Abstract
Purpose: 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.Experimental Design: By using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, in vitro 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.Results: 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.Conclusions: 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. Clin Cancer Res; 24(22); 5622-34. ©2018 AACR.
Highlights
Tumor microenvironment (TME) is the overall cellular surroundings of tumor cells formed by blood vessels, extracellular matrix, and some nonmalignant cells, including mesenchymal stem/stromal cells, bone marrow–derived dendritic cells, fibroblasts, and immune cells [1]
Given the fact that inflammatory infiltration usually occurs with androgen deprivation therapy (ADT) and metformin is capable of repressing prostate cancer progression by inhibiting the infiltration of tumor-associated macrophages, we propose that a combination of ADT with metformin could be a more effective therapeutic strategy in prostate cancer treatment
At week 25, more adenocarcinoma lesions than PIN were seen in the control group, whereas more PINs than adenocarcinoma lesions in the metformin group (Fig. 1G), indicating that metformin might be able to inhibit the transformation from PIN to adenocarcinoma
Summary
Tumor microenvironment (TME) is the overall cellular surroundings of tumor cells formed by blood vessels, extracellular matrix, and some nonmalignant cells, including mesenchymal stem/stromal cells, bone marrow–derived dendritic cells, fibroblasts, and immune cells [1]. Tumor-associated macrophages (TAM), one of the most important constituents of the TME, are recruited by tumor cells and subsequently polarized into M2-like cells. Multiple lines of evidence indicate that TME plays critical roles in the initiation, progression, and metastasis and is implicated in the development of therapeutic resistance of different cancers [3, 4]. Stromal cells within the TME have been suggested as an attractive therapeutic target and, due to their genetically stable trait, targeting these cells is usually accompanied with reduced risk of resistance and recurrence [5]
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