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Mediators of Inflammation
Volume 2017 (2017), Article ID 9294018, 13 pages
https://doi.org/10.1155/2017/9294018
Review Article

Inflammation and Cancer: Extra- and Intracellular Determinants of Tumor-Associated Macrophages as Tumor Promoters

1Avidin Ltd., Alsó Kikötő sor 11/D., Szeged 6726, Hungary
2Synaptogenex Ltd., Őzsuta utca 20995/1, Budapest 1037, Hungary
3Department of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged 6726, Hungary
4Department of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged 6726, Hungary

Correspondence should be addressed to Gabor J. Szebeni

Received 25 August 2016; Accepted 26 December 2016; Published 18 January 2017

Academic Editor: Yona Keisari

Copyright © 2017 Gabor J. Szebeni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Mantovani, B. Bottazzi, F. Colotta, S. Sozzani, and L. Ruco, “The origin and function of tumor-associated macrophages,” Immunology Today, vol. 13, no. 7, pp. 265–270, 1992. View at Publisher · View at Google Scholar · View at Scopus
  2. J. Kim and J.-S. Bae, “Tumor-associated macrophages and neutrophils in tumor microenvironment,” Mediators of Inflammation, vol. 2016, Article ID 6058147, 11 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  3. A. Sica, M. Erreni, P. Allavena, and C. Porta, “Macrophage polarization in pathology,” Cellular and Molecular Life Sciences, vol. 72, no. 21, pp. 4111–4126, 2015. View at Publisher · View at Google Scholar · View at Scopus
  4. R. A. Franklin and M. O. Li, “Ontogeny of tumor-associated macrophages and its implication in cancer regulation,” Trends in Cancer, vol. 2, no. 1, pp. 20–34, 2016. View at Publisher · View at Google Scholar
  5. D. Laoui, E. Van Overmeire, P. De Baetselier, J. A. Van Ginderachter, and G. Raes, “Functional relationship between tumor-associated macrophages and macrophage colony-stimulating factor as contributors to cancer progression,” Frontiers in Immunology, vol. 5, article 489, 2014. View at Publisher · View at Google Scholar · View at Scopus
  6. W. Zhang, C. Zhang, W. Li et al., “CD8+ T-cell immunosurveillance constrains lymphoid premetastatic myeloid cell accumulation,” European Journal of Immunology, vol. 45, no. 1, pp. 71–81, 2015. View at Publisher · View at Google Scholar · View at Scopus
  7. N. Caronni, B. Savino, and R. Bonecchi, “Myeloid cells in cancer-related inflammation,” Immunobiology, vol. 220, no. 2, pp. 249–253, 2015. View at Publisher · View at Google Scholar · View at Scopus
  8. S. K. Biswas, P. Allavena, and A. Mantovani, “Tumor-associated macrophages: functional diversity, clinical significance, and open questions,” Seminars in Immunopathology, vol. 35, no. 5, pp. 585–600, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. G. J. Szebeni, C. Vizler, L. I. Nagy, K. Kitajka, and L. G. Puskas, “Pro-tumoral inflammatory myeloid cells as emerging therapeutic targets,” International Journal of Molecular Sciences, vol. 17, no. 11, p. 1958, 2016. View at Publisher · View at Google Scholar
  10. L. Strauss, S. Sangaletti, F. M. Consonni et al., “RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis,” Cancer Cell, vol. 28, no. 2, pp. 253–269, 2015. View at Publisher · View at Google Scholar · View at Scopus
  11. A. R. Pyzer, L. Cole, J. Rosenblatt, and D. E. Avigan, “Myeloid-derived suppressor cells as effectors of immune suppression in cancer,” International Journal of Cancer, vol. 139, no. 9, pp. 1915–1926, 2016. View at Publisher · View at Google Scholar · View at Scopus
  12. V. Kumar, S. Patel, E. Tcyganov, and D. I. Gabrilovich, “The nature of myeloid-derived suppressor cells in the tumor microenvironment,” Trends in Immunology, vol. 37, no. 3, pp. 208–220, 2016. View at Publisher · View at Google Scholar · View at Scopus
  13. V. Bronte, S. Brandau, S.-H. Chen et al., “Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards,” Nature Communications, vol. 7, Article ID 12150, 2016. View at Publisher · View at Google Scholar · View at Scopus
  14. C. Porta, E. Riboldi, A. Ippolito, and A. Sica, “Molecular and epigenetic basis of macrophage polarized activation,” Seminars in Immunology, vol. 27, no. 4, pp. 237–248, 2015. View at Publisher · View at Google Scholar · View at Scopus
