title: In vivo inhibition of c-MYC in myeloid cells impairs tumor-associated macrophage maturation and pro-tumoral activities.
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.
authors.affiliation: Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Pello
authors.forename: Raphael
authors.initials: R
authors.lastname: Chèvre
authors.forename: Damya
authors.initials: D
authors.lastname: Laoui
authors.forename: Alba
authors.initials: A
authors.lastname: De Juan
authors.forename: Fidel
authors.initials: F
authors.lastname: Lolo
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Andrés-Manzano
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.forename: Vicente
authors.initials: V
authors.lastname: Andrés
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016271:Proto-Oncogene Proteins c-myc