Skip to main content

The Role of Tumor-Associated Macrophages and Other Innate Immune Cells in Metastatic Progression of Lung Cancer

  • Chapter
  • First Online:
Lung Cancer Metastasis

Abstract

There is increasing evidence that the immune cells within the tumor microenvironment play a key role in the ability of tumor cells to proliferate and spread. Given that macrophages are the most frequent hematopoietic cells found in the tumor microenvironment, they play an especially important part in tumor biology. There are numerous mechanisms by which tumor-associated innate immune cells can influence most aspects of the metastatic process. They play a role in the epithelial to mesenchymal transformation occurring in the original tumor cells and enhance basement membrane breakdown by the cancer cells invading neighboring tissue, lymph nodes, and blood vessels. Tumor-associated innate immune cells have been shown to have a crucial role in angiogenesis, in immunosuppression, and eventually in priming distant sites for the development of metastases. Unfortunately, we still know relatively little about the roles of these cells in lung cancer. Further work in animal models and using patient lung cancer samples is very much needed. With this knowledge, a better understanding of the role that these cells play in the metastatic process may facilitate development of new therapeutics, as well as the recognition of new diagnostic and prognostic markers. Modulation of the metastatic phenotype through intervention in the host innate immune response remains a promising future area of cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Gupta, G.P. and Massague, J. 2006. Cancer metastasis: Building a framework. Cell 127: 679–695.

    Article  PubMed  CAS  Google Scholar 

  2. Virchow, R. 1863. Aetologie der neoplastichen geschwulste/pathogenie der neoplastichen geschwulste In Die krankhaften geschwulste (Berlin: Verlag von August Hirschwald; reprint).

    Google Scholar 

  3. Pollard, J. 2004. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4: 71–78.

    Article  PubMed  CAS  Google Scholar 

  4. Murdoch, C., Giannoudis, A., and Lewis, C.E. 2004. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104: 2224–2234.

    Article  PubMed  CAS  Google Scholar 

  5. Luboshits, G., Shina, S., Kaplan, O., Engelberg, S., Nass, D., Lifshitz-Mercer, B., Chaitchik, S., Keydar, I., and Ben-Baruch, A. 1999. Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res. 59: 4681–4687.

    PubMed  CAS  Google Scholar 

  6. Ueno, T., Toi, M., Saji, H., Muta, M., Bando, H., Kuroi, K., Koike, M., Inadera, H., and Matsushima, K. 2000. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin. Cancer Res. 6: 3282–3289.

    PubMed  CAS  Google Scholar 

  7. Scotton, C., Milliken, D., Wilson, J., Raju, S., and Balkwill, F. 2001. Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours. Brit. J. Cancer 85: 891.

    Article  PubMed  CAS  Google Scholar 

  8. Balkwill, F. 2003. Chemokine biology in cancer. Semin. Immunol. 15: 49–55.

    Article  PubMed  CAS  Google Scholar 

  9. Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M.E., Mcclanahan, T., Murphy, E., Yuan, W., Wagner, S.N., Barrera, J.L., Mohar, A., Verastegui, E., and Zlotnik, A. 2001. Involvement of chemokine receptors in breast cancer metastasis. Nature 410: 50–56.

    Article  PubMed  CAS  Google Scholar 

  10. Scotton, C.J., Wilson, J.L., Scott, K., Stamp, G., Wilbanks, G.D., Fricker, S., Bridger, G., and Balkwill, F.R. 2002. Multiple actions of the chemokine CXCL2 on epithelial tumor cells in human ovarian cancer. Cancer Res. 62: 5930–5938.

    PubMed  CAS  Google Scholar 

  11. Phillips, R.J., Burdick, M.D., Lutz, M., Belperio, J.A., Keane, M.P., and Strieter, R.M. 2003. The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am. J. Respir. Crit. Care Med. 167: 1676–1686.

    Article  PubMed  Google Scholar 

  12. Biswas, S.K., Sica, A., and Lewis, C.E. 2008. Plasticity of macrophage function during tumor progression: Regulation by distinct molecular mechanisms. J. Immunol. 180: 2011–2017.

    PubMed  CAS  Google Scholar 

  13. Keller, R, K.R., Keist, R., Wechsler, A., Leist, T.P., and van der Meide, P.H. 1990. Mechanisms of macrophage-mediated tumor cell killing: A comparative analysis of the roles of reactive nitrogen intermediates and tumor necrosis factor. Int. J. Cancer 46: 682–686.