  15. G. Hoeffel, J. Chen, Y. Lavin et al., “C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages,” Immunity, vol. 42, no. 4, pp. 665–678, 2015. View at Publisher · View at Google Scholar · View at Scopus
  16. E. Van Overmeire, D. Laoui, J. Keirsse, J. A. Van Ginderachter, and A. Sarukhan, “Mechanisms driving macrophage diversity and specialization in distinct tumor microenvironments and parallelisms with other tissues,” Frontiers in Immunology, vol. 5, article 127, 2014. View at Publisher · View at Google Scholar · View at Scopus
  17. S. J. Jenkins, D. Ruckerl, P. C. Cook et al., “Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation,” Science, vol. 332, no. 6035, pp. 1284–1288, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. V. Cortez-Retamozo, M. Etzrodt, A. Newton et al., “Origins of tumor-associated macrophages and neutrophils,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 7, pp. 2491–2496, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. V. Cortez-Retamozo, M. Etzrodt, A. Newton et al., “Angiotensin II drives the production of tumor-promoting macrophages,” Immunity, vol. 38, no. 2, pp. 296–308, 2013. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Ugel, F. De Sanctis, S. Mandruzzato, and V. Bronte, “Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages,” The Journal of Clinical Investigation, vol. 125, no. 9, pp. 3365–3376, 2015. View at Publisher · View at Google Scholar · View at Scopus
  21. Y. De Vlaeminck, A. González-Rascón, C. Goyvaerts, and K. Breckpot, “Cancer-associated myeloid regulatory cells,” Frontiers in Immunology, vol. 7, article 113, 2016. View at Publisher · View at Google Scholar · View at Scopus
  22. B. Wang, Q. Li, L. Qin, S. Zhao, J. Wang, and X. Chen, “Transition of tumor-associated macrophages from MHC class IIhi to MHC class IIlow mediates tumor progression in mice,” BMC Immunology, vol. 12, article 43, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. S. K. Biswas, L. Gangi, S. Paul et al., “A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation),” Blood, vol. 107, no. 5, pp. 2112–2122, 2006. View at Publisher · View at Google Scholar · View at Scopus
  24. P. Murray, J. Allen, S. Biswas et al., “Macrophage activation and polarization: nomenclature and experimental guidelines,” Immunity, vol. 41, no. 1, pp. 14–20, 2014. View at Publisher · View at Google Scholar · View at Scopus
  25. L. V. Kalialis, K. T. Drzewiecki, and H. Klyver, “Spontaneous regression of metastases from melanoma: review of the literature,” Melanoma Research, vol. 19, no. 5, pp. 275–282, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Patyar, R. Joshi, D. S. P. Byrav, A. Prakash, B. Medhi, and B. K. Das, “Bacteria in cancer therapy: a novel experimental strategy,” Journal of Biomedical Science, vol. 17, no. 1, article no. 21, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. B. Krone, K. F. Kölmel, J. M. Grange et al., “Impact of vaccinations and infectious diseases on the risk of melanoma—evaluation of an EORTC case-control study,” European Journal of Cancer, vol. 39, no. 16, pp. 2372–2378, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. A. Pfahlberg, K. F. Kölmel, J. M. Grange et al., “Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: results of the FEBIM study,” Journal of Investigative Dermatology, vol. 119, no. 3, pp. 570–575, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. K. Buzás, A. Marton, C. Vizler et al., “Bacterial sepsis increases survival in metastatic melanoma: chlamydophila pneumoniae induces macrophage polarization and tumor regression,” Journal of Investigative Dermatology, vol. 136, no. 4, pp. 862–865, 2016. View at Publisher · View at Google Scholar · View at Scopus
  30. S. P. Gadani, J. T. Walsh, I. Smirnov, J. Zheng, and J. Kipnis, “The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury,” Neuron, vol. 85, no. 4, pp. 703–709, 2015. View at Publisher · View at Google Scholar · View at Scopus
  31. A. I. Ségaliny, A. Mohamadi, B. Dizier et al., “Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment,” International Journal of Cancer, vol. 137, no. 1, pp. 73–85, 2015. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Locati, A. Mantovani, and A. Sica, “Macrophage activation and polarization as an adaptive component of innate immunity,” Advances in Immunology, vol. 120, pp. 163–184, 2013. View at Publisher · View at Google Scholar · View at Scopus
