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


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.


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



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

Conflicts of interest



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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

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