    Article  PubMed  CAS  Google Scholar 

  14. Martin, J.H. and Edwards, S.W. 1993. Changes in mechanisms of monocyte/macrophage-mediated cytotoxicity during culture. Reactive oxygen intermediates are involved in monocyte- mediated cytotoxicity, whereas reactive nitrogen intermediates are employed by macrophages in tumor cell killing. J. Immunol. 150: 3478–3486.

    PubMed  CAS  Google Scholar 

  15. Grabstein, K.H., Urdal, D.L., Tushinski, R.J., Mochizuki, D.Y, Price, V.L., Cantrell, M.A., Gillis, S., and Conlon, P.J. 1986. Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factor. Science 232: 506–508.

    Article  PubMed  CAS  Google Scholar 

  16. Kamimura, A., Kamachi, M., Nishihira, J., Ogura, S., Isobe, H., Dosaka-Akita, H., Ogata, A., Shindoh, M., Ohbuchi, T., and Kawakami, Y. 2000. Intracellular distribution of macrophage migration inhibitory factor predicts the prognosis of patients with adenocarcinoma of the lung. Cancer 89: 334–341.

    Article  PubMed  CAS  Google Scholar 

  17. Janat-Amsbury, M.M., Yockman, J.W., Lee, M., Kern, S., Furgeson, D.Y., Bikram, M., and Kim, S.W. 2004. Combination of local, nonviral IL-12 gene therapy and systemic paclitaxel treatment in a metastatic breast cancer model. Mol. Ther. 9: 829–836.

    Article  PubMed  CAS  Google Scholar 

  18. Li, Q., Carr, A.L., Donald, E.J., Skitzki, J.J., Okuyama, R., Stoolman, L.M., and Chang, A.E. 2005. Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern. Cancer Res. 65: 1063–1070.

    PubMed  Google Scholar 

  19. Lewis, C.E. and Pollard, J.W. 2006. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66: 605–612.

    Article  PubMed  CAS  Google Scholar 

  20. Coussens, L.M. and Werb, Z. 2002. Inflammation and cancer. Nature 420: 860–867.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. Stout, R.D., Jiang, C., Matta, B., Tietzel, I., Watkins, S.K., and Suttles, J. 2005. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J. Immunol. 175: 342–349.

    PubMed  CAS  Google Scholar 

  23. Mills, C.D., Kincaid, K., Alt, J.M., Heilman, M.J., and Hill, A.M. 2000. M-1/m-2 macrophages and the TH1/TH2 paradigm. J. Immunol. 164: 6166–6173.

    PubMed  CAS  Google Scholar 

  24. Munder, M., Eichmann, K., and Modolell, M. 1998. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: Competitive regulation by CD4+ t cells correlates with TH1/TH2 phenotype. J. Immunol. 160: 5347–5354.

    PubMed  CAS  Google Scholar 

  25. Bonecchi, R., Sozzani, S., Stine, J.T., Luini, W., D’amico, G., Allavena, P., Chantry, D., and Mantovani, A. 1998. Divergent effects of interleukin-4 and interferon-gamma on macrophage-derived chemokine production: An amplification circuit of polarized T helper 2 responses. Blood 92: 2668–2671.

    PubMed  CAS  Google Scholar 

  26. Lewis, J.S., Landers, R.J., Underwood, J.C.E., Harris, A.L., and Lewis, C.E. 2000. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J. Pathol. 192: 150–158.

    Article  PubMed  CAS  Google Scholar 

  27. Welch, D.R., Schissel, D.J., Howrey, R.P., and Aeed, P.A. 1989. Tumor-elicited polymorphonuclear cells, in contrast to ``normal'' circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells. Proc. Natl. Acad. Sci. 86: 5859–5863.

    Article  PubMed  CAS  Google Scholar 

  28. Heifets, L. 1982. Centennial of Metchnikoff’s discovery. J. Reticuloendothel Soc. 31: 381–391.

    PubMed  CAS  Google Scholar 

  29. Di Carlo, E., Forni, G., Lollini, P., Colombo, M.P., Modesti, A., and Musiani, P. 2001. The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood 97: 339–345.