  33. A. Sica, A. Saccani, B. Bottazzi et al., “Autocrine production of IL-10 mediates defective IL-12 production and NF-κB activation in tumor-associated macrophages,” Journal of Immunology, vol. 164, no. 2, pp. 762–767, 2000. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Chittezhath, M. K. Dhillon, J. Y. Lim et al., “Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression,” Immunity, vol. 41, no. 5, pp. 815–829, 2014. View at Publisher · View at Google Scholar · View at Scopus
  35. J. Li, Y. Liu, B. Wang et al., “Myeloid TGF-β signaling contributes to colitis-associated tumorigenesis in mice,” Carcinogenesis, vol. 34, no. 9, pp. 2099–2108, 2013. View at Publisher · View at Google Scholar · View at Scopus
  36. J. Krstic and J. F. Santibanez, “Transforming growth factor-beta and matrix metalloproteinases: functional interactions in tumor stroma-infiltrating myeloid cells,” The Scientific World Journal, vol. 2014, Article ID 521754, 14 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  37. B. Yang, H. Kang, A. Fung, H. Zhao, T. Wang, and D. Ma, “The role of interleukin 17 in tumour proliferation, angiogenesis, and metastasis,” Mediators of Inflammation, vol. 2014, Article ID 623759, 12 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  38. L. Liu, D. Ge, L. Ma et al., “Interleukin-17 and prostaglandin E2 are involved in formation of an M2 macrophage-dominant microenvironment in lung cancer,” Journal of Thoracic Oncology, vol. 7, no. 7, pp. 1091–1100, 2012. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Mantovani, W. J. Ming, C. Balotta, B. Abdeljalil, and B. Bottazzi, “Origin and regulation of tumor-associated macrophages: the role of tumor-derived chemotactic factor,” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer, vol. 865, no. 1, pp. 59–67, 1986. View at Publisher · View at Google Scholar · View at Scopus
  40. H. Roca, Z. S. Varcos, S. Sud, M. J. Craig, and K. J. Pienta, “CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization,” Journal of Biological Chemistry, vol. 284, no. 49, pp. 34342–34354, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. G. Jin, H. I. Kawsar, S. A. Hirsch et al., “An antimicrobial peptide regulates tumor-associated macrophage trafficking via the chemokine receptor CCR2, a model for tumorigenesis,” PLoS ONE, vol. 5, no. 6, article 10993, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. H. Wang, L. Zhang, I. Y. Zhang et al., “S100B promotes glioma growth through chemoattraction of myeloid-derived macrophages,” Clinical Cancer Research, vol. 19, no. 14, pp. 3764–3775, 2013. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Becker, N. G. Hokamp, S. Zenker et al., “Optical in vivo imaging of the alarmin S100A9 in tumor lesions allows for estimation of the individual malignant potential by evaluation of tumor-host cell interaction,” Journal of Nuclear Medicine, vol. 56, no. 3, pp. 450–456, 2015. View at Publisher · View at Google Scholar · View at Scopus
  44. E. Eruslanov, T. Stoffs, W.-J. Kim et al., “Expansion of CCR8+ inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas,” Clinical Cancer Research, vol. 19, no. 7, pp. 1670–1680, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. C. Rolny, L. Capparuccia, A. Casazza et al., “The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment,” The Journal of Experimental Medicine, vol. 205, no. 5, pp. 1155–1171, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Casazza, D. Laoui, M. Wenes et al., “Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity,” Cancer Cell, vol. 24, no. 6, pp. 695–709, 2013. View at Publisher · View at Google Scholar · View at Scopus
  47. S.-C. Wang, J.-H. Hong, C. Hsueh, and C.-S. Chiang, “Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model,” Laboratory Investigation, vol. 92, no. 1, pp. 151–162, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. L. Sánchez-Martín, A. Estecha, R. Samaniego, S. Sánchez-Ramón, M. Á. Vega, and P. Sánchez-Mateos, “The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression,” Blood, vol. 117, no. 1, pp. 88–97, 2011. View at Publisher · View at Google Scholar · View at Scopus
