Tumor-Suppressive Effect of Metformin via the Regulation of M2 Macrophages and Myeloid-Derived Suppressor Cells in the Tumor Microenvironment of Colorectal Cancer

by Selleckchem | Oct 17 2023

Myeloid-derived suppressor cells (MDSCs) and M2 macrophages in the tumor microenvironment contribute to tumor progression by inducing immune tolerance to tumor antigens and cancer cells. Metformin, one of the most common diabetes drugs, has shown anti-inflammatory and anti-tumor effects. However, the effects of metformin on inflammatory cells of the tumor microenvironment and its underlying mechanisms remain unclarified. In this study, we investigated the effect of metformin on M2 macrophages and MDSCs using monocyte THP-1 cells and a dextran sodium sulfate (DSS)-treated ApcMin/+ mouse model of colon cancer. Metformin decreased the fractions of MDSCs expressing CD33 and arginase, as well as M2 macrophages expressing CD206 and CD163. The inhibitory effect of metformin and rapamycin on MDSCs and M2 macrophages was reversed by the co-treatment of Compound C (an AMP-activated protein kinase (AMPK) inhibitor) or mevalonate. To examine the effect of protein prenylation and cholesterol synthesis (the final steps of the mevalonate pathway) on the MDSC and M2 macrophage populations, we used respective inhibitors (YM53601; SQLE inhibitor, FTI-277; farnesyl transferase inhibitor, GGTI-298; geranylgeranyl transferase inhibitor) and found that the MDSC and M2 populations were suppressed by the protein prenylation inhibitors. In the DSS-treated ApcMin/+ mouse colon cancer model, metformin reduced the number and volume of colorectal tumors with decreased populations of MDSCs and M2 macrophages in the tumor microenvironment. In conclusion, the inhibitory effect of metformin on MDSCs and M2 macrophages in the tumor microenvironment of colon cancers is mediated by AMPK activation and subsequent mTOR inhibition, leading to the downregulation of the mevalonate pathway.

Comments:

The study you described investigated the effects of metformin, a commonly used diabetes medication, on two types of immune cells in the tumor microenvironment: myeloid-derived suppressor cells (MDSCs) and M2 macrophages. These cells are known to contribute to tumor progression by promoting immune tolerance to tumor antigens and cancer cells.

The researchers conducted their study using both in vitro and in vivo models. They used monocyte THP-1 cells (a cell line commonly used to study monocytes and macrophages) and a mouse model of colon cancer treated with dextran sodium sulfate (DSS) to simulate tumor growth. They observed the effects of metformin on the populations of MDSCs and M2 macrophages in these models.

The results of the study demonstrated that metformin decreased the fractions of MDSCs expressing CD33 and arginase, as well as M2 macrophages expressing CD206 and CD163. This suggests that metformin has an inhibitory effect on these immune cell populations in the tumor microenvironment.

To understand the underlying mechanisms of metformin's effects, the researchers explored the involvement of several signaling pathways. They found that the inhibitory effect of metformin on MDSCs and M2 macrophages was reversed when co-treated with Compound C, an inhibitor of AMP-activated protein kinase (AMPK), or mevalonate. This suggests that metformin's impact on these immune cells is mediated through AMPK activation and subsequent inhibition of the mTOR pathway, which is known to regulate cell growth and metabolism.

The researchers also investigated the role of protein prenylation and cholesterol synthesis, which are the final steps of the mevalonate pathway, in regulating the populations of MDSCs and M2 macrophages. They used specific inhibitors to target these processes and found that the MDSC and M2 macrophage populations were suppressed by the protein prenylation inhibitors. This suggests that the mevalonate pathway plays a role in the regulation of these immune cells and that metformin's effects are mediated through downregulation of this pathway.

Finally, the study examined the effects of metformin in the DSS-treated ApcMin/+ mouse model of colon cancer. The researchers found that metformin reduced the number and volume of colorectal tumors in this model, accompanied by a decrease in the populations of MDSCs and M2 macrophages in the tumor microenvironment.

In conclusion, this study demonstrated that metformin has an inhibitory effect on MDSCs and M2 macrophages in the tumor microenvironment of colon cancers. This effect is mediated by AMPK activation, subsequent mTOR inhibition, and downregulation of the mevalonate pathway. These findings suggest that metformin may have potential as an anti-inflammatory and anti-tumor agent by targeting immune cell populations involved in tumor progression.