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A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors.

Mira E, Carmona-Rodríguez L, Tardáguila M, Azcoitia I, González-Martín A, Almonacid L, Casas J, Fabriás G, Mañes S - Oncotarget (2013)

Bottom Line: Beyond their ability to inhibit cholesterol biosynthesis, the statins have pleiotropic effects that include anti-inflammatory and immunomodulatory activities.We found that Lov enhanced tumor infiltration by effector T cells, and reduced the number of immunosuppressive and pro-angiogenic M2-like tumor-associated macrophages (TAM).Our results identify a role for lovastatin in the shaping and re-education of the inflammatory infiltrate in tumors, with functional consequences in angiogenesis and antitumor immunity.

View Article: PubMed Central - PubMed

ABSTRACT
Beyond their ability to inhibit cholesterol biosynthesis, the statins have pleiotropic effects that include anti-inflammatory and immunomodulatory activities. Statins could have clinical utility, alone or in combination with other chemotherapeutics, in the treatment of cancer. The mechanisms that underlie the anti-tumor activity of the statins are nonetheless poorly defined. No studies have analyzed how they alter the tumor-associated leukocyte infiltrate, a central factor that influences tumor stroma and cancer evolution. Here we used HER2/neu transgenic (Tg-neu) mice to analyze the effect of lovastatin (Lov) on the inflammatory reaction of spontaneous mammary tumors. Lov treatment of tumor-bearing Tg-neu mice did not alter growth of established tumors, but significantly reduced the number of new oncogenic lesions in these mice. Moreover, Lov inhibited the growth of newly implanted Tg-neu tumors in immunocompetent but not in immunodeficient mice. We found that Lov enhanced tumor infiltration by effector T cells, and reduced the number of immunosuppressive and pro-angiogenic M2-like tumor-associated macrophages (TAM). Concomitantly, the drug improved the structure and function of the tumor vasculature, measured as enhanced tumor oxygenation and penetration of cytotoxic drugs. Microarray analysis identified a Lov-elicited genetic program in Tg-neu tumors that might explain these effects; we observed Lov-induced downregulation of placental growth factor, which triggers aberrant angiogenesis and M2-like TAM polarization. Our results identify a role for lovastatin in the shaping and re-education of the inflammatory infiltrate in tumors, with functional consequences in angiogenesis and antitumor immunity.

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Lovastatin triggers a genetic program that targets angiogenesis, oxidative stress and inflammation(A,B) Main gene ontology processes significantly induced (A) or repressed (B) by Lov treatment (FDR <0.05). (C) PlGF levels in tumor extracts from Vhcl- or Lov-treated Tg-neu mice. Values show mean ± SEM of triplicates in one representative experiment of two (n = 6 tumors/group). (D) VEGF and PlGF mRNA levels in Vhcl- or Lov-treated Tg-neu tumors. Relative quantity was calculated using as reference the sample with the lowest VEGF or PlGF mRNA value. Mean ± SEM (n = 5). (E) PlGF mRNA quantification in CD24+, CD31+ and CD45+ cell populations isolated from Vhcl- or Lov-treated tumors (n = 4). C, D, ** p <0.01, two-tailed Student's t-test.
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Figure 5: Lovastatin triggers a genetic program that targets angiogenesis, oxidative stress and inflammation(A,B) Main gene ontology processes significantly induced (A) or repressed (B) by Lov treatment (FDR <0.05). (C) PlGF levels in tumor extracts from Vhcl- or Lov-treated Tg-neu mice. Values show mean ± SEM of triplicates in one representative experiment of two (n = 6 tumors/group). (D) VEGF and PlGF mRNA levels in Vhcl- or Lov-treated Tg-neu tumors. Relative quantity was calculated using as reference the sample with the lowest VEGF or PlGF mRNA value. Mean ± SEM (n = 5). (E) PlGF mRNA quantification in CD24+, CD31+ and CD45+ cell populations isolated from Vhcl- or Lov-treated tumors (n = 4). C, D, ** p <0.01, two-tailed Student's t-test.

Mentions: Gene ontology analysis of differentially regulated transcripts predicted a number of biological processes significantly altered by Lov treatment (Fig. 5A, B; FDR <0.05). Lov-affected processes included oxidation/reduction, which concurs with the changes in tumor oxygenation, metabolism, including the downregulation of the glycolytic enzyme 6-phosphofructokinase/fructose-2,6-bisphosphate (pfkfb3) gene, as well as the downmodulation of positive regulators of angiogenesis. We found that Lov downregulated the placental growth factor (plgf) gene, whose elevation is associated with the abnormalization of tumor vessels [34]. Lov-induced downregulation of PlGF was validated at the mRNA (Table S2) and protein levels (Fig. 5C). VEGF mRNA levels were comparable in Vhcl- and Lov-treated tumors (Fig. 5D), suggesting that the Lov effect was specific for PlGF expression.


A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors.

