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.
Highlights
The progression or inhibition of a tumor is intimately linked to the integration of complex signals delivered from its microenvironment
Transgenic FVB/N-Tg(MMTVneu) mice (Tg-neu), which overexpress the neu protoncogene in the mammary www.impactjournals.com/oncotarget 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)
We found that Lov downregulated the placental growth factor gene, whose elevation is associated with the abnormalization of tumor vessels [34]
Summary
The progression or inhibition of a tumor is intimately linked to the integration of complex signals delivered from its microenvironment. Evidence indicates that immune cells in the tumor vicinity are major regulators of the outcome. Tumor infiltration by cells of the adaptive immune arm is associated with good prognosis in glioblastoma, colon and ovarian cancers [1-. 3]; in contrast, massive accumulation of cells of the innate immune system, macrophages, is linked to poor prognosis [4,5,6,7]. Tumor-associated macrophages (TAM) have contrasting activities, depending on their differentiation state. Progressing tumors skew TAM differentiation towards an alternatively activated (M2-like) state that induces angiogenesis and aids tumor cell evasion of antitumor immunity. In non-progressing or regressing tumors, TAM tend to a classic, prowww.impactjournals.com/oncotarget
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