  49. J. R. Reed, M. D. Stone, T. C. Beadnell, Y. Ryu, T. J. Griffin, and K. L. Schwertfeger, “Fibroblast growth factor receptor 1 activation in mammary tumor cells promotes macrophage recruitment in a CX3CL1-dependent manner,” PLoS ONE, vol. 7, no. 9, Article ID e45877, 2012. View at Publisher · View at Google Scholar · View at Scopus
  50. S. Aharinejad, P. Paulus, M. Sioud et al., “Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice,” Cancer Research, vol. 64, no. 15, pp. 5378–5384, 2004. View at Publisher · View at Google Scholar · View at Scopus
  51. A.-J. Casbon, M. Lohelay, and Z. Werb, “Delineating CSF-1-dependent regulation of myeloid cell diversity in tumors,” OncoImmunology, vol. 4, no. 6, Article ID e1008871, 2015. View at Publisher · View at Google Scholar · View at Scopus
  52. S. T. Dougherty, C. J. Eaves, W. H. McBride, and G. J. Dougherty, “Role of macrophage-colony-stimulating factor in regulating the accumulation and phenotype of tumor-associated macrophages,” Cancer Immunology Immunotherapy, vol. 44, no. 3, pp. 165–172, 1997. View at Publisher · View at Google Scholar · View at Scopus
  53. D. Abraham, K. Zins, M. Sioud et al., “Stromal cell-derived CSF-1 blockade prolongs xenograft survival of CSF-1-negative neuroblastoma,” International Journal of Cancer, vol. 126, no. 6, pp. 1339–1352, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. P. Tymoszuk, H. Evens, V. Marzola et al., “In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors,” European Journal of Immunology, vol. 44, no. 8, pp. 2247–2262, 2014. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Bergenfelz, C. Medrek, E. Ekström et al., “Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients,” Journal of Immunology, vol. 188, no. 11, pp. 5448–5458, 2012. View at Publisher · View at Google Scholar · View at Scopus
  56. E.-J. Yeo, L. Cassetta, B.-Z. Qian et al., “Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer,” Cancer Research, vol. 74, no. 11, pp. 2962–2973, 2014. View at Publisher · View at Google Scholar · View at Scopus
  57. J.-H. Lee, G. T. Lee, S. H. Woo et al., “BMP-6 in renal cell carcinoma promotes tumor proliferation through IL-10-dependent M2 polarization of tumor-associated macrophages,” Cancer Research, vol. 73, no. 12, pp. 3604–3614, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. D. P. Nguyen, J. Li, S. S. Yadav, and A. K. Tewari, “Recent insights into NF-κB signalling pathways and the link between inflammation and prostate cancer,” BJU International, vol. 114, no. 2, pp. 168–176, 2014. View at Publisher · View at Google Scholar · View at Scopus
  59. Z. Yuan, H. J. Mehta, K. Mohammed et al., “TREM-1 is induced in tumor associated macrophages by cyclo-oxygenase pathway in human non-small cell lung cancer,” PLoS ONE, vol. 9, no. 5, Article ID e94241, 2014. View at Publisher · View at Google Scholar · View at Scopus
  60. Z. Yuan, M. A. Syed, D. Panchal et al., “Triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated Bcl-2 induction prolongs macrophage survival,” The Journal of Biological Chemistry, vol. 289, no. 21, pp. 15118–15129, 2014. View at Publisher · View at Google Scholar · View at Scopus
  61. E. P. Chen, N. Markosyan, E. Connolly et al., “Myeloid Cell COX-2 deletion reduces mammary tumor growth through enhanced cytotoxic T-lymphocyte function,” Carcinogenesis, vol. 35, no. 8, pp. 1788–1797, 2014. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Kujawski, M. Kortylewski, H. Lee, A. Herrmann, H. Kay, and H. Yu, “Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice,” The Journal of Clinical Investigation, vol. 118, no. 10, pp. 3367–3377, 2008. View at Publisher · View at Google Scholar · View at Scopus
  63. C. Rébé, F. Végran, H. Berger, and F. Ghiringhelli, “STAT3 activation,” JAK-STAT, vol. 2, no. 1, Article ID e23010, 2014. View at Publisher · View at Google Scholar
  64. F. Cheng, H.-W. Wang, A. Cuenca et al., “A critical role for Stat3 signaling in immune tolerance,” Immunity, vol. 19, no. 3, pp. 425–436, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. M. Kortylewski, M. Kujawski, A. Herrmann et al., “Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy,” Cancer Research, vol. 69, no. 6, pp. 2497–2505, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. Fujiwara, Y. Komohara, T. Ikeda, and M. Takeya, “Corosolic acid inhibits glioblastoma cell proliferation by suppressing the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B in tumor cells and tumor-associated macrophages,” Cancer Science, vol. 102, no. 1, pp. 206–211, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. K. Pandima Devi, T. Rajavel, G. L. Russo, M. Daglia, S. F. Nabavi, and S. M. Nabavi, “Molecular targets of omega-3 fatty acids for cancer therapy,” Anti-Cancer Agents in Medicinal Chemistry, vol. 15, no. 7, pp. 888–895, 2015. View at Publisher · View at Google Scholar · View at Scopus
