br Concluding remarks The past decade has seen rapid advance
Concluding remarks The past decade has seen rapid advances in our understanding of the metabolic reprogramming that occurs during tumorigenesis. Strategies to target specific nodes of cancer cell amino PRT-060318 metabolism have progressed from preclinical studies to clinical trials, and are showing efficacy in some contexts. To date, research in this field has relied heavily on cancer cell lines grown in standard culture media. However, recent work reveals that remarkable metabolic adaptations can take place when cells are transitioned between microenvironments (Box 1). Furthermore, metabolic phenotypes differ greatly between tumor types, and even between distinct regions of a single tumor. This highlights the importance of recognizing the limitations of any particular model system for studying cancer metabolism. Drugs that target amino acid metabolism will probably be most effective as a component of personalized cancer therapy, with genetic and metabolomic biomarkers being assessed before selection of a treatment strategy. A broader understanding of tumor metabolism in vivo, technological advances for imaging and profiling metabolism in patients, and continuing efforts to discover potent and selective inhibitors together have the potential to yield effective novel therapies for cancer.
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Introduction The regulation and dynamics of central metabolic pathways and energy production differ between normal and malignant cells. Fast-growing, poorly differentiated tumor cells typically exhibit increased aerobic glycolysis, even in the presence of O2, by converting a majority of glucose-derived pyruvate to lactate, a phenomenon known as the Warburg effect (Pavlova and Thompson, 2016; Warburg, 1956). Because of this, tumor cells depend on glutamine anaplerosis to replenish tricarboxylic acid (TCA) cycle intermediates for macromolecular biosynthesis and nicotinamide adenine dinucleotide phosphate (NADPH) production (DeBerardinis et al., 2007). As such, reprogramming of glucose and glutamine metabolism not only provides tumor cells with building blocks for an array of growth promoting pathways but also rescues them from a