Park J, et al. Yonsei Med J. 2021 Feb;62(2):99-108. https://doi.org/10.3349/ymj.2021.62.2.99

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 Apc^Min/+ 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 Apc^Min/+ 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.

The disease-related knowledge levels in patients with inflammatory bowel disease (IBD) are important because it could affect the self-management ability and adaptive coping strategies. We set out to determine whether higher levels of disease-related knowledge reduce medical acceleration. We evaluated the levels of disease-related knowledge in all patients at the time of enrollment for SNUBH IBD cohort using the validated IBD-KNOW questionnaire. Clinical data were prospectively collected and the factors related to step-up therapy were analyzed. Step-up therapy was defined as the new use of corticosteroids, immunomodulators, or biologics after the enrollment. Between April 2017 and January 2019, 298 patients were enrolled (mean age, 39.8 years; males, 69.5%); 193 patients (64.8%) had ulcerative colitis and 105 (35.2%) had Crohn's disease. The mean disease duration was 35.8 months. During the mean follow-up of 14.7 months, 90 patients (30.2%) underwent step-up therapy and 208 (69.8%) underwent continuous therapy. The prevalence of continuous therapy increased with increasing IBD-KNOW scores (p for trend = 0.019). Cox proportional hazards analysis revealed that high IBD-KNOW scores (≥ 16) (hazards ratio [HR]: 0.498, 95% confidence interval [CI]: 0.276-0.897, p = 0.020) was negatively associated with the step-up therapy. Higher disease-related knowledge could reduce the requirement of step-up therapy in IBD. The IBD-KNOW score was independently predictive of step-up therapy.

Hye Kyung Hyun, Hye Won Lee, Jihye Park, Soo Jung Park, Jae Jun Park, Tae Il Kim, Jae Seung Lee, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Seung Up Kim, Jae Hee Cheon. Gut and Liver 2024;18:294-304. https://doi.org/10.5009/gnl220409