Advertisement

Tumor Biology

, Volume 37, Issue 3, pp 3321–3329 | Cite as

HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism

  • Armando Rojas
  • Fernando Delgado-López
  • Ramón Perez-Castro
  • Ileana Gonzalez
  • Jacqueline Romero
  • Israel Rojas
  • Paulina Araya
  • Carolina Añazco
  • Erik Morales
  • Jorge Llanos
Original Article

Abstract

The monocyte-macrophage lineage shows a high degree of diversity and plasticity. Once they infiltrate tissues, they may acquire two main functional phenotypes, being known as the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2). The M1 phenotype can be induced by bacterial products and interferon-γ and exerts a cytotoxic effect on cancer cells. Conversely, the alternatively activated M2 phenotype is induced by Il-4/IL13 and promotes tumor cell growth and vascularization. Although receptor for advanced glycation end-products (RAGE) engagement in M1 macrophages has been reported by several groups to promote inflammation, nothing is known about the functionality of RAGE in M2 macrophages. In the current study, we demonstrate that RAGE is equally expressed in both macrophage phenotypes and that RAGE activation by high-mobility group protein box1 (HMGB1) promotes protumoral activities of M2 macrophages. MKN45 cells co-cultured with M2 macrophages treated with HMGB1 at different times displayed higher invasive abilities. Additionally, conditioned medium from HMGB1-treated M2 macrophages promotes angiogenesis in vitro. RAGE-targeting knockdown abrogates these activities. Overall, the present findings suggest that HMGB1 may contribute, by a RAGE-dependent mechanism, to the protumoral activities of the M2 phenotype.

Keywords

Receptor for advanced glycation end-products (RAGE) HMGB1 Macrophage polarization Tumor-associated macrophages 

Notes

Acknowledgments

This work was supported by grant 1130337 from Programa Fondecyt, Comisión Nacional de Ciencia y Teconología, Chile.

