Obesity and type 2 diabetes (T2D) are common and comorbid diseases, reflecting significant dysregulation of human carbohydrate and lipid metabolism. These are well known risk factors for cardiovascular disease, whereas their association with cancer risk and poor cancer outcomes are less well known. The process of cancer development is complex, influenced by many factors, and typically takes years to occur. Patterns of obesity associated risk for cancer are influenced by gender, although there is significant overlap. T2D further enhances risk of cancer. Ethnicity, inherited genetic factors, socioeconomic variables, some infectious diseases, environmental exposure, access to healthcare and geography also influence obesity associated cancer risk, so that different subpopulations may experience dissimilar patterns of cancer development even in the same organ. Cancer cells are adaptable to both their environment and mechanisms of energy generation, utilizing both aerobic and anaerobic respiration even under conditions of relative hypoxia. Cellular free energy has been shown to be an important predictor of cancer cell survival and replication (growth). Obesity and T2D, as well as energy excess provided through and sugar and fat rich diet appear to facilitate this process.
Modern medicine promotes diet and exercise, as well as pharmaceutical agents to treat patients with diabetes and/or obesity. Metformin is an oral agent that has minimal toxicity and is available worldwide at low cost. There is abundant evidence that metformin reduces the risk of cancer and improves cancer associated outcomes in patients with metabolic dysregulation. This is in contrast to all other diabetes drugs including insulin, that promote rather than reduce the risk of cancer. Given its potent anti-cancer activity, there have been numerous clinical trials of metformin in cancer patients with some apparent benefits.
The Thor lab has focused on the mechanisms of metformin action against breast cancer for well over a decade. We have shown that metformin induces unique biological and molecular responses in the various subtypes of breast cancer, that it is especially potent against triple negative cancer. Additionally, we have shown that metformin targets stem cells, receptor tyrosine kinase signaling, Stat3, erbB2/IGF-1 receptors, cell cycle inhibition, glycolysis, fatty acid and cholesterol biosynthesis, glucose transport proteins, organic cation transported 2, motility associated cytoskeletal proteins, TGF-ß signaling, internal and external mechanisms of apoptosis and GM1 lipid raft stabilization. Furthermore, its effects are influenced by extracellular glucose homeostasis (critical in the diabetic patient) as well as deletions or polymorphisms of the OCT1 gene. Finally, we and others have shown that metformin may interact with anti-cancer agents to enhance cell death and improve patient outcomes.
Todd Professor and Chair, Department of Pathology, University of Colorado Anschutz Medical CampusView Slides
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