Therefore, platelet and neutrophil activation and tumor infiltration, TGF-β1/Smad2/3 signaling and HMGB1/RAGE signaling all play substantial roles in the obesity-driven aggressiveness of cancer, with each being a potential target for the anticancer actions of metformin. This evidence concerns the gene TGFB1 and obesity due to melanocortin 4 receptor deficiency.