  68. N. Faragó, L. Z. Fehér, K. Kitajka, U. N. Das, and L. G. Puskás, “MicroRNA profile of polyunsaturated fatty acid treated glioma cells reveal apoptosis-specific expression changes,” Lipids in Health and Disease, vol. 10, article 173, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Serini, R. Ottes Vasconcelos, E. Fasano, and G. Calviello, “Epigenetic regulation of gene expression and M2 macrophage polarization as new potential omega-3 polyunsaturated fatty acid targets in colon inflammation and cancer,” Expert Opinion on Therapeutic Targets, vol. 20, no. 7, pp. 843–858, 2016. View at Publisher · View at Google Scholar · View at Scopus
  70. E. Mira, L. Carmona-Rodríguez, M. Tardáguila et al., “A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors,” Oncotarget, vol. 4, no. 12, pp. 2288–2301, 2013. View at Publisher · View at Google Scholar · View at Scopus
  71. L. G. Puskás, E. Bereczki, M. Sántha et al., “Cholesterol and cholesterol plus DHA diet-induced gene expression and fatty acid changes in mouse eye and brain,” Biochimie, vol. 86, no. 11, pp. 817–824, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. S. Ostrand-Rosenberg, M. J. Grusby, and V. K. Clements, “Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma,” The Journal of Immunology, vol. 165, no. 11, pp. 6015–6019, 2000. View at Publisher · View at Google Scholar · View at Scopus
  73. P. Sinha, V. K. Clements, and S. Ostrand-Rosenberg, “Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease,” The Journal of Immunology, vol. 174, no. 2, pp. 636–645, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. T. Lawrence and G. Natoli, “Transcriptional regulation of macrophage polarization: enabling diversity with identity,” Nature Reviews Immunology, vol. 11, no. 11, pp. 750–761, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. A. Sica and V. Bronte, “Altered macrophage differentiation and immune dysfunction in tumor development,” Journal of Clinical Investigation, vol. 117, no. 5, pp. 1155–1166, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. A. Sica and A. Mantovani, “Macrophage plasticity and polarization: in vivo veritas,” Journal of Clinical Investigation, vol. 122, no. 3, pp. 787–795, 2012. View at Publisher · View at Google Scholar · View at Scopus
  77. A. Saccani, T. Schioppa, C. Porta et al., “p50 nuclear factor-κB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance,” Cancer Research, vol. 66, no. 23, pp. 11432–11440, 2006. View at Publisher · View at Google Scholar · View at Scopus
  78. C. Porta, M. Rimoldi, G. Raes et al., “Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 35, pp. 14978–14983, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. C. H. Y. Fong, M. Bebien, A. Didierlaurent et al., “An antiinflammatory role for IKKβ through the inhibition of ‘classical’ macrophage activation,” The Journal of Experimental Medicine, vol. 205, no. 6, pp. 1269–1276, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. T. Hagemann, T. Lawrence, I. McNeish et al., “'Re-educating' tumor-associated macrophages by targeting NF-κB,” Journal of Experimental Medicine, vol. 205, no. 6, pp. 1261–1268, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. A. Sica, C. Porta, S. Morlacchi et al., “Origin and functions of Tumor-Associated Myeloid Cells (TAMCs),” Cancer Microenvironment, vol. 5, no. 2, pp. 133–149, 2012. View at Publisher · View at Google Scholar · View at Scopus
  82. T. J. Standiford, R. Kuick, U. Bhan, J. Chen, M. Newstead, and V. G. Keshamouni, “TGF-β-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth,” Oncogene, vol. 30, no. 21, pp. 2475–2484, 2011. View at Publisher · View at Google Scholar · View at Scopus
