Figure 3.

Proposed role of metformin in inhibiting neutrophil extracellular trap (NET)-induced tumor cell metastasis. In addition to decreasing neutrophil recruitment (not shown), metformin has been shown to inhibit protein kinase C beta II (PKCβII) translocation to the plasma membrane and prevent the downstream activation of NADPH oxidase (NOX) that would otherwise result in the expulsion of neutrophil extracellular trap (NET) components into the extracellular space [71]. Tumor cells have been shown to adhere to NETs, which contain DNA, histones, neutrophil elastase, and other proteins. In the case of ovarian cancer (OvCa), NET formation was especially critical to the ability of tumor cells to colonize the omentum in vivo, while having no effect on the primary tumor or other intra-abdominal sites [70]. The ability for metformin to inhibit this NET-dependent adhesion and colonization of the omentum has not yet been investigated but is a potential mechanism for its antitumor activity. Cited experiments are denoted by their respective reference numbers [70,71]. Blue arrows indicate activation, red arrows indicate inhibition, red T symbols indicate direct inactivation, and red X symbols indicate inhibition of this pathway by metformin.