    Article  PubMed  Google Scholar 

  30. Ishihara, Y.F.T., Iijima, H., Saito, K., Matsunaga, K. 1998. The role of neutrophils as cytotoxic cells in lung metastasis: Suppression of tumor cell metastasis by a biological response modifier (psk). In Vivo 12: 175–182.

    PubMed  CAS  Google Scholar 

  31. Ishihara, Y.I.H. and Matsunaga, K. 1998. Contribution of cytokines on the suppression of lung metastasis. Biotherapy 11: 267–275.

    Article  PubMed  CAS  Google Scholar 

  32. Scapini, P., Lapinet-Vera, J.A., Gasperini, S., Calzetti, F., Bazzoni, F., and Cassatella, M.A. 2000. The neutrophil as a cellular source of chemokines. Immunol. Rev. 177: 195–203.

    Article  PubMed  CAS  Google Scholar 

  33. Wu, Q.D., Wang, J.H., Condron, C., Bouchier-Hayes, D., and Redmond, H.P. 2001. Human neutrophils facilitate tumor cell transendothelial migration. Am. J. Physiol. Cell Physiol. 280: C814–822.

    PubMed  CAS  Google Scholar 

  34. Orr, F.W. and Warner, D.J.A. 1990. Effects of systemic complement activation and neutrophil-mediated pulmonary injury on the retention and metastasis of circulating cancer cells in mouse lungs. Lab. Invest. 62: 331–338.

    PubMed  CAS  Google Scholar 

  35. Orr, F.W. and Warner, D.J.A. 2001. Tumor cell interactions with the microvasculature: A rate-limiting step in metastasis. Surg. Oncol. Clin. N. Am. 10: 357–381.

    PubMed  CAS  Google Scholar 

  36. Doi, K., Horiuchi, T., Uchinami, M., Tabo, T., Kimura, N., Yokomachi, J., Yoshida, M., and Tanaka, K. 2002. Neutrophil elastase inhibitor reduces hepatic metastases induced by ischaemia-reprefusion in rats. Eur. J. Surg. 168: 507.

    Article  PubMed  CAS  Google Scholar 

  37. Aeed, P.A., Nakajima, M., and Welch, D.R. 1988. The role of polymorphonuclear leukocytes (PMN) on the growth and metastatic potential of 13762nf mammary adenocarcinoma cells. Int. J. Cancer 42: 748–759.

    Article  PubMed  CAS  Google Scholar 

  38. Nozawa, H., Chiu, C., and Hanahan, D. 2006. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl. Acad. Sci. 103: 12493–12498.

    Article  PubMed  CAS  Google Scholar 

  39. Schmielau, J. and Finn, O.J. 2001. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 61: 4756–4760.

    PubMed  CAS  Google Scholar 

  40. Zea, A.H., Rodriguez, P.C., Atkins, M.B., Hernandez, C., Signoretti, S., Zabaleta, J., McDermott, D., Quiceno, D., Youmans, A., O’neill, A., Mier, J., and Ochoa, A.C. 2005. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: A mechanism of tumor evasion. Cancer Res. 65: 3044–3048.

    PubMed  CAS  Google Scholar 

  41. Schmidt, H., Bastholt, L., Geertsen, P., Christensen, I.J., Larsen, S., Gehl, J., and Von Der Maase, H. 2005. Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: A prognostic model. Brit. J. Cancer 93: 273–278.

    Article  PubMed  CAS  Google Scholar 

  42. McGary, C.T., Miele, M.F., and Welch, D.R. 1995. Highly metastatic 13762NF rat mammary adenocarcinoma cell clones stimulate bone marrow by secretion of granulocyte-macrophage colony-stimulating factor/interleukin-3 activity. Am. J. Pathol. 147: 1668–1681.

    PubMed  CAS  Google Scholar 

  43. De Larco, J.E., Wuertz, B.R.K., and Furcht, L.T. 2004. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin. Cancer Res. 10: 4895–4900.

    Article  PubMed  Google Scholar 

  44. De Larco, J.E., Wuertz, B.R.K., Yee, D., Rickert, B.L., and Furcht, L.T. 2003. Atypical methylation of the interleukin-8 gene correlates strongly with the metastatic potential of breast carcinoma cells. Proc. Natl. Acad. Sci. 100: 13988–13993.