  83. S. Banerjee, K. Halder, A. Bose et al., “TLR signaling-mediated differential histone modification at IL-10 and IL-12 promoter region leads to functional impairments in tumor-associated macrophages,” Carcinogenesis, vol. 32, no. 12, pp. 1789–1797, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. E. Riboldi, C. Porta, S. Morlacchi, A. Viola, A. Mantovani, and A. Sica, “Hypoxia-mediated regulation of macrophage functions in pathophysiology,” International Immunology, vol. 25, no. 2, pp. 67–75, 2013. View at Publisher · View at Google Scholar · View at Scopus
  85. C. A. Corzo, T. Condamine, L. Lu et al., “HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment,” Journal of Experimental Medicine, vol. 207, no. 11, pp. 2439–2453, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. A. L. Doedens, C. Stockmann, M. P. Rubinstein et al., “Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression,” Cancer Research, vol. 70, no. 19, pp. 7465–7475, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. P. Chaturvedi, D. M. Gilkes, N. Takano, and G. L. Semenza, “Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 20, pp. E2120–E2129, 2014. View at Publisher · View at Google Scholar · View at Scopus
  88. E. P. Cummins, E. Berra, K. M. Comerford et al., “Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 48, pp. 18154–18159, 2006. View at Publisher · View at Google Scholar · View at Scopus
  89. J. Rius, M. Guma, C. Schachtrup et al., “NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α,” Nature, vol. 453, no. 7196, pp. 807–811, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. H. Z. Imtiyaz, E. P. Williams, M. M. Hickey et al., “Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation,” The Journal of Clinical Investigation, vol. 120, no. 8, pp. 2699–2714, 2010. View at Publisher · View at Google Scholar · View at Scopus
  91. D. J. Ceradini, A. R. Kulkarni, M. J. Callaghan et al., “Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1,” Nature Medicine, vol. 10, no. 8, pp. 858–864, 2004. View at Publisher · View at Google Scholar · View at Scopus
  92. T. Schioppa, B. Uranchimeg, A. Saccani et al., “Regulation of the chemokine receptor CXCR4 by hypoxia,” Journal of Experimental Medicine, vol. 198, no. 9, pp. 1391–1402, 2003. View at Publisher · View at Google Scholar · View at Scopus
  93. M. Z. Noman, G. Desantis, B. Janji et al., “PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced: MDSC-mediated T cell activation,” Journal of Experimental Medicine, vol. 211, no. 5, pp. 781–790, 2014. View at Publisher · View at Google Scholar · View at Scopus
  94. D. Laoui, E. Van Overmeire, G. Di Conza et al., “Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population,” Cancer Research, vol. 74, no. 1, pp. 24–30, 2014. View at Publisher · View at Google Scholar · View at Scopus
  95. Y.-J. Jung, J. S. Isaacs, S. Lee, J. Trepel, and L. Neckers, “IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis,” The FASEB Journal, vol. 17, no. 14, pp. 2115–2117, 2003. View at Google Scholar · View at Scopus
  96. W. Chen, T. Ma, X.-N. Shen et al., “Macrophage-induced tumor angiogenesis is regulated by the TSC2-mTOR pathway,” Cancer Research, vol. 72, no. 6, pp. 1363–1372, 2012. View at Publisher · View at Google Scholar · View at Scopus
  97. Y.-C. Wang, F. He, F. Feng et al., “Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses,” Cancer Research, vol. 70, no. 12, pp. 4840–4849, 2010. View at Publisher · View at Google Scholar · View at Scopus
  98. S. Loges, T. Schmidt, M. Tjwa et al., “Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6,” Blood, vol. 115, no. 11, pp. 2264–2273, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. O. M. Pello, M. De Pizzol, M. Mirolo et al., “Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology,” Blood, vol. 119, no. 2, pp. 411–421, 2012. View at Publisher · View at Google Scholar · View at Scopus
  100. D. Gurusamy, J. K. Gray, P. Pathrose, R. M. Kulkarni, F. D. Finkleman, and S. E. Waltz, “Myeloid-specific expression of Ron receptor kinase promotes prostate tumor growth,” Cancer Research, vol. 73, no. 6, pp. 1752–1763, 2013. View at Publisher · View at Google Scholar · View at Scopus
  101. J. Jin, Y. Xiao, H. Hu et al., “Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages,” Nature Communications, vol. 6, article 5930, 2015. View at Publisher · View at Google Scholar · View at Scopus
  102. J. Zhang, S. Li, L. Li et al., “Exosome and exosomal microRNA: trafficking, sorting, and function,” Genomics, Proteomics and Bioinformatics, vol. 13, no. 1, pp. 17–24, 2015. View at Publisher · View at Google Scholar · View at Scopus
