Perspective Perspective on Bhalla et al . , p . 544 Metformin and Hepatic Carcinogenesis

Retrospective, hypothesis-generating population studies suggest that diabetics treated with metformin have a substantially reduced risk of several cancers, including hepatoma, relative to diabetics on other therapies. In this issue of the journal (beginning on page 544), Bhalla and colleagues contribute to the growing literature on metformin effects in experimental carcinogenesis models, showing reduced carcinogen-induced hepatoma in mice. The clinical need to develop novel prevention strategies for hepatoma is obvious, given an increasing prevalence and poor prognosis. The clues thatmetformin or related biguanides may have utility in this area justify accelerated laboratory research, as more data concerning mechanism, pharmacokinetics, andpredictors of efficacywill help tooptimize thedesignof clinical trials.Cancer PrevRes; 5(4); 500–2. 2012 AACR. The literature on metformin and cancer has grown rapidly in the past few years. There is tantalizing evidence that this widely used, well-tolerated biguanide molecule may have applications in cancer prevention or treatment (1). In this issue of the journal, Bhalla and colleagues present interesting experimental evidence for an action of metformin in inhibiting the development of chemically induced hepatocellular carcinoma in mice (2), yet many important questions remain unanswered. Several proposed mechanisms of action of metformin may underlie its activity as a cancer preventive agent. Some (but not all) of these mechanisms may overlap with the actions that are responsible for the utility of the compound in the treatment of type II diabetes. It is now thought that the pleiotropic effects of metformin originate with the primary actions of the drug on the mitochondria (3), where it inhibits oxidative phosphorylation (at respiratory complex I) in a manner that has not yet been described in detail. Sequelae to this inhibition occur at the local mitochondrial level, at the cellular level, and at the level of the whole organism. The best known local consequence is the decline of mitochondrial ATP production (1), but there is also recent evidence for altered redox status, a decrease in reactive oxygen species (ROS) production, and a decrease in mutations attributable to ROS (4). At the cellular level, the reduction in ATP production by oxidative phosphorylation leads to a degree of energy stress. This stress can have different effects depending on the cellular context. Some cells have the ability to sense and respond to the stress by decreasing energy-consuming processes such as lipid synthesis, protein synthesis, and proliferation (1, 3). This decrease results in a new steady state characterized by reduced ATP production, reduced ATP consumption, and an energetically "sleepy" phenotype, which may tend to slow carcinogenesis and may also be cytostatic for a subset of established cancers. Another compensation involves increasing glycolysis to help correct the ATP deficit. This process may seem paradoxical at first, as it represents a situation of increased glucose uptake and a glycolytic phenotype associated with growth inhibition, thus contrasting with classic views originating with Warburg (5) that a shift to glycolysis is associatedwithmore aggressive behavior and increased proliferation. A special case of response to metformin-induced energy stress is seen in the hepatocyte. The process of gluconeogenesis, by which hepatocytes export glucose to the circulation, is an important part of whole-organism carbohydrate metabolism; from the point of view of the hepatocyte, gluconeogenesis represents export of energy, and so it is not surprising that metformin-induced energetic stress inhibits gluconeogenesis (3, 6, 7). This inhibition then improves hyperglycemia and hyperinsulinemia in patients with type II diabetes. These systemic effects might reduce the proliferation rate of any cancers or premalignant lesions that thrive in a high-glucose, high-insulin environment. The fact that metformin reduces glucose and insulin levels only when baseline levels are elevated contributes to its safety, but also implies that this mechanism can only contribute to antineoplastic activity in a metabolically defined subpopulation. Many experimental studies demonstrate cancer treatment or prevention activity of metformin attributable to direct actions of the drug on target cells that are independent of Authors' Affiliations: Lady Davis Research Institute and McGill University, Montreal, Quebec, Canada; and Breast Medical Oncology and Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas CorrespondingAuthor:Michael Pollak, LadyDavis Research Institute and McGill University, Montreal, Quebec, 3999 Chemin Cote Sainte Catherine, Montreal Quebec H3T 1E2, Canada. E-mail: michael.pollak@mcgill.ca doi: 10.1158/1940-6207.CAPR-12-008