCL5 as a potential prognostic factor predicting disease progression in stage II breast cancer patients. Clin Cancer Res 12:4474–4480PubMedGoogle Scholar
  104. 104.
    Scholl SM, Crocker P, Tang R, Pouillart P, Pollard JW (1993) Is colony-stimulating factor-1 a key mediator of breast cancer invasion and metastasis? Mol Carcinog 7:207–211PubMedGoogle Scholar
  105. 105.
    Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedGoogle Scholar
  106. 106.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964PubMedGoogle Scholar
  107. 107.
    Biswas SK, Sica A, Lewis CE (2008) Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol 180:2011–2017PubMedGoogle Scholar
  108. 108.
    Goerdt S, Orfanos CE (1999) Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 10:137–142PubMedGoogle Scholar
  109. 109.
    O’Sullivan C, Lewis CE (1994) Tumour-associated leucocytes: friends or foes in breast carcinoma. J Pathol 172:229–235PubMedGoogle Scholar
  110. 110.
    Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629PubMedGoogle Scholar
  111. 111.
    Mantovani A (1994) Tumor-associated macrophages in neoplastic progression: a paradigm for the in vivo function of chemokines. Lab Invest 71:5–16PubMedGoogle Scholar
  112. 112.
    Konur A, Kreutz M, Knuchel R, Krause SW, Andreesen R (1998) Cytokine repertoire during maturation of monocytes to macrophages within spheroids of malignant and non-malignant urothelial cell lines. Int J Cancer 78:648–653PubMedGoogle Scholar
  113. 113.
    Wyckoff JB et al. (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656PubMedGoogle Scholar
  114. 114.
    Kaplan RN et al. (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827PubMedGoogle Scholar
  115. 115.
    Kaplan RN, Rafii S, Lyden D (2006) Preparing the “soil”: the premetastatic niche. Cancer Res 66:11089–11093PubMedGoogle Scholar
  116. 116.
    Mantovani A, Schioppa T, Porta C, Allavena P, Sica A (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25:315–322PubMedGoogle Scholar
  117. 117.
    Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5:641–654PubMedGoogle Scholar
  118. 118.
    Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174PubMedGoogle Scholar
  119. 119.
    Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S (2007) Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 179:977–983PubMedGoogle Scholar
  120. 120.
    Gounaris E et al. (2008) Live imaging of cysteine-cathepsin activity reveals dynamics of focal inflammation, angiogenesis, and polyp growth. PLoS One 3:e2916PubMedGoogle Scholar
  121. 121.
    Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540–550PubMedGoogle Scholar
  122. 122.
    Steidl C et al. (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362:875–885PubMedGoogle Scholar
  123. 123.
    Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R (2007) High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 13:1472–1479PubMedGoogle Scholar
  124. 124.
    Ohno S et al. (2003) The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients. Anticancer Res 23:5015–5022PubMedGoogle Scholar
  125. 125.
    Barbera-Guillem E, Nyhus JK, Wolford CC, Friece CR, Sampsel JW (2002) Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res 62:7042–7049PubMedGoogle Scholar
  126. 126.
    Jedinak A, Dudhgaonkar S, Sliva D (2010) Activated macrophages induce metastatic behavior of colon cancer cells. Immunobiology 215:242–249PubMedGoogle Scholar
  127. 127.
    Xu L et al. (2009) Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res 69:7905–7910PubMedGoogle Scholar
  128. 128.
    Popovic ZV et al. (2007) Sulfated glycosphingolipid as mediator of phagocytosis: SM4s enhances apoptotic cell clearance and modulates macrophage activity. J Immunol 179:6770–6782PubMedGoogle Scholar
  129. 129.
    Herbeuval JP, Lelievre E, Lambert C, Dy M, Genin C (2004) Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J Immunol 172:4630–4636PubMedGoogle Scholar
  130. 130.
    Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428PubMedGoogle Scholar
  131. 131.
    Massague J (2008) TGFbeta in cancer. Cell 134:215–230PubMedGoogle Scholar
  132. 132.
    Reinacher-Schick A et al. (2004) Loss of Smad4 correlates with loss of the invasion suppressor E-cadherin in advanced colorectal carcinomas. J Pathol 202:412–420PubMedGoogle Scholar
  133. 133.
    Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A (2006) Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol 174:175–183PubMedGoogle Scholar
  134. 134.
    Illemann M et al. (2006) MMP-9 is differentially expressed in primary human colorectal adenocarcinomas and their metastases. Mol Cancer Res 4:293–302PubMedGoogle Scholar
  135. 135.
    Kaler P, Godasi BN, Augenlicht L, Klampfer L (2009) The NF-kappaB/AKT-dependent induction of Wnt signaling in colon cancer cells by macrophages and IL-1beta. Cancer MicroenvironGoogle Scholar
  136. 136.
    Bienz M, Clevers H (2000) Linking colorectal cancer to Wnt signaling. Cell 103:311–320PubMedGoogle Scholar
  137. 137.
    Segditsas S, Tomlinson I (2006) Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25:7531–7537PubMedGoogle Scholar
  138. 138.