  103. M. K. McDonald, Y. Tian, R. A. Qureshi et al., “Functional significance of macrophage-derived exosomes in inflammation and pain,” Pain, vol. 155, no. 8, pp. 1527–1539, 2014. View at Publisher · View at Google Scholar · View at Scopus
  104. M.-J. Su, H. Aldawsari, and M. Amiji, “Pancreatic cancer cell exosome-mediated macrophage reprogramming and the role of microRNAs 155 and 125b2 transfection using nanoparticle delivery systems,” Scientific Reports, vol. 6, Article ID 30110, 2016. View at Publisher · View at Google Scholar · View at Scopus
  105. K. Essandoh, Y. Li, J. Huo, and G.-C. Fan, “MiRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response,” Shock, vol. 46, no. 2, pp. 122–131, 2016. View at Publisher · View at Google Scholar · View at Scopus
  106. X.-Q. Wu, Y. Dai, Y. Yang et al., “Emerging role of microRNAs in regulating macrophage activation and polarization in immune response and inflammation,” Immunology, vol. 148, no. 3, pp. 237–248, 2016. View at Publisher · View at Google Scholar · View at Scopus
  107. M. L. Squadrito, M. Etzrodt, M. De Palma, and M. J. Pittet, “MicroRNA-mediated control of macrophages and its implications for cancer,” Trends in Immunology, vol. 34, no. 7, pp. 350–359, 2013. View at Publisher · View at Google Scholar · View at Scopus
  108. K. D. Taganov, M. P. Boldin, K.-J. Chang, and D. Baltimore, “NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 33, pp. 12481–12486, 2006. View at Publisher · View at Google Scholar · View at Scopus
  109. M. A. Nahid, K. M. Pauley, M. Satoh, and E. K. L. Chan, “miR-146a is critical for endotoxin-induced tolerance: implication in innate immunity,” The Journal of Biological Chemistry, vol. 284, no. 50, pp. 34590–34599, 2009. View at Publisher · View at Google Scholar · View at Scopus
  110. M. El Gazzar, A. Church, T. F. Liu, and C. E. McCall, “MicroRNA-146a regulates both transcription silencing and translation disruption of TNF-α during TLR4-induced gene reprogramming,” Journal of Leukocyte Biology, vol. 90, no. 3, pp. 509–519, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Etzrodt, V. Cortez-Retamozo, A. Newton et al., “Regulation of monocyte functional heterogeneity by miR-146a and Relb,” Cell Reports, vol. 1, no. 4, pp. 317–324, 2012. View at Publisher · View at Google Scholar · View at Scopus
  112. O. Antal, L. Hackler, J. Shen et al., “Combination of unsaturated fatty acids and ionizing radiation on human glioma cells: cellular, biochemical and gene expression analysis,” Lipids in Health and Disease, vol. 13, no. 1, article no. 142, 2014. View at Publisher · View at Google Scholar · View at Scopus
  113. G. Curtale, M. Mirolo, T. A. Renzi, M. Rossato, F. Bazzoni, and M. Locati, “Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 28, pp. 11499–11504, 2013. View at Publisher · View at Google Scholar · View at Scopus
  114. Y. Zhang, M. Zhang, M. Zhong, Q. Suo, and K. Lv, “Expression profiles of miRNAs in polarized macrophages,” International Journal of Molecular Medicine, vol. 31, no. 4, pp. 797–802, 2013. View at Publisher · View at Google Scholar · View at Scopus
  115. X. Cai, Y. Yin, N. Li et al., “Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155,” Journal of Molecular Cell Biology, vol. 4, no. 5, pp. 341–343, 2012. View at Publisher · View at Google Scholar · View at Scopus
  116. G. Liu and E. Abraham, “MicroRNAs in immune response and macrophage polarization,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 2, pp. 170–177, 2013. View at Publisher · View at Google Scholar · View at Scopus
  117. P. Wang, J. Hou, L. Lin et al., “Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1,” The Journal of Immunology, vol. 185, no. 10, pp. 6226–6233, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. M. Nazari-Jahantigh, Y. Wei, H. Noels et al., “MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages,” Journal of Clinical Investigation, vol. 122, no. 11, pp. 4190–4202, 2012. View at Publisher · View at Google Scholar · View at Scopus
  119. R. M. O'Connell, A. A. Chaudhuri, D. S. Rao, and D. Baltimore, “Inositol phosphatase SHIP1 is a primary target of miR-155,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 17, pp. 7113–7118, 2009. View at Publisher · View at Google Scholar · View at Scopus
