In vivo inhibition of c-MYC in myeloid cells impairs tumor-associated macrophage maturation and pro-tumoral activities

PLoS One. 2012;7(9):e45399. doi: 10.1371/journal.pone.0045399. Epub 2012 Sep 20.

Abstract

Although tumor-associated macrophages (TAMs) are involved in tumor growth and metastasis, the mechanisms controlling their pro-tumoral activities remain largely unknown. The transcription factor c-MYC has been recently shown to regulate in vitro human macrophage polarization and be expressed in macrophages infiltrating human tumors. In this study, we exploited the predominant expression of LysM in myeloid cells to generate c-Myc(fl/fl) LysM(cre/+) mice, which lack c-Myc in macrophages, to investigate the role of macrophage c-MYC expression in cancer. Under steady-state conditions, immune system parameters in c-Myc(fl/fl) LysM(cre/+) mice appeared normal, including the abundance of different subsets of bone marrow hematopoietic stem cells, precursors and circulating cells, macrophage density, and immune organ structure. In a model of melanoma, however, TAMs lacking c-Myc displayed a delay in maturation and showed an attenuation of pro-tumoral functions (e.g., reduced expression of VEGF, MMP9, and HIF1α) that was associated with impaired tissue remodeling and angiogenesis and limited tumor growth in c-Myc(fl/fl) LysM(cre/+) mice. Macrophage c-Myc deletion also diminished fibrosarcoma growth. These data identify c-Myc as a positive regulator of the pro-tumoral program of TAMs and suggest c-Myc inactivation as an attractive target for anti-cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Flow Cytometry
  • Immunohistochemistry
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • Male
  • Mice
  • Microscopy, Confocal
  • Myeloid Cells / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Real-Time Polymerase Chain Reaction

Substances

  • Proto-Oncogene Proteins c-myc

Grant support

The V.A. lab is supported by grant SAF2010-16044 from the Spanish Ministry of Science and Innovation (MICINN) and the European Regional Development Fund, grant RD06/0014/0021 (RECAVA, Instituto de Salud Carlos III), and the Dr. Léon Dumont Prize 2010 (Belgian Society of Cardiology). O.M.P. holds a Juan de la Cierva contract from the Spanish Ministry of Economy and Competition (MINECO). The CNIC is supported by the MINECO and the Pro-CNIC Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.