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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 reduces tumor multiplicity in Tg-neu miceTg-neu mice were assigned for Vhcl or Lov treatment after lump detection (n = 8, Vhcl; n = 11, Lov). (A) Volume of individual tumors at treatment onset. (B) Growth kinetics of primary Tg-neu tumors in Vhcl- or Lov-treated mice. (C) Weight of each initial tumor after sacrifice. (D, E) Representative images of sections from the initial tumor, stained for TUNEL (D) and p-H3+ (E); bar = 100 µm. (F) Quantification of images in E (n = 15 sections from 5 tumors/group; p = 0.35, Mann-Whitney test). (G) Tumor number for each mouse. *p <0.05, two-tailed Student's t-test.
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Figure 1: Lovastatin reduces tumor multiplicity in Tg-neu miceTg-neu mice were assigned for Vhcl or Lov treatment after lump detection (n = 8, Vhcl; n = 11, Lov). (A) Volume of individual tumors at treatment onset. (B) Growth kinetics of primary Tg-neu tumors in Vhcl- or Lov-treated mice. (C) Weight of each initial tumor after sacrifice. (D, E) Representative images of sections from the initial tumor, stained for TUNEL (D) and p-H3+ (E); bar = 100 µm. (F) Quantification of images in E (n = 15 sections from 5 tumors/group; p = 0.35, Mann-Whitney test). (G) Tumor number for each mouse. *p <0.05, two-tailed Student's t-test.

Mentions: Transgenic FVB/N-Tg(MMTVneu) mice (Tg-neu), which overexpress the neu protoncogene in the mammary gland and develop spontaneous mammary tumors, were randomly assigned for treatment with vehicle (Vhcl) or Lov as soon as lumps were detected by palpation (Fig. 1A). The Lov dose used (10 mg/Kg every 3 days, i.p.) is comparable to that for humans treated with 40 mg/day [31].


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 reduces tumor multiplicity in Tg-neu miceTg-neu mice were assigned for Vhcl or Lov treatment after lump detection (n = 8, Vhcl; n = 11, Lov). (A) Volume of individual tumors at treatment onset. (B) Growth kinetics of primary Tg-neu tumors in Vhcl- or Lov-treated mice. (C) Weight of each initial tumor after sacrifice. (D, E) Representative images of sections from the initial tumor, stained for TUNEL (D) and p-H3+ (E); bar = 100 µm. (F) Quantification of images in E (n = 15 sections from 5 tumors/group; p = 0.35, Mann-Whitney test). (G) Tumor number for each mouse. *p <0.05, 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 1: Lovastatin reduces tumor multiplicity in Tg-neu miceTg-neu mice were assigned for Vhcl or Lov treatment after lump detection (n = 8, Vhcl; n = 11, Lov). (A) Volume of individual tumors at treatment onset. (B) Growth kinetics of primary Tg-neu tumors in Vhcl- or Lov-treated mice. (C) Weight of each initial tumor after sacrifice. (D, E) Representative images of sections from the initial tumor, stained for TUNEL (D) and p-H3+ (E); bar = 100 µm. (F) Quantification of images in E (n = 15 sections from 5 tumors/group; p = 0.35, Mann-Whitney test). (G) Tumor number for each mouse. *p <0.05, two-tailed Student's t-test.
Mentions: Transgenic FVB/N-Tg(MMTVneu) mice (Tg-neu), which overexpress the neu protoncogene in the mammary gland and develop spontaneous mammary tumors, were randomly assigned for treatment with vehicle (Vhcl) or Lov as soon as lumps were detected by palpation (Fig. 1A). The Lov dose used (10 mg/Kg every 3 days, i.p.) is comparable to that for humans treated with 40 mg/day [31].

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