  120. R. T. Martinez-Nunez, F. Louafi, and T. Sanchez-Elsner, “The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor α1 (IL13Rα1),” The Journal of Biological Chemistry, vol. 286, no. 3, pp. 1786–1794, 2011. View at Publisher · View at Google Scholar · View at Scopus
  121. S. Bala, M. Marcos, K. Kodys et al., “Up-regulation of microRNA-155 in macrophages contributes to increased Tumor Necrosis Factor α (TNFα) production via increased mRNA half-life in alcoholic liver disease,” Journal of Biological Chemistry, vol. 286, no. 2, pp. 1436–1444, 2011. View at Publisher · View at Google Scholar · View at Scopus
  122. D. Ruffell, F. Mourkioti, A. Gambardella et al., “A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 41, pp. 17475–17480, 2009. View at Publisher · View at Google Scholar · View at Scopus
  123. M. He, Z. Xu, T. Ding, D.-M. Kuang, and L. Zheng, “MicroRNA-155 regulates inflammatory cytokine production in tumor-associated macrophages via targeting C/EBPβ,” Cellular and Molecular Immunology, vol. 6, no. 5, pp. 343–352, 2009. View at Publisher · View at Google Scholar · View at Scopus
  124. T. B. Huffaker, R. Hu, M. C. Runtsch et al., “Epistasis between MicroRNAs 155 and 146a during T cell-mediated antitumor immunity,” Cell Reports, vol. 2, no. 6, pp. 1697–1709, 2012. View at Publisher · View at Google Scholar · View at Scopus
  125. E. Zonari, F. Pucci, M. Saini et al., “A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice,” Blood, vol. 122, no. 2, pp. 243–252, 2013. View at Publisher · View at Google Scholar · View at Scopus
  126. N. Valeri, P. Gasparini, M. Fabbri et al., “Modulation of mismatch repair and genomic stability by miR-155,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 15, pp. 6982–6987, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. E. Tili, J.-J. Michaille, D. Wernicke et al., “Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 12, pp. 4908–4913, 2011. View at Publisher · View at Google Scholar · View at Scopus
  128. H. Mathsyaraja, K. Thies, D. A. Taffany et al., “CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth,” Oncogene, vol. 34, no. 28, pp. 3651–3661, 2015. View at Publisher · View at Google Scholar · View at Scopus
  129. Z. Wang, S. Brandt, A. Medeiros et al., “MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation,” PLoS ONE, vol. 10, no. 2, Article ID e0115855, 2015. View at Publisher · View at Google Scholar · View at Scopus
  130. M. L. Squadrito, F. Pucci, L. Magri et al., “MiR-511-3p modulates genetic programs of tumor-associated macrophages,” Cell Reports, vol. 1, no. 2, pp. 141–154, 2012. View at Publisher · View at Google Scholar · View at Scopus
  131. A. A. Chaudhuri, A. Y.-L. So, N. Sinha et al., “MicroRNA-125b potentiates macrophage activation,” Journal of Immunology, vol. 187, no. 10, pp. 5062–5068, 2011. View at Publisher · View at Google Scholar · View at Scopus
  132. S. Banerjee, H. Cui, N. Xie et al., “MiR-125a-5p regulates differential activation of macrophages and inflammation,” Journal of Biological Chemistry, vol. 288, no. 49, pp. 35428–35436, 2013. View at Publisher · View at Google Scholar · View at Scopus
  133. J.-L. Zhao, F. Huang, F. He et al., “Forced activation of notch in macrophages represses tumor growth by upregulating MIR-125a and disabling tumor-associated macrophages,” Cancer Research, vol. 76, no. 6, pp. 1403–1415, 2016. View at Publisher · View at Google Scholar · View at Scopus
  134. Z. Wang, L. Xu, Y. Hu et al., “MiRNA let-7b modulates macrophage polarization and enhances tumor-associated macrophages to promote angiogenesis and mobility in prostate cancer,” Scientific Reports, vol. 6, Article ID 25602, 2016. View at Publisher · View at Google Scholar · View at Scopus
  135. M. Ouimet, H. N. Ediriweera, U. Mahesh Gundra et al., “MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis,” Journal of Clinical Investigation, vol. 125, no. 12, pp. 4334–4348, 2015. View at Publisher · View at Google Scholar · View at Scopus
  136. G. Zhuang, C. Meng, X. Guo et al., “A novel regulator of macrophage activation: miR-223 in obesity-associated adipose tissue inflammation,” Circulation, vol. 125, no. 23, pp. 2892–2903, 2012. View at Publisher · View at Google Scholar · View at Scopus