Conflicts of interest

None

References

  1. 1.
    Mantovani A, Sica A, Allavena P, Garlanda C, Locati M. Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol. 2009;70:325–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Mantovani A, Germano G, Marchesi F, Locatelli M, Biswas SK. Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol. 2011;41:2522–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.CrossRefPubMedGoogle Scholar
  4. 4.
    Biswas SK, Allavena P, Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol. 2013;35:585–600.CrossRefPubMedGoogle Scholar
  5. 5.
    Eljaszewicz A, Wiese M, Helmin-Basa A, Jankowski M, Gackowska L, Kubiszewska I, et al. Collaborating with the enemy: function of macrophages in the development of neoplastic disease. Mediat Inflamm. 2013;831387.Google Scholar
  6. 6.
    Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol. 2013;228:1404–12.CrossRefPubMedGoogle Scholar
  7. 7.
    Hao NB, Lü MH, Fan YH, Cao YL, Zhang ZR, Yang SM. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol. 2012;2012:948098.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rojas A, Figueroa H, Morales E. Fueling inflammation at tumor microenvironment: the role of multiligand/RAGE axis. Carcinogenesis. 2010;31:334–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Logsdon CD, Fuentes MK, Huang EH, Arumugam T. RAGE and RAGE ligands in cancer. Curr Mol Med. 2007;7:777–89.CrossRefPubMedGoogle Scholar
  10. 10.
    Rojas A, Caveda L, Romay C, López E, Valdés S, Padrón JL, et al. Effect of advanced glycosylation end products on the induction of nitric oxide synthase in murine macrophages. Biochem Biophys Res Commun. 1996;225:358–62.CrossRefPubMedGoogle Scholar
  11. 11.
    Wautier MP, Chappey O, Corda S, et al. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab. 2001;280:E685–94.PubMedGoogle Scholar
  12. 12.
    Wu CH, Huang CM, Lin CH, et al. Advanced glycosylation end products induce NF-kappaB dependent iNOS expression in RAW 264.7 cells. Mol Cell Endocrinol. 2002;194:9–17.CrossRefPubMedGoogle Scholar
  13. 13.
    Rashid G, Korzets Z, Bernheim J. Advanced glycation end products stimulate tumor necrosis factor-alpha and interleukin-1 beta secretion by peritoneal macrophages in patients on continuous ambulatory peritoneal dialysis. Isr Med Assoc J. 2006;8:36–9.PubMedGoogle Scholar
  14. 14.
    Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177:7303–11.CrossRefPubMedGoogle Scholar
  15. 15.
    Beyer M, Mallmann MR, Xue J, Staratschek-Jox A, Vorholt D, Krebs W, et al. High-resolution transcriptome of human macrophages. PLoS One. 2012;7, e45466.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kuniyasu H, Oue N, Wakikawa A, Shigeishi H, Matsutani N, Kuraoka K, et al. Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol. 2002;196:163–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Kumar P, Raghavan S, Shanmugam G, Shanmugam N. Ligation of RAGE with ligand S100B attenuates ABCA1 expression in monocytes. Metabolism. 2013;62:1149–58.CrossRefPubMedGoogle Scholar
  18. 18.
    Xu Y, Toure F, Qu W, Lin L, Song F, Shen X, et al. Advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1 in hypoxic macrophages. J Biol Chem. 2010;285:23233–40.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tjiu J-W, Chen J-S, Shun C-T, Lin S-J, Liao Y-H, Chu C-Y, et al. Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Invest Dermatol. 2009;129:1016–25.CrossRefPubMedGoogle Scholar
  20. 20.
    Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 2010;28:367–88.CrossRefPubMedGoogle Scholar
  21. 21.
    Kong LY, Wu AS, Doucette T, Wei J, Priebe W, Fuller GN, et al. Intratumoral mediated immunosuppression is prognostic in genetically engineered murine models of glioma and correlates to immunotherapeutic responses. Clin Cancer Res. 2010;16:5722–33.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev. 2007;220:35–46.CrossRefPubMedGoogle Scholar
  23. 23.
    Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A, et al. Masquerader: high mobility group box-1 and cancer. Clin Cancer Res. 2007;13:2836–48.CrossRefPubMedGoogle Scholar
  24. 24.
    Andersson UG, Tracey KJ. HMGB1, a pro-inflammatory cytokine of clinical interest: introduction. J Intern Med. 2004;255:318–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Palumbo R, Bianchi ME. High mobility group box 1 protein, a cue for stem cell recruitment. Biochem Pharmacol. 2004;68:1165–70.CrossRefPubMedGoogle Scholar
  26. 26.
    Tang D, Kang R, Zeh III HJ, Lotze MT. High-mobility group box 1 and cancer. Biochim Biophys Acta. 2010;1799:131–40.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Inoue K, Kawahara K, Biswas KK, Ando K, Mitsudo K, Nobuyoshi M, et al. HMGB1 expression by activated vascular smooth muscle cells in advanced human atherosclerosis plaques. Cardiovasc Pathol. 2007;16:136–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Schroeder JA, Adriance MC, Thompson MC, Camenisch TD, Gendler SJ. MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion. Oncogene. 2003;22:1324–32.CrossRefPubMedGoogle Scholar
  29. 29.
    Gao J, McConnell MJ, Yu B, Li J, Balko JM, et al. MUC1 is a downstream target of STAT3 and regulates lung cancer cell survival and invasion. Int J Oncol. 2009;35:337–45.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 2006;25:315–22.CrossRefPubMedGoogle Scholar
  31. 31.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8:618–31.CrossRefPubMedGoogle Scholar
  32. 32.
    Hudson BI, Stickland MH. Grant PJ Identification of polymorphisms in the receptor for advanced glycation end products (RAGE) gene: prevalence in type 2 diabetes and ethnic groups. Diabetes. 1998;47:1155–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Alexiou P, Chatzopoulou M, Pegklidou K, Demopoulos VJ. RAGE: a multi-ligand receptor unveiling novel insights in health and disease. Curr Med Chem. 2010;17:2232–52.CrossRefPubMedGoogle Scholar
  34. 34.
    Nogueira-Machado JA, Volpe CM, Veloso CA. Chaves MM.HMGB1, TLR and RAGE: a functional tripod that leads to diabetic inflammation. Expert Opin Ther Targets. 2011;15:1023–35.CrossRefPubMedGoogle Scholar
  35. 35.
    Armour CL, Phipps S, Sukkar MB. AGE and TLRs: relatives, friends or neighbours? Mol Immunol. 2013;56:739–44.CrossRefPubMedGoogle Scholar
  36. 36.
    Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005;5:331–42.CrossRefPubMedGoogle Scholar
  37. 37.
    Whyte CS, Bishop ET, Rückerl D, Gaspar-Pereira S, Barker RN, Allen JE, et al. Suppressor of cytokine signaling SOCS1 is a key determinant of differential macrophage activation and function. J Leukoc Biol. 2011;90:845–54.CrossRefPubMedGoogle Scholar
  38. 38.
    Sly LM, Rauh MJ, Kalesnikoff J, Song CH, Krystal G. LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity. 2004;21:227–39.CrossRefPubMedGoogle Scholar
  39. 39.
    Sakaguchi M, Murata H, Yamamoto K-I, Ono T, Sakaguchi Y, et al. TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS ONE. 2011;6, e23132.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kang R, Zhang Q, Zeh 3rd HJ, Lotze MT, Tang D. HMGB1 in cancer: good, bad, or both? Clin Cancer Res. 2013;19:4046–57.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Yang S, Xu L, Yang T, Wang F. High-mobility group box-1 and its role in angiogenesis. J Leukoc Biol. 2014;95:563–74.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Armando Rojas
    • 1
  • Fernando Delgado-López
    • 1
  • Ramón Perez-Castro
    • 1
  • Ileana Gonzalez
    • 1
  • Jacqueline Romero
    • 1
  • Israel Rojas
    • 1
  • Paulina Araya
    • 1
  • Carolina Añazco
    • 1
  • Erik Morales
    • 2
  • Jorge Llanos
    • 3
  1. 1.Biomedical Research Labs, Medicine FacultyCatholic University of MauleTalcaChile
  2. 2.Pathology UnitRegional HospitalTalcaChile
  3. 3.Gastroenterology UnitRegional HospitalTalcaChile

Personalised recommendations