Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway.
It is unknown whether zoledronic acid (ZA) at clinically relevant doses is active against tumours not located in bone. Mice transgenic for the activated ErbB-2 oncogene were treated with a cumulative number of doses equivalent to that recommended in human beings. A significant increase in tumour-free and overall survival was observed in mice treated with ZA. At clinically compatible concentrations, ZA modulated the mevalonate pathway and affected protein prenylation in both tumour cells and macrophages. A marked reduction in the number of tumour-associated macrophages was paralleled by a significant decrease in tumour vascularization. The local production of vascular endothelial growth factor and interleukin-10 was drastically down-regulated in favour of interferon-γ production. Peritoneal macrophages and tumour-associated macrophages of ZA-treated mice recovered a full M1 antitumoral phenotype, as shown by nuclear translocation of nuclear factor kB, inducible nitric oxide synthase expression and nitric oxide production. These data indicate that clinically achievable doses of ZA inhibit spontaneous mammary cancerogenesis by targeting the local microenvironment, as shown by a decreased tumour vascularization, a reduced number of tumour-associated macrophages and their reverted polarization from M2 to M1 phenotype.
Coscia
Marta
M
Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliero Universitaria S. Giovanni Battista di Torino, Torino, Italy. marta.coscia@unito.it
Quaglino
Elena
E
Iezzi
Manuela
M
Curcio
Claudia
C
Pantaleoni
Francesca
F
Riganti
Chiara
C
Holen
Ingunn
I
Mönkkönen
Hannu
H
Boccadoro
Mario
M
Forni
Guido
G
Musiani
Piero
P
Bosia
Amalia
A
Cavallo
Federica
F
Massaia
Massimo
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D018734:Genes, erbB-2; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D017368:Protein Prenylation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D009569:Nitric Oxide; D000077211:Zoledronic Acid; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D008798:Mevalonic Acid