Metformin Mitigated Obesity-Driven Cancer Aggressiveness in Tumor-Bearing Mice

Abstract

Metformin may offer benefits to certain cancer populations experiencing metabolic abnormalities. To extend the anticancer studies of metformin, a tumor model was established through the implantation of murine Lewis Lung Carcinoma (LLC) cells to Normal Diet (ND)-fed and High-Fat Diet (HFD)-fed C57BL/6 mice. The HFD-fed mice displayed metabolic and pro-inflammatory alterations together with accompanying aggressive tumor growth. Metformin mitigated tumor growth in HFD-fed mice, paralleled by reductions in circulating glucose, insulin, soluble P-selectin, TGF-β1 and High Mobility Group Box-1 (HMGB1), as well as tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets and neutrophils molecules. The suppressive effects of metformin on cell proliferation, migration and oncogenic signaling molecules were confirmed in cell study. Moreover, tumor-bearing HFD-fed mice had higher contents of circulating and tumor immunopositivity of Neutrophil Extracellular Traps (NETs)-associated molecules, with a suppressive effect from metformin. Data taken from neutrophil studies confirmed the inhibitory effect that metformin has on NET formation induced by HMGB1. Furthermore, HMGB1 was identified as a promoting molecule to boost the transition process towards NETs. The current study shows that metabolic, pro-inflammatory and NET alterations appear to play roles in the obesity-driven aggressiveness of cancer, while also representing candidate targets for anticancer potential of metformin.

Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma and the Immune System: Pathogenesis, Immunotherapy and Future Perspectives

“…Studies have demonstrated that metformin decreases NET production, even in the presence of NET stimulants and recent evidence in hepatocellular carcinoma and pancreatic cancer confirmed that metformin reduced the production of NETs and the metastatic potential of these two cancers [ 246 , 247 , 248 ]. This has subsequently been corroborated in preclinical animal models [ 249 ].…”

Immune Checkpoint Inhibitors, Small-Molecule Immunotherapies and the Emerging Role of Neutrophil Extracellular Traps in Therapeutic Strategies for Head and Neck Cancer

“…New evidence in hepatocellular carcinoma (HCC) and pancreatic cancer (PC) demonstrated that metformin attenuated NET production and reduced the metastatic potential of HCC and PC cells [253,254]. The role of metformin in attenuating NET-mediated carcinogenesis was corroborated in further murine models [255]. Interestingly, a recent presentation at AACR's Annual Meeting revealed that patients with type 2 diabetes mellitus suffering from colorectal cancer had significantly improved DFS in the presence of metformin, with tissue analysis identifying a significant reduction in tumor-associated NETs and a significant increase in CD8 + T-cells.…”

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“…In addition, HMGB1 was identified as a facilitator molecule that promotes the transition process to NETS. These results suggest that metformin plays a role in obesity-induced cancer aggressiveness by inhibiting HMGB1-induced NET formation and may be a potential target drug ( Chen et al, 2022b ).…”