    Article  PubMed  CAS  Google Scholar 

  45. Caruso, R.A., Bellocco, R., Pagano, M., Bertoli, G., Rigoli, L., and Inferrera, C. 2002. Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern Italy. Mod. Pathol. 15: 831–837.

    Article  PubMed  Google Scholar 

  46. Gregoire, C., Chasson, L., Luci, C., Tomasello, E., Geissmann, F., Vivier, E., and Walzer, T. 2007. The trafficking of natural killer cells. Immunol. Rev. 220: 169–182.

    Article  PubMed  CAS  Google Scholar 

  47. Yang, Q., Goding, S., Hokland, M., and Basse, P. 2006. Antitumor activity of NK cells. Immunol. Res. 36: 13–25.

    Article  PubMed  Google Scholar 

  48. Lu, L.-M., Zavitz, C.C.J., Chen, B., Kianpour, S., Wan, Y., and Stampfli, M.R. 2007. Cigarette smoke impairs NK cell-dependent tumor immune surveillance. J. Immunol. 178: 936–943.

    PubMed  CAS  Google Scholar 

  49. Ribatti, D., Crivellato, E., Roccaro, A.M., Ria, R., and Vacca, A. 2004. Mast cell contribution to angiogenesis related to tumour progression. Clin. Exper. Allergy 34: 1660–1664.

    Article  CAS  Google Scholar 

  50. Tomita, M., Matsuzaki, Y., and Onitsuka, T. 2000. Effect of mast cells on tumor angiogenesis in lung cancer. Ann. Thorac. Surg. 69: 1686–1690.

    Article  PubMed  CAS  Google Scholar 

  51. Azizkhan, R.G., Azizkhan, J.C., Zetter, B.R., and Folkman, J. 1980. Mast cell heparin stimulates migration of capillary endothelial cells in vitro. J. Exp. Med. 152: 931–944.

    Article  PubMed  CAS  Google Scholar 

  52. Tomita, M., Matsuzaki, Y., Edagawa, M., Shimizu, T., Hara, M., and Onitsuka, T. 2003. Distribution of mast cells in mediastinal lymph nodes from lung cancer patients. World J. Surg. Oncol. 1: 25.

    Article  PubMed  Google Scholar 

  53. Ibaraki, T., Muramatsu, M., Takai, S., Jin, D., Maruyama, H., Orino, T., Katsumata, T., and Miyazaki, M. 2005. The relationship of tryptase- and chymase-positive mast cells to angiogenesis in stage 1 non-small cell lung cancer. Eur. J. Cardio-Thorac. Surg. 28: 617–621.

    Article  Google Scholar 

  54. Akhurst, R.J. and Derynck, R. 2001. TGF-β signaling in cancer – a double-edged sword. Trends Cell Biol. 11: S44–S51.

    PubMed  CAS  Google Scholar 

  55. Ashley, D.M., Kong, F.M., Bigner, D.D., and Hale, L.P. 1998. Endogenous expression of transforming growth factor beta-1 inhibits growth and tumorigenicity and enhances fas-mediated apoptosis in a murine high-grade glioma model. Cancer Res. 58: 302–309.

    PubMed  CAS  Google Scholar 

  56. Wrzesinski, S.H., Wan, Y.Y., and Flavell, R.A. 2007. Transforming growth factor-β and the immune response: Implications for anticancer therapy. Clin Cancer Res. 13: 5262–5270.

    Article  PubMed  CAS  Google Scholar 

  57. Bacman, D., Merkel, S., Croner, R., Papadopoulos, T., Brueckl, W., and Dimmler, A. 2007. TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: A retrospective study. BMC Cancer 7: 156.

    Article  PubMed  CAS  Google Scholar 

  58. Hagemann, T., Wilson, J., Kulbe, H., Li, N.F., Leinster, D.A., Charles, K., Klemm, F., Pukrop, T., Binder, C., and Balkwill, F.R. 2005. Macrophages induce invasiveness of epithelial cancer cells via NFκB and JNK. J. Immunol. 175: 1197–1205.

    PubMed  CAS  Google Scholar 

  59. Wyckoff, J., Wang, W., Lin, E.Y., Wang, Y., Pixley, F., Stanley, E.R., Graf, T., Pollard, J.W., Segall, J., and Condeelis, J. 2004. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64: 7022–7029.

