Cancer and Metastasis Reviews

, Volume 29, Issue 2, pp 243–248 | Cite as

Inflammation-mediated promotion of invasion and metastasis

  • Graziella Solinas
  • Federica Marchesi
  • Cecilia Garlanda
  • Alberto Mantovani
  • Paola Allavena


Inflammation has been suggested to represent the seventh hallmark of cancer. Myelomonocytic cells are a key component of cancer-related inflammation. Tumor-associated macrophages and their mediators affect key elements in the multistep process of invasion and metastasis, from interaction with the extracellular matrix to the construction of a pre-metastatic niche. Evidence indicating that inflammatory mediators affect genetic stability and cause persistent epigenetic alterations suggests that inflammatory components of the tumor microenvironment impacts on fundamental mechanisms responsible for the generation of metastatic variants. These results provide impetus for efforts aimed at translating cancer-related inflammation into diagnostic–prognostic markers and innovative therapeutic strategies.


Cancer Myelomonocytic cells Macrophages Metastasis Invasion 


  1. 1.
    Balkwill, F., & Mantovani, A. (2001). Inflammation and cancer: back to Virchow? Lancet, 357, 539–545.CrossRefPubMedGoogle Scholar
  2. 2.
    Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420, 860–867.CrossRefPubMedGoogle Scholar
  3. 3.
    Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008). Cancer-related inflammation. Nature, 454, 436–444.CrossRefPubMedGoogle Scholar
  4. 4.
    Mantovani, A. (2009). Cancer: inflaming metastasis. Nature, 457, 36–37.CrossRefPubMedGoogle Scholar
  5. 5.
    De Palma, M., Murdoch, C., Venneri, M. A., Naldini, L., & Lewis, C. E. (2007). Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol, 28, 519–524.CrossRefPubMedGoogle Scholar
  6. 6.
    Mantovani, A., & Sica, A. (2010). Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol, 22, 231–237.Google Scholar
  7. 7.
    Pollard, J. W. (2009). Trophic macrophages in development and disease. Nat Rev Immunol, 9, 259–270.CrossRefPubMedGoogle Scholar
  8. 8.
    Bollrath, J., & Greten, F. R. (2009). IKK/NF-kappaB and STAT3 pathways: central signalling hubs in inflammation-mediated tumour promotion and metastasis. EMBO Rep, 10, 1314–1319.CrossRefPubMedGoogle Scholar
  9. 9.
    Wang, D., Dubois, R. N., & Richmond, A. (2009). The role of chemokines in intestinal inflammation and cancer. Curr Opin Pharmacol, 9, 688–696.CrossRefPubMedGoogle Scholar
  10. 10.
    Wels, J., Kaplan, R. N., Rafii, S., & Lyden, D. (2008). Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev, 22, 559–574.CrossRefPubMedGoogle Scholar
  11. 11.
    Yu, H., Pardoll, D., & Jove, R. (2009). STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer, 9, 798–809.CrossRefPubMedGoogle Scholar
  12. 12.
    Karin, M. (2006). Nuclear factor-kappaB in cancer development and progression. Nature, 441, 431–436.CrossRefPubMedGoogle Scholar
  13. 13.
    Balkwill, F. (2009). Tumour necrosis factor and cancer. Nat Rev Cancer, 9, 361–371.CrossRefPubMedGoogle Scholar
  14. 14.
    Giavazzi, R., Garofalo, A., Bani, M. R., Abbate, M., Ghezzi, P., Boraschi, D., et al. (1990). Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice. Cancer Res, 50, 4771–4775.PubMedGoogle Scholar
  15. 15.
    Colotta, F., Allavena, P., Sica, A., Garlanda, C., & Mantovani, A. (2009). Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 30, 1073–1081.CrossRefPubMedGoogle Scholar
  16. 16.
    Niwa, T., Tsukamoto, T., Toyoda, T., Mori, A., Tanaka, H., Maekita, T., et al. (2010). Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res, 70, 1430–1440.CrossRefPubMedGoogle Scholar
  17. 17.
    Barash, H., Gross, E., Edrei, Y., Ella, E., Israel, A., Cohen, I., et al. (2010). Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks. Proc Natl Acad Sci U S A, 107, 2207–2212.CrossRefPubMedGoogle Scholar
  18. 18.
    Ishii, M., Wen, H., Corsa, C. A., Liu, T., Coelho, A. L., Allen, R. M., et al. (2009). Epigenetic regulation of the alternatively activated macrophage phenotype. Blood, 114, 3244–3254.CrossRefPubMedGoogle Scholar
  19. 19.
    Mantovani, A., & Locati, M. (2009). Orchestration of macrophage polarization. Blood, 114, 3135–3136.CrossRefPubMedGoogle Scholar
  20. 20.
    Iliopoulos, D., Hirsch, H. A., & Struhl, K. (2009). An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell, 139, 693–706.CrossRefPubMedGoogle Scholar
  21. 21.
    Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer, 3, 453–458.CrossRefPubMedGoogle Scholar
  22. 22.
