Metformin Inhibits Prostate Cancer Progression by Targeting Tumor-Associated Inflammatory Infiltration

Abstract

Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer. By using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer. Treating TRAMP mice with metformin delays prostate cancer progression from low-grade prostatic intraepithelial neoplasia to high-grade PIN, undifferentiated to well-differentiated, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after androgen deprivation therapy (ADT) induced by surgically castration in mice, bicalutamide treatment in patients, and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells. Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting the COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment. .

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

“…In the TRAMP transgenic model of spontaneous prostate cancer, transgene-mediated overexpression of GDF-15 reduced the growth of the primary tumor (176). As tumor-promoting inflammation (which has been declared a hallmark of cancer since 2011) (134) critically contributes to spontaneous tumor development in this model (177,178), suppression of tumor growth by GDF-15 may be explained by its anti-inflammatory effects. Metastasis is, however, limited by immune surveillance in this (179) and in many other tumor models (179)(180)(181)(182)(183).…”

Metformin inhibits prostate cancer growth induced by a high‐fat diet in Pten‐deficient model mice

“…Metformin did not significantly change the prostate weights and the local MDSCs of CD‐fed mice. In the TRAMP mouse model, metformin inhibited prostate cancer progression through inflammatory responses . These findings suggest that inhibition of prostate cancer progression by metformin might be mostly mediated by inflammation, whereas several reports showed that the mechanism was mediated by other pathways, including 5’ adenosine monophosphate‐activated protein kinase activation .…”

Synergistic Effects of Metformin and Cocoa Flavanol on Inflammatory and Oxidant Markers Induced by Carrageenan: Pathophysiological Approach

“…[29] Also, Liu et al found that metformin treatment can reduce synthesis of COX2 and PGE2 and suppress the functions of macrophages, such as LPS induced synthesis of IL-6 and TNF-α. [30] They also, found that metformin uses its anticancer effects by inhibiting COX2/PGE 2 cells. [44] Metformin cleans the ROS from brain tissue By prompting the production and increasing the activity of the antioxidant system, such as SOD.…”