    Article  PubMed  CAS  Google Scholar 

  60. Domagala, W.S.G., Szadowska, A., Dukowicz, A., Weber, K., and Osborn, M. 1992. Cathepsin B in invasive ductal nos breast carcinoma as defined by immunohistochemistry. No correlation with survival at 5 years. Am. J. Pathol. 141: 1003–1012.

    PubMed  CAS  Google Scholar 

  61. Hagemann, T., Robinson, S.C., Schulz, M., Trumper, L., Balkwill, F.R., and Binder, C. 2004. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-α dependent up-regulation of matrix metalloproteases. Carcinogenesis 25: 1543–1549.

    Article  PubMed  CAS  Google Scholar 

  62. Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J.M., Senior, R.M., and Shibuya, M. 2002. Mmp9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2: 289–300.

    Article  PubMed  CAS  Google Scholar 

  63. Chen, X., Su, Y., Fingleton, B., Acuff, H., Matrisian, L.M., Zent, R., and Pozzi, A. 2005. Increased plasma MMP9 in integrin α1-null mice enhances lung metastasis of colon carcinoma cells. Int. J. Cancer 116: 52–61.

    Article  PubMed  CAS  Google Scholar 

  64. Williams, T.M., Medina, F., Badano, I., Hazan, R.B., Hutchinson, J., Muller, W.J., Chopra, N.G., Scherer, P.E., Pestell, R.G., and Lisanti, M.P. 2004. Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo: Role of cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion. J. Biol. Chem. 279: 51630–51646.

    Article  PubMed  CAS  Google Scholar 

  65. Zhongyun Dong, R.K., Xiulan, Y., and Fidler, I.J. 1997. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 88: 801–810.

    Article  Google Scholar 

  66. Koide, N., Nishio, A., Sato, T., Sugiyama, A., and Miyagawa, S. 2004. Significance of macrophage infiltration in squamous cell carcinoma of the esophagus. Am. J. Gastroenterol. 99: 1667–1674.

    Article  PubMed  CAS  Google Scholar 

  67. Takanami, T., Takeuchi, K., and Kodaira, S. 1999. Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: Association with angiogenesis and poor prognosis. Oncology 57: 138–142.

    Article  PubMed  CAS  Google Scholar 

  68. Koukourakis Mi, G.A., Kakolyris, S., O’Byrne, K.J., Apostolikas, N., Skarlatos, J., Gatter, K.C., andHarris A.L. 1998. Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: Impact on tumour neoangiogenesis and survival. Brit. J. Cancer. 77: 1696–1703.

    Article  PubMed  Google Scholar 

  69. Barleon, B., Sozzani, S., Zhou, D., Weich, H.A., Mantovani, A., and 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.

    PubMed  CAS  Google Scholar 

  70. Robinson-Smith, T.M., Isaacsohn, I., Mercer, C.A., Zhou, M., Van Rooijen, N., Husseinzadeh, N., Mcfarland-Mancini, M.M., and Drew, A.F. 2007. Macrophages mediate inflammation-enhanced metastasis of ovarian tumors in mice. Cancer Res. 67: 5708–5716.

    Article  PubMed  CAS  Google Scholar 

  71. Queen, M.M., Ryan, R.E., Holzer, R.G., Keller-Peck, C.R., and Jorcyk, C.L. 2005. Breast cancer cells stimulate neutrophils to produce oncostatin M: Potential implications for tumor progression. Cancer Res. 65: 8896–8904.

    Article  PubMed  CAS  Google Scholar 

  72. Li, A., Dubey, S., Varney, M.L., Dave, B.J., and Singh, R.K. 2003. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J. Immunol. 170: 3369–3376.

    PubMed  CAS  Google Scholar 

  73. White, E.S., Strom, S.R.B., Wys, N.L., and Arenberg, D.A. 2001. Non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity. J. Immunol. 166: 7549–7555.

    PubMed  CAS  Google Scholar 

  74. White, E.S., Flaherty, K.R., Carskadon, S., Brant, A., Iannettoni, M.D., Yee, J., Orringer, M.B., and Arenberg, D.A. 2003. Macrophage migration inhibitory factor and cxc chemokine expression in non-small cell lung cancer: Role in angiogenesis and prognosis. Clin. Cancer Res. 9: 853–860.

