Antineoplastic potential of metformin in colorectal cancer

I read with interest the article “Colon neoplasia in patients with type 2 diabetes on metformin: A meta-analysis” by Rokkas and Portincasa [ ]. As the authors note, the mechanisms underlying the antineoplastic potential of metformin in colon neoplasia are probably manifold and not yet completely understood. Experimental data support a direct effect of metformin in antagonizing specific pathways that promote cell proliferation, motility, invasion, and migration. As Rokkas and Portincasa mention, metformin activates AMP-activated protein kinase (AMPK), leading to downregulation of the mTOR pathway that is crucial to tumor cell metabolism. I would like to mention another possible mechanism. In a recent study [ ], it was demonstrated that activating KRAS mutation imposes an embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Metformin inhibits KRAS signaling through mislocalization of KRAS from the plasma membrane to the cytoplasm [ ], and, interestingly, in other studies [ , ], this anti-diabetic agent was most effective against tumors with activating mutations in KRAS. KRAS mutations are found in 30–50% of patients with sporadic colorectal cancer [ ] and, in clinical practice, KRAS mutation testing permits the selection of individuals (those with RAS wild-type tumors) who might benefit from agents that target the epidermal growth factor receptor, as cetuximab. It would also be interesting to know whether metformin together with conventional chemotherapy might have a role in treatment of a subgroup of patients with colorectal cancer.