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

Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Mönkkönen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M - J. Cell. Mol. Med. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliero Universitaria S. Giovanni Battista di Torino, Torino, Italy. marta.coscia@unito.it

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ZA’s antitumour effect is associated with its ability to reverse TAM polarization from M2 to M1, and is dependent on IFN-γ. Immunohistochemical analysis of representative mammary glands of 18-week-old control (A, C) versus ZA-treated (B, D) BALB-neuT mice. (A, B) Anti IL-10 staining (green) showed a clear reduction of IL-10 release in the tumour microenvironment of ZA-treated mammary tumours. (C, D) A significant enhancement of IFN-γ release (green) is observed in the microenvironment of ZA-treated mammary tumours. Scale bars, 40 μm. (E, F) ZA antitumour activity in BALB-neuT/IFN-γ KO. BALB-neuT/IFN-γ KO female mice received weekly i.v. courses of ZA (black line, n= 6) or saline (dotted grey line, n= 7). ZA-treated BALB-neuT/IFN-γ KO mice displayed the same tumour incidence (E) and tumour multiplicity (F) as control mice.
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fig04: ZA’s antitumour effect is associated with its ability to reverse TAM polarization from M2 to M1, and is dependent on IFN-γ. Immunohistochemical analysis of representative mammary glands of 18-week-old control (A, C) versus ZA-treated (B, D) BALB-neuT mice. (A, B) Anti IL-10 staining (green) showed a clear reduction of IL-10 release in the tumour microenvironment of ZA-treated mammary tumours. (C, D) A significant enhancement of IFN-γ release (green) is observed in the microenvironment of ZA-treated mammary tumours. Scale bars, 40 μm. (E, F) ZA antitumour activity in BALB-neuT/IFN-γ KO. BALB-neuT/IFN-γ KO female mice received weekly i.v. courses of ZA (black line, n= 6) or saline (dotted grey line, n= 7). ZA-treated BALB-neuT/IFN-γ KO mice displayed the same tumour incidence (E) and tumour multiplicity (F) as control mice.

Mentions: As VEGF plays a key role in inducing a M2 polarization of TAMs [31, 32], we evaluated whether the decrease of VEGF observed in the tumour microenvironment of ZA-treated mice was associated with a recovered M1 functional program. Indeed, TAMs of 18-week-old control mice expressed IL-10 (Fig. 4A) but not IFN-γ (Fig. 4C), whereas TAMs of ZA-treated mice stained negative for IL-10 (Fig. 4B), and became strongly positive for IFN- g (Fig. 4D).


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

Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Mönkkönen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M - J. Cell. Mol. Med. (2010)

ZA’s antitumour effect is associated with its ability to reverse TAM polarization from M2 to M1, and is dependent on IFN-γ. Immunohistochemical analysis of representative mammary glands of 18-week-old control (A, C) versus ZA-treated (B, D) BALB-neuT mice. (A, B) Anti IL-10 staining (green) showed a clear reduction of IL-10 release in the tumour microenvironment of ZA-treated mammary tumours. (C, D) A significant enhancement of IFN-γ release (green) is observed in the microenvironment of ZA-treated mammary tumours. Scale bars, 40 μm. (E, F) ZA antitumour activity in BALB-neuT/IFN-γ KO. BALB-neuT/IFN-γ KO female mice received weekly i.v. courses of ZA (black line, n= 6) or saline (dotted grey line, n= 7). ZA-treated BALB-neuT/IFN-γ KO mice displayed the same tumour incidence (E) and tumour multiplicity (F) as control mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3822730&req=5

fig04: ZA’s antitumour effect is associated with its ability to reverse TAM polarization from M2 to M1, and is dependent on IFN-γ. Immunohistochemical analysis of representative mammary glands of 18-week-old control (A, C) versus ZA-treated (B, D) BALB-neuT mice. (A, B) Anti IL-10 staining (green) showed a clear reduction of IL-10 release in the tumour microenvironment of ZA-treated mammary tumours. (C, D) A significant enhancement of IFN-γ release (green) is observed in the microenvironment of ZA-treated mammary tumours. Scale bars, 40 μm. (E, F) ZA antitumour activity in BALB-neuT/IFN-γ KO. BALB-neuT/IFN-γ KO female mice received weekly i.v. courses of ZA (black line, n= 6) or saline (dotted grey line, n= 7). ZA-treated BALB-neuT/IFN-γ KO mice displayed the same tumour incidence (E) and tumour multiplicity (F) as control mice.
Mentions: As VEGF plays a key role in inducing a M2 polarization of TAMs [31, 32], we evaluated whether the decrease of VEGF observed in the tumour microenvironment of ZA-treated mice was associated with a recovered M1 functional program. Indeed, TAMs of 18-week-old control mice expressed IL-10 (Fig. 4A) but not IFN-γ (Fig. 4C), whereas TAMs of ZA-treated mice stained negative for IL-10 (Fig. 4B), and became strongly positive for IFN- g (Fig. 4D).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliero Universitaria S. Giovanni Battista di Torino, Torino, Italy. marta.coscia@unito.it

Show MeSH
Related in: MedlinePlus