    Torroella-Kouri, M., Silvera, R., Rodriguez, D., Caso, R., Shatry, A., Opiela, S., et al. (2009). Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res, 69, 4800–4809.CrossRefPubMedGoogle Scholar
  23. 23.
    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, 549–555.CrossRefPubMedGoogle Scholar
  24. 24.
    Martinez, F. O., Helming, L., & Gordon, S. (2009). Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol, 27, 451–483.CrossRefPubMedGoogle Scholar
  25. 25.
    Ojalvo, L. S., Whittaker, C. A., Condeelis, J. S., & Pollard, J. W. (2010). Gene expression analysis of macrophages that facilitate tumor invasion supports a role for Wnt-signaling in mediating their activity in primary mammary tumors. J Immunol, 184, 702–712.CrossRefPubMedGoogle Scholar
  26. 26.
    Wilcox, R. A., Wada, D. A., Ziesmer, S. C., Elsawa, S. F., Comfere, N. I., Dietz, A. B., et al. (2009). Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells. Blood, 114, 2936–2944.CrossRefPubMedGoogle Scholar
  27. 27.
    Zheng, Y., Cai, Z., Wang, S., Zhang, X., Qian, J., Hong, S., et al. (2009). Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood, 114, 3625–3628.CrossRefPubMedGoogle Scholar
  28. 28.
    Jaiswal, S., Jamieson, C. H., Pang, W. W., Park, C. Y., Chao, M. P., Majeti, R., et al. (2009). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell, 138, 271–285.CrossRefPubMedGoogle Scholar
  29. 29.
    Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., et al. (2009). Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell, 15, 35–44.CrossRefPubMedGoogle Scholar
  30. 30.
    Hagemann, T., Wilson, J., Burke, F., Kulbe, H., Li, N. F., Pluddemann, A., et al. (2006). Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol, 176, 5023–5032.PubMedGoogle Scholar
  31. 31.
    Kim, S., Takahashi, H., Lin, W.-W., Descargues, P., Grivennikov, S., Kim, Y., et al. (2009). Carcinoma produced factors activate myeloid cells via TLR2 to stimulate metastasis. Nature, 457, 102–106.CrossRefPubMedGoogle Scholar
  32. 32.
    Kuang, D. M., Wu, Y., Chen, N., Cheng, J., Zhuang, S. M., & Zheng, L. (2007). Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood, 110, 587–595.CrossRefPubMedGoogle Scholar
  33. 33.
    Goswami, S., Sahai, E., Wyckoff, J. B., Cammer, M., Cox, D., Pixley, F. J., et al. (2005). Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res, 65, 5278–5283.CrossRefPubMedGoogle Scholar
  34. 34.
    Priceman, S. J., Sung, J. L., Shaposhnik, Z., Burton, J. B., Torres-Collado, A. X., Moughon, D. L., et al. (2010). Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood, 115, 1461–1471.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang, J., Patel, L., & Pienta, K. J. (2010). CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev, 21, 41–48.CrossRefPubMedGoogle Scholar
  36. 36.
    Dehmel, S., Wang, S., Schmidt, C., Kiss, E., Loewe, R. P., Chilla, S., et al. (2010). Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long-term renal allograft outcome. Eur J Immunol, 40, 267–278.CrossRefPubMedGoogle Scholar
  37. 37.
    Roca, H., Varsos, Z. S., Sud, S., Craig, M. J., Ying, C., & Pienta, K. J. (2009). CCL2 and IL-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem, 284, 34342–34354.CrossRefPubMedGoogle Scholar
  38. 38.
    Balkwill, F., & Mantovani, A. (2010). Cancer and Inflammation: Implications for Pharmacology and Therapeutics. Clin Pharmacol Ther (in press).Google Scholar
  39. 39.
    Aspord, C., Pedroza-Gonzalez, A., Gallegos, M., Tindle, S., Burton, E. C., Su, D., et al. (2007). Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J Exp Med, 204, 1037–1047.CrossRefPubMedGoogle Scholar
  40. 40.
    DeNardo, D. G., Barreto, J. B., Andreu, P., Vasquez, L., Tawfik, D., Kolhatkar, N., et al. (2009). CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell, 16, 91–102.CrossRefPubMedGoogle Scholar
  41. 41.
    de Visser, K. E., Korets, L. V., & Coussens, L. M. (2005). De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell, 7, 411–423.CrossRefPubMedGoogle Scholar
  42. 42.
    Andreu, P., Johansson, M., Affara, N. I., Pucci, F., Tan, T., Junankar, S., et al. (2010). FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell, 17, 121–134.CrossRefPubMedGoogle Scholar
  43. 43.
    Markiewski, M. M., DeAngelis, R. A., Benencia, F., Ricklin-Lichtsteiner, S. K., Koutoulaki, A., Gerard, C., et al. (2008). Modulation of the antitumor immune response by complement. Nat Immunol, 9, 1225–1235.CrossRefPubMedGoogle Scholar
  44. 44.
