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Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway.

ABSTRACT: 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-? 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.

SUBMITTER: Coscia M

PROVIDER: S-EPMC3822730 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway.

Coscia Marta M 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

Journal of cellular and molecular medicine 20101201 12

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 macr ...[more]

PMID: 19818098

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Project description:Background and aim: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreparable scarring of lung tissue, with most patients succumbing rapidly after diagnosis. The mevalonate pathway, which is involved in the regulation of cell proliferation, survival, and motility, is targeted by the bisphosphonate zoledronic acid (ZA). The aim of this study was to assess the antifibrotic effects of ZA and to elucidate the mechanisms by which potential IPF treatment occurs. Methods: A series of in vitro and in vivo models were employed to identify the therapeutic potential of ZA in treating IPF. In vitro transwell assays were used to assess the ability of ZA to reduce fibrotic-related immune cell recruitment. Farnesyl diphosphate synthase (FDPS) was screened as a potential antifibrotic target using a bleomycin mouse model. FDPS-targeting siRNA and ZA were administered to mice following the onset of experimentally-induced lung fibrosis. Downstream analyses were conducted on murine lung tissues and lung fluids including 23-plex cytokine array, flow cytometry, histology, Western blotting, immunofluorescent staining, and PCR analysis. Results: In vitro administration of ZA reduced myofibroblast transition and blocked NF-κB signaling in macrophages leading to impaired immune cell recruitment in a transwell assay. FDPS-targeting siRNA administration significantly attenuated profibrotic cytokine production and lung damage in a murine lung fibrosis model. Furthermore, ZA treatment of mice with bleomycin-induced lung damage displayed decreased cytokine levels in the BALF, plasma, and lung tissue, resulting in less histologically visible fibrotic scarring. Bleomycin-induced upregulation of the ZA target, FDPS, was reduced in lung tissue and fibroblasts upon ZA treatment. Confirmatory increases in FDPS immunoreactivity was seen in human IPF resected lung samples compared to control tissue indicating potential translational value of the approach. Additionally, ZA polarized macrophages towards a less profibrotic phenotype contributing to decreased IPF pathogenesis. Conclusion: This study highlights ZA as an expedient and efficacious treatment option against IPF in a clinical setting.

Project description:Hepatic transcatheter arterial chemoembolization (TACE), a minimally invasive procedure to block the blood supply of tumors and release of cytotoxic agents, is preferentially applied to patients with hepatocellular carcinoma (HCC) who are not able to receive radical treatments. However, the long-term effects of TACE are unsatisfactory, as the microenvironment following procedure stimulates tumor angiogenesis, which promotes recurrence and metastasis of residual tumors. Tumor associated macrophages (TAMs) have been revealed to stimulate tumor growth and angiogenesis associated with poor prognosis in HCC. The present study focused on the changes in TAMs following TACE, and explored the effects of TACE in combination with the TAM inhibitor zoledronic acid (ZA) in rat HCC models. Orthotropic HCC rats were divided into three groups: Sham TACE, TACE alone and TACE combined with ZA treatment. At 7 or 14 days following TACE, tumor growth was evaluated by magnetic resonance imaging (MRI). Infiltration of TAMs was assessed by histological analysis and flow cytometry. Tumor angiogenesis was measured as the mean vessel density, and initial slope was calculated from dynamic contrast enhancement MRI. Local and systemic levels of vascular endothelial growth factor (VEGF) were determined by western blotting or an ELISA, respectively. The results revealed that TACE inhibited tumor growth at 7 days following the procedure, but this inhibition was attenuated at 14 days following the procedure compared with the sham TACE control. If combined with ZA treatment, TACE exhibited a stable inhibition effect on tumor growth until the end of observation. Investigation of the underlying mechanisms demonstrated that TACE combined with ZA treatment inhibited infiltration of F4/80 positive TAMs and tumor angiogenesis compared with the TACE alone group at 14 days following the procedure. Additionally, the combination treatment significantly inhibited secretion of VEGF in the present models. In conclusion, ZA treatment enhanced the effects of TACE through inhibiting TAM infiltration and tumor angiogenesis in rat HCC models.

Dataset Information

Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway.

Publications

Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway.

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