    Pancione M et al. (2009) Reduced beta-catenin and peroxisome proliferator-activated receptor-gamma expression levels are associated with colorectal cancer metastatic progression: correlation with tumor-associated macrophages, cyclooxygenase 2, and patient outcome. Hum Pathol 40:714–725PubMedGoogle Scholar
  139. 139.
    Ohtani H, Naito Y, Saito K, Nagura H (1997) Expression of costimulatory molecules B7-1 and B7-2 by macrophages along invasive margin of colon cancer: a possible antitumor immunity? Lab Invest 77:231–241PubMedGoogle Scholar
  140. 140.
    Sugita J et al. (2002) Close association between Fas ligand (FasL; CD95L)-positive tumor-associated macrophages and apoptotic cancer cells along invasive margin of colorectal carcinoma: a proposal on tumor-host interactions. Jpn J Cancer Res 93:320–328PubMedGoogle Scholar
  141. 141.
    Khorana AA, Ryan CK, Cox C, Eberly S, Sahasrabudhe DM (2003) Vascular endothelial growth factor, CD68, and epidermal growth factor receptor expression and survival in patients with Stage II and Stage III colon carcinoma: a role for the host response in prognosis. Cancer 97:960–968PubMedGoogle Scholar
  142. 142.
    Funada Y, Noguchi T, Kikuchi R, Takeno S, Uchida Y, Gabbert HE (2003) Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncol Rep 10:309–313PubMedGoogle Scholar
  143. 143.
    Zhou Q et al. (2010) The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Transl Med 8:13PubMedGoogle Scholar
  144. 144.
    Bailey C et al. (2007) Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis 24:121–130PubMedGoogle Scholar
  145. 145.
    Mantovani A, Sica A, Allavena P, Garlanda C, Locati M (2009) Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol 70:325–330PubMedGoogle Scholar
  146. 146.
    Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360PubMedGoogle Scholar
  147. 147.
    Gabrilovich DI et al. (2007) The terminology issue for myeloid-derived suppressor cells. Cancer Res 67:425, author reply 426PubMedGoogle Scholar
  148. 148.
    Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949PubMedGoogle Scholar
  149. 149.
    Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9:641–649PubMedGoogle Scholar
  150. 150.
    Santarlasci V et al. (2009) TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells. Eur J Immunol 39:207–215PubMedGoogle Scholar
  151. 151.
    Das J et al. (2009) Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med 206:2407–2416PubMedGoogle Scholar
  152. 152.
    Langrish CL et al. (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240PubMedGoogle Scholar
  153. 153.
    Buonocore S et al. (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464:1371–1375PubMedGoogle Scholar
  154. 154.
    Wang YQ et al. (2003) Induction of systemic immunity by expression of interleukin-23 in murine colon carcinoma cells. Int J Cancer 105:820–824PubMedGoogle Scholar
  155. 155.
    Langowski JL et al. (2006) IL-23 promotes tumour incidence and growth. Nature 442:461–465PubMedGoogle Scholar
  156. 156.
    Stanilov N, Miteva L, Mintchev N, Stanilova S (2009) High expression of Foxp3, IL-23p19 and survivin mRNA in colorectal carcinoma. Int J Colorectal Dis 24:151–157PubMedGoogle Scholar
  157. 157.
    Colonna M (2009) Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31:15–23PubMedGoogle Scholar
  158. 158.
    Kryczek I, Wei S, Szeliga W, Vatan L, Zou W (2009) Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood 114:357–359PubMedGoogle Scholar
  159. 159.
    Lee JW et al. (2008) Differential regulation of chemokines by IL-17 in colonic epithelial cells. J Immunol 181:6536–6545PubMedGoogle Scholar
  160. 160.
    Bettelli E et al. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedGoogle Scholar
  161. 161.
    Veldhoen M, Stockinger B (2006) TGFbeta1, a “Jack of all trades”: the link with pro-inflammatory IL-17-producing T cells. Trends Immunol 27:358–361PubMedGoogle Scholar
  162. 162.
    Savage ND et al. (2008) Human anti-inflammatory macrophages induce Foxp3+ GITR+CD25+ regulatory T cells, which suppress via membrane-bound TGFbeta-1. J Immunol 181:2220–2226PubMedGoogle Scholar
  163. 163.
    Izcue A, Coombes JL, Powrie F (2009) Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27:313–338PubMedGoogle Scholar
  164. 164.
    Loddenkemper C, Schernus M, Noutsias M, Stein H, Thiel E, Nagorsen D (2006) In situ analysis of FOXP3+ regulatory T cells in human colorectal cancer. J Transl Med 4:52PubMedGoogle Scholar
  165. 165.
    Salama P et al. (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192PubMedGoogle Scholar
  166. 166.
    Erdman SE et al. (2005) CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res 65:3998–4004PubMedGoogle Scholar
  167. 167.
    Chaput N et al. (2009) Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 58:520–529PubMedGoogle Scholar
  168. 168.
    Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC (2010) Regulatory T cells in cancer. Adv Cancer Res 107:57–117PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Marco Erreni
    • 1
  • Alberto Mantovani
    • 1
    • 2
  • Paola Allavena
    • 1
    Email author
  1. 1.Department of Immunology and InflammationIRCCS Istituto Clinico HumanitasRozzanoItaly
  2. 2.Department of Translational MedicineUniversity of MilanMilanItaly

Personalised recommendations