Metformin Treatment Reduces CRC Aggressiveness in a Glucose-Independent Manner: An In Vitro and Ex Vivo Study

SIMPLE SUMMARY: In 2020, colorectal cancer (CRC) was ranked third among the most common cancers in the world, and second in terms of cancer-related mortality. Epithelial–mesenchymal transition (EMT) is mainly recognized by the loss of epithelial markers (such as E-cadherin) and cell movement activation, partially due to extracellular matrix remodeling by metalloproteinases, such as MMP2 and MMP9. It constitutes a critical step that promotes the spread of cancerous cells in oncogenesis, especially in epithelial cancers like CRC. Metformin is an anti-diabetic drug used in the treatment of type 2 diabetes; it targets mitochondrial metabolism and APMK. The EMT inhibitory effect from metformin used in the treatment of type 2 diabetic patients has been studied in large cohorts of patients with different cancer types; however, the mechanism of protection from metformin to colorectal cancer spread is still unknown, especially in the context of non-diabetes. Sortilin is a poor prognostic marker in CRC that may be related to signaling pathways that metformin could downregulate. This study focuses on the metformin-mediated effect on colorectal cancer aggressiveness according to different glucose conditions. ABSTRACT: (1) Background: Metformin, an anti-diabetic drug, seems to protect against aggressive acquisition in colorectal cancers (CRCs). However, its mechanisms are still really unknown, raising questions about the possibility of its positive impact on non-diabetic patients with CRC. (2) Methods: An in vitro study based on human colon cancer cell lines and an ex vivo study with different colon cancer stages with proteomic and transcriptomic analyses were initiated. (3) Results: Metformin seems to protect from colon cancer invasive acquisition, irrespective of glucose concentration. (4) Conclusions: Metformin could be used as an adjuvant treatment to surgery for both diabetic and non-diabetic patients in order to prevent the acquisition of aggressiveness and, ultimately, recurrences.