    PubMed  CAS  Google Scholar 

  75. Schoppmann, S.F., Birner, P., Stockl, J., Kalt, R., Ullrich, R., Caucig, C., Kriehuber, E., Nagy, K., Alitalo, K., and Kerjaschki, D. 2002. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am. J. Pathol. 161: 947–956.

    Article  PubMed  CAS  Google Scholar 

  76. Leek, R.D. and Lewis, C.L. 1999. Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Brit. J. Cancer 79: 991–995.

    Article  PubMed  CAS  Google Scholar 

  77. Leek, R.D., Hunt, N.C., Landers, R.J., Lewis, C.E., Royds, J.A., and Harris, A.L. 2000. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J. Pathol. 190: 430–436.

    Article  PubMed  CAS  Google Scholar 

  78. Dinapoli, M.R., Calderon, C.L., and Lopez, D.M. 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: 1323–1329.

    Article  PubMed  CAS  Google Scholar 

  79. Sica, A., Saccani, A., Bottazzi, B., Polentarutti, N., Vecchi, A., Damme, J.V., and Mantovani, A. 2000. Autocrine production of il-10 mediates defective IL-12 production and NFκB activation in tumor-associated macrophages. J. Immunol. 164: 762–767.

    PubMed  CAS  Google Scholar 

  80. Li, M.O., Wan, Y.Y., Sanjabi, S., Robertson, A.-K.L., and Flavell, R.A. 2006. Transforming growth factor-β; regulation of immune responses. Ann. Rev. Immunol. 24: 99–146.

    Article  CAS  Google Scholar 

  81. Teicher, B.A. 2007. Transforming growth factor-β and the immune response to malignant disease. Clin. Cancer Res. 13: 6247–6251.

    Article  PubMed  CAS  Google Scholar 

  82. Rodriguez, P.C., Quiceno, D.G., Zabaleta, J., Ortiz, B., Zea, A.H., Piazuelo, M.B., Delgado, A., Correa, P., Brayer, J., Sotomayor, E.M., Antonia, S., Ochoa, J.B., and Ochoa, A.C. 2004. Arginase 1 production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 64: 5839–5849.

    Article  PubMed  CAS  Google Scholar 

  83. Mrass, P. and Weninger, W. 2006. Immune cell migration as a means to control immune privilege: Lessons from the CNS and tumors. Immunol. Rev. 213: 195–212.

    Article  PubMed  Google Scholar 

  84. Kobie, J.J., Wu, R.S., Kurt, R.A., Lou, S., Adelman, M.K., Whitesell, L.J., Ramanathapuram, L.V., Arteaga, C.L., and Akporiaye, E.T. 2003. Transforming growth factor–β inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res. 63: 1860–1864.

    PubMed  CAS  Google Scholar 

  85. Marie, J.C., Letterio, J.J., Gavin, M., and Rudensky, A.Y. 2005. TGF-²1 maintains suppressor function and foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201: 1061–1067.

    Article  PubMed  CAS  Google Scholar 

  86. Liu, V.C., Wong, L.Y., Jang, T., Shah, A.H., Park, I., Yang, X., Zhang, Q., Lonning, S., Teicher, B.A., and Lee, C. 2007. Tumor evasion of the immune system by converting CD4+CD25– T-cells into CD4+CD25+ T regulatory cells: Role of tumor-derived TGF-β. J. Immunol. 178: 2883–2892.

    PubMed  CAS  Google Scholar 

  87. Chang, C.-J., Liao, C.-H., Wang, F.-H., and Lin, C.-M. 2003. Transforming growth factor-β² induces apoptosis in antigen-specific CD4+ T cells prepared for adoptive immunotherapy. Immunol. Lett. 86: 37–43.

    Article  PubMed  CAS  Google Scholar 

  88. Thomas, D.A. and Massague, J. 2005. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8: 369–380.

    Article  PubMed  CAS  Google Scholar 

  89. Ahmadzadeh, M. and Rosenberg, S.A. 2005. TGF-β1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J. Immunol. 174: 5215–5223.

    PubMed  CAS  Google Scholar 

  90. Jakobisiak, M., Lasek, W., and Golab, J. 2003. Natural mechanisms protecting against cancer. Immunol. Lett. 90: 103–122.