    Erez, N., Truitt, M., Olson, P., & Hanahan, D. (2010). Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell, 17, 135–147.CrossRefPubMedGoogle Scholar
  45. 45.
    Cassatella, M. A., Locati, M., & Mantovani, A. (2009). Never underestimate the power of a neutrophil. Immunity, 31, 698–700.CrossRefPubMedGoogle Scholar
  46. 46.
    Mantovani, A. (2009). The yin-yang of tumor-associated neutrophils. Cancer Cell, 16, 173–174.CrossRefPubMedGoogle Scholar
  47. 47.
    Zhang, X., Majlessi, L., Deriaud, E., Leclerc, C., & Lo-Man, R. (2009). Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity, 31, 761–771.CrossRefPubMedGoogle Scholar
  48. 48.
    Nozawa, H., Chiu, C., & Hanahan, D. (2006). Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A, 103, 12493–12498.CrossRefPubMedGoogle Scholar
  49. 49.
    Pekarek, L. A., Starr, B. A., Toledano, A. Y., & Schreiber, H. (1995). Inhibition of tumor growth by elimination of granulocytes. J Exp Med, 181, 435–440.CrossRefPubMedGoogle Scholar
  50. 50.
    Fridlender, Z. G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L., et al. (2009). Polarization of tumor-associated neutrophil (TAN) phenotype by TGF-beta: “N1” versus “N2” TAN—a new paradigm? Cancer Cell, 16, 183–194.CrossRefPubMedGoogle Scholar
  51. 51.
    Balkwill, F. (2004). Cancer and the chemokine network. Nat Rev Cancer, 4, 540–550.CrossRefPubMedGoogle Scholar
  52. 52.
    Nguyen, D. X., Chiang, A. C., Zhang, X. H., Kim, J. Y., Kris, M. G., Ladanyi, M., et al. (2009). WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell, 138, 51–62.CrossRefPubMedGoogle Scholar
  53. 53.
    Hiratsuka, S., Watanabe, A., Aburatani, H., & Maru, Y. (2006). Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol, 8, 1369–1375.CrossRefPubMedGoogle Scholar
  54. 54.
    Kaplan, R. N., Rafii, S., & Lyden, D. (2006). Preparing the “soil”: the premetastatic niche. Cancer Res, 66, 11089–11093.CrossRefPubMedGoogle Scholar
  55. 55.
    Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., et al. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438, 820–827.CrossRefPubMedGoogle Scholar
  56. 56.
    Murdoch, C., Muthana, M., Coffelt, S. B., & Lewis, C. E. (2008). The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer, 8, 618–631.CrossRefPubMedGoogle Scholar
  57. 57.
    Padua, D., Zhang, X. H., Wang, Q., Nadal, C., Gerald, W. L., Gomis, R. R., et al. (2008). TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell, 133, 66–77.CrossRefPubMedGoogle Scholar
  58. 58.
    Barleon, B., Sozzani, S., Zhou, D., Weich, H. A., Mantovani, A., & Marme, D. (1996). Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood, 87, 3336–3343.PubMedGoogle Scholar
  59. 59.
    Coussens, L. M., Tinkle, C. L., Hanahan, D., & Werb, Z. (2000). MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell, 103, 481–490.CrossRefPubMedGoogle Scholar
  60. 60.
    Gocheva, V., Wang, H. W., Gadea, B. B., Shree, T., Hunter, K. E., Garfall, A. L., et al. (2010). IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev, 24, 241–255.CrossRefPubMedGoogle Scholar
  61. 61.
    Ding, T., Xu, J., Wang, F., Shi, M., Zhang, Y., Li, S. P., et al. (2009). High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum Pathol, 40, 381–389.CrossRefPubMedGoogle Scholar
  62. 62.
    Kuang, D. M., Zhao, Q., Peng, C., Xu, J., Zhang, J. P., Wu, C., et al. (2009). Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med, 206, 1327–1337.CrossRefPubMedGoogle Scholar
  63. 63.
    Zhang, J. P., Yan, J., Xu, J., Pang, X. H., Chen, M. S., Li, L., et al. (2009). Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol, 50, 980–989.CrossRefPubMedGoogle Scholar
  64. 64.
    DeVita, V. T., Jr., & Costa, J. (2010). Toward a personalized treatment of Hodgkin's disease. N Engl J Med, 362, 942–943.CrossRefPubMedGoogle Scholar
  65. 65.
    Steidl, C., Lee, T., Shah, S. P., Farinha, P., Han, G., Nayar, T., et al. (2010). Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med, 362, 875–885.CrossRefPubMedGoogle Scholar
  66. 66.
    Chiodoni C, Colombo MP, Sangaletti S. Matricellular proteins: form homeostasis to inflammation, cancer and metastasis. Cancer Metastasis Reviews, in press (this issue).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Graziella Solinas
    • 1
  • Federica Marchesi
    • 1
  • Cecilia Garlanda
    • 1
  • Alberto Mantovani
    • 1
    • 2
  • Paola Allavena
    • 1
  1. 1.Laboratory for Immunology and InflammationIRCCS Istituto Clinico HumanitasMilanItaly
  2. 2.Dipartimento di Medicina TraslazionaleUniversity of MilanMilanItaly

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