Mira E, Carmona-Rodríguez L, Tardáguila M, Azcoitia I, González-Martín A, Almonacid L, Casas J, Fabriás G, Mañes S - Oncotarget (2013)

Lovastatin triggers a genetic program that targets angiogenesis, oxidative stress and inflammation(A,B) Main gene ontology processes significantly induced (A) or repressed (B) by Lov treatment (FDR <0.05). (C) PlGF levels in tumor extracts from Vhcl- or Lov-treated Tg-neu mice. Values show mean ± SEM of triplicates in one representative experiment of two (n = 6 tumors/group). (D) VEGF and PlGF mRNA levels in Vhcl- or Lov-treated Tg-neu tumors. Relative quantity was calculated using as reference the sample with the lowest VEGF or PlGF mRNA value. Mean ± SEM (n = 5). (E) PlGF mRNA quantification in CD24+, CD31+ and CD45+ cell populations isolated from Vhcl- or Lov-treated tumors (n = 4). C, D, ** p <0.01, two-tailed Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926827&req=5

Figure 5: Lovastatin triggers a genetic program that targets angiogenesis, oxidative stress and inflammation(A,B) Main gene ontology processes significantly induced (A) or repressed (B) by Lov treatment (FDR <0.05). (C) PlGF levels in tumor extracts from Vhcl- or Lov-treated Tg-neu mice. Values show mean ± SEM of triplicates in one representative experiment of two (n = 6 tumors/group). (D) VEGF and PlGF mRNA levels in Vhcl- or Lov-treated Tg-neu tumors. Relative quantity was calculated using as reference the sample with the lowest VEGF or PlGF mRNA value. Mean ± SEM (n = 5). (E) PlGF mRNA quantification in CD24+, CD31+ and CD45+ cell populations isolated from Vhcl- or Lov-treated tumors (n = 4). C, D, ** p <0.01, two-tailed Student's t-test.
Mentions: Gene ontology analysis of differentially regulated transcripts predicted a number of biological processes significantly altered by Lov treatment (Fig. 5A, B; FDR <0.05). Lov-affected processes included oxidation/reduction, which concurs with the changes in tumor oxygenation, metabolism, including the downregulation of the glycolytic enzyme 6-phosphofructokinase/fructose-2,6-bisphosphate (pfkfb3) gene, as well as the downmodulation of positive regulators of angiogenesis. We found that Lov downregulated the placental growth factor (plgf) gene, whose elevation is associated with the abnormalization of tumor vessels [34]. Lov-induced downregulation of PlGF was validated at the mRNA (Table S2) and protein levels (Fig. 5C). VEGF mRNA levels were comparable in Vhcl- and Lov-treated tumors (Fig. 5D), suggesting that the Lov effect was specific for PlGF expression.

Bottom Line: Beyond their ability to inhibit cholesterol biosynthesis, the statins have pleiotropic effects that include anti-inflammatory and immunomodulatory activities.We found that Lov enhanced tumor infiltration by effector T cells, and reduced the number of immunosuppressive and pro-angiogenic M2-like tumor-associated macrophages (TAM).Our results identify a role for lovastatin in the shaping and re-education of the inflammatory infiltrate in tumors, with functional consequences in angiogenesis and antitumor immunity.

View Article: PubMed Central - PubMed

ABSTRACT
Beyond their ability to inhibit cholesterol biosynthesis, the statins have pleiotropic effects that include anti-inflammatory and immunomodulatory activities. Statins could have clinical utility, alone or in combination with other chemotherapeutics, in the treatment of cancer. The mechanisms that underlie the anti-tumor activity of the statins are nonetheless poorly defined. No studies have analyzed how they alter the tumor-associated leukocyte infiltrate, a central factor that influences tumor stroma and cancer evolution. Here we used HER2/neu transgenic (Tg-neu) mice to analyze the effect of lovastatin (Lov) on the inflammatory reaction of spontaneous mammary tumors. Lov treatment of tumor-bearing Tg-neu mice did not alter growth of established tumors, but significantly reduced the number of new oncogenic lesions in these mice. Moreover, Lov inhibited the growth of newly implanted Tg-neu tumors in immunocompetent but not in immunodeficient mice. We found that Lov enhanced tumor infiltration by effector T cells, and reduced the number of immunosuppressive and pro-angiogenic M2-like tumor-associated macrophages (TAM). Concomitantly, the drug improved the structure and function of the tumor vasculature, measured as enhanced tumor oxygenation and penetration of cytotoxic drugs. Microarray analysis identified a Lov-elicited genetic program in Tg-neu tumors that might explain these effects; we observed Lov-induced downregulation of placental growth factor, which triggers aberrant angiogenesis and M2-like TAM polarization. Our results identify a role for lovastatin in the shaping and re-education of the inflammatory infiltrate in tumors, with functional consequences in angiogenesis and antitumor immunity.

Show MeSH
Related in: MedlinePlus