    Article  PubMed  CAS  Google Scholar 

  91. Hanna, N. 1982. Role of natural killer cells in control of cancer metastasis. Cancer Metastasis Rev. 1: 45–64.

    Article  PubMed  CAS  Google Scholar 

  92. Kaplan, R.N., Riba, R.D., Zacharoulis, S., Bramley, A.H., Vincent, L., Costa, C., Macdonald, D.D., Jin, D.K., Shido, K., Kerns, S.A., Zhu, Z., Hicklin, D., Wu, Y., Port, J.L., Altorki, N., Port, E.R., Ruggero, D., Shmelkov, S.V., Jensen, K.K., Rafii, S., and Lyden, D. 2005. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438: 820–827.

    Article  PubMed  CAS  Google Scholar 

  93. Hiratsuka, S., Watanabe, A., Aburatani, H., and Maru, Y. 2006. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biol. 8: 1369–1375.

    Article  PubMed  CAS  Google Scholar 

  94. Oberg, A., Samii, S., Stenling, R., and Lindmark, G. 2002. Different occurrence of cd8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors. Int. J. Colorectal Dis. 17: 25–29.

    Article  PubMed  CAS  Google Scholar 

  95. Lin, E.Y., Nguven, A.V., Russell, R.G., and Pollard J.W. 2001. Colony stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193: 727–740.

    Article  PubMed  CAS  Google Scholar 

  96. Yano, S., Nishioka, Y., Izumi, K., Tsuruo, T., Tanaka, T., Miyasaka, M., and Sone, S. 1996. Novel metastasis model of human lung cancer in SCID mice depleted of NK cells. Int. J. Cancer 67: 211–217.

    Article  PubMed  CAS  Google Scholar 

  97. Young, M.R. and Newby, M. 1986. Differential induction of suppressor macrophages by cloned lewis lung carcinoma variants in mice. J. Natl. Cancer Inst. 77: 1255–1260.

    Google Scholar 

  98. Henry, N., Van Lamsweerde, A.-L., and Vaes, G. 1983. Collagen degradation by metastatic variants of lewis lung carcinoma: Cooperation between tumor cells and macrophages. Cancer Res. 43: 5321–5327.

    PubMed  CAS  Google Scholar 

  99. Gorelik, E., Wiltrout, R.H., Brunda, M.J., Holden, H.T., andHerberman, R.B. 1982. Augmentation of metastasis formation by thioglycollate-elicited macrophages. Int. J. Cancer 29: 575–581.

    Article  PubMed  CAS  Google Scholar 

  100. Duffie, G.P. and Young, M.R. 1991. Tumoricidal activity of alveolar and peritoneal macrophages of C57bl/6 mice bearing metastatic or nonmetastatic variants of lewis lung carcinoma. J. Leukoc. Biol. 49: 8–14.

    PubMed  CAS  Google Scholar 

  101. Luo, Y., Zhou H., Krueger, J., Kaplan, C., Lee, S., Dolman, C., Markowitz, D., Wu, W., Liu, C., Reisfeld, R.A., Xiang, R. 2006. Targeting tumor-associated macrophages as a novel strategy against breast cancer. J. Clin. Invest. 116: 2132–2141.

    Article  PubMed  CAS  Google Scholar 

  102. Chen, J.J.W., Yao, P.-L., Yuan, A., Hong, T.-M., Shun, C.-T., Kuo, M.-L., Lee, Y.-C., and Yang, P.-C. 2003. Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: Its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clin. Cancer Res. 9: 729–737.

    PubMed  CAS  Google Scholar 

  103. Cornelius, L.A., Nehring, L.C., Harding, E., Bolanowski, M., Welgus, H.G., Kobayashi, D.K., Pierce, R.A., and Shapiro, S.D. 1998. Matrix metalloproteinases generate angiostatin: Effects on neovascularization. J. Immunol. 161: 6845–6852.

    PubMed  CAS  Google Scholar 

  104. Dong, Z., Kumar, R., Yang, X., and Fidler, I.J. 1997. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in lewis lung carcinoma. Cell 88: 801–810.

    Article  PubMed  CAS  Google Scholar 

  105. Montuenga, L.M. and Pio, R. 2007. Tumour-associated macrophages in nonsmall cell lung cancer: The role of interleukin-10. Eur. Respir. J. 30: 608–610.

    Article  PubMed  CAS  Google Scholar 

  106. Sato, T., Takahashi, S., Mizumoto, T., Harao, M., Akizuki, M., Takasugi, M., Fukutomi, T., and Yamashita, J.-I. 2006. Neutrophil elastase and cancer. Surg. Oncol. 15: 217–222.

