From the guest editor: an integrated multidisciplinary view of tumor metabolism.

This special issue of The Cancer Journal is dedicated to the subject of tumor metabolism. There is no disputing the fact that the earliest pioneer in this field was Otto Warburg. Dr Warburg published his first article defining the propensity for tumor cells to metabolize glucose to lactate by “fermentation” in 1924,1 but his 1956 review in Science received the most acclaim, having garnered nearly 4000 citations to date.2 His landmark observations on the nature of the respiratory enzyme led to his Nobel Prize in Physiology and Medicine in 1931. Dr Warburg’s theory of tumorigenesis was rooted by his observation of a deficit in respiration by tumor cells. It was his belief that damage to mitochondria was the root cause of malignancy. Although this theory was proven to be incorrect in most cases, it has nevertheless had a profound influence on research in cancer metabolism. In his article in Science in 1956, he said: For many decades, the so-called “Warburg effect” was an admitted characteristic of cancer, but the root cause and biological and clinical implications were not understood. Dr Warburg’s works were cited at a fairly constant rate until around 2001, when the number of citations per year increased exponentially. This increase in interest in his work was associated with the acceptance of 18F-FDG PET (18F-fluorodeoxyglucose positron emission tomography) as an imaging biomarker for cancer detection and monitoring of treatment response.3–5 In the decade and a half since the clinical acceptance of 18F-FDG PET and the 90 years since Warburg’s landmark article of 1924, knowledge of the nature, causes, and consequences of the novelties of tumor metabolism is exploding. The importance of tumor metabolism has been recognized as an emerging “hallmark of cancer” by Hanahan and Weinberg in their most recent review.6 While altered glucose metabolism is a cornerstone of tumor energy production, we now know that tumor cells use many substrates from their external milieu. These substrates are used for formation of precursors for protein, lipid, and nucleotides as well as for energy production. Keenan and Chi provide a comprehensive review of alternative fuels for cancer cells in this issue. Cairns provides an overview of the drivers of the Warburg phenotype. The signal transduction pathways and enzymes that drive tumor metabolism have received substantial interest, and, as a result, a multitude of new therapeutic targets have emerged, which may exhibit highly selective antitumor effects. This subject is examined in exquisite detail in an article by Kishton and Rathmell. He et al focus on the selective advantages that metformin, the drug approved for treatment of type 2 diabetes, has in altering tumor metabolism and treatment responses. When discussing tumor metabolism, it is important to examine the tumor microenvironment. The microenvironment can influence substrate utilization. Many features of the tumor microenvironment stresses are caused by the altered metabolisms and further contribute to the changes in tumor metabolism. At the same time, the substrates can in turn influence the microenvironment. Payen et al discuss the importance of hypoxia and lactic acid in the tumor microenvironment and compare these features with wounds, where similar metabolism occurs. Furthermore, Payen et al emphasize the influence of lactic acid in driving angiogenesis, an essential feature of tumor growth and wound healing. Gillies and Gatenby provide an intriguing theory of tumor cell evolution, which starts with selective pressure for cells that can survive the acidotic microenvironment of tumors. Repasky et al examine the effects of the tumor microenvironment on the function of the immune system. One cannot ignore the fact that tumor metabolism is also influenced by a patient’s lifestyle, diet, and level of activity.