    Article  PubMed  Google Scholar 

  107. Bingle, L., Brown, N., and Lewis, C.E. 2002. The role of tumor-associated macrophages in tumor progression: Implications for new anticancer therapies. J. Pathol. 196: 254–265.

    Article  PubMed  CAS  Google Scholar 

  108. Chen, J.J., Lin, Y.C., Yao, P.L., Yuan, A., Chen, H.Y., Shun, C.T., Tsai, M.F., Chen, C.H., and Yang, P.C. 2005. Tumor-associated macrophages: The double-edged sword in cancer progression. J. Clin. Oncol. 23: 953–964.

    Article  PubMed  CAS  Google Scholar 

  109. Takeo, S., Yasumoto, K., Nagashima, A., Nakahashi, H., Sugimachi, K., and Nomoto, K. 1986. Role of tumor-associated macrophages in lung cancer. Cancer Res. 46: 3179–3182.

    PubMed  CAS  Google Scholar 

  110. Johnson, S.K., Kerr, K.M., Chapman, A.D., Kennedy, M.M., King, G., Cockburn, J.S., and Jeffrey, R.R. 1999. Immune cell infiltrates and prognosis in primary carcinoma of the lung. Lung Cancer 27: 27–35.

    Article  Google Scholar 

  111. Toomey, D., Symthe, G., Condron, C., Kelly, J., Byrne, A.M., Kay, E., Conroy, R.M., Broe, P., and Bouchier-Hayes, D. 2003. Infiltrating immune cells, but not tumour cells, express fasl in non-small cell lung cancer: No association with prognosis identified in 3-year follow-up. Intl. J. Cancer 103: 408–412.

    Article  CAS  Google Scholar 

  112. Welsh, T.J., Green, R.H., Richardson, D., Waller, D.A., O’byrne, K.J., and Bradding, P. 2005. Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J. Clin. Oncol. 23: 8959–8967.

    Article  PubMed  Google Scholar 

  113. Zeni, E., Mazzetti, L., Miotto, D., Lo Cascio, N., Maestrelli, P., Querzoli, P., Pedriali, M., De Rosa, E., Fabbri, L.M., Mapp, C.E., and Boschetto, P. 2007. Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer. Eur. Respir. J. 30: 627–632.

    Article  CAS  Google Scholar 

  114. Junker, N., Johansen, J.S., Andersen, C.B., and Kristjansen, P.E.G. 2005. Expression of YKL-40 by peritumoral macrophages in human small cell lung cancer. Lung Cancer 48: 223–231.

    Article  PubMed  Google Scholar 

  115. Ferrigno, D.B.G. 2003. Hematologic counts and clinical correlates in 1201 newly diagnosed lung cancer patients. Monaldi Arch. Chest Dis. 59: 193–198.

    PubMed  CAS  Google Scholar 

  116. Kerr, K.M., Johnson, S.K., King, G., Kennedy, M.M., Weir, J. and Jeffrey, R. 1998. Partial regression in primary carcinoma of the lung: Does it occur? Histopathology 33:55–63.

    PubMed  CAS  Google Scholar 

  117. Arenberg, D.A., Keane, M.P. Digiovine, B., Kunkle, S.L., Strom, S.R, Burdick, M.D., Iannettoni, M.D., and Strieter, R.M. 2000. Macrophage infiltration in human non-small-cell lung cancer: The role of cc chemokines. Cancer Immunol. Immunother 49:63–70.

    Article  PubMed  CAS  Google Scholar 

  118. Tataroglu, C., Kargi, A., Ozkal, S., Esrefoglu, N., and Akkoclu, A. 2004. Association of macrophages, mast cells and eosinophil leukocytes with angiogenesis and tumor stage in non-small cell lung carcinomas (nsclc). Lung Cancer 43: 47–54.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zvi G. Fridlender .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Fridlender, Z.G., Crisanti, M.C., Albelda, S.M. (2009). The Role of Tumor-Associated Macrophages and Other Innate Immune Cells in Metastatic Progression of Lung Cancer. In: Keshamouni, V., Arenberg, D., Kalemkerian, G. (eds) Lung Cancer Metastasis. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0772-1_11

Download citation

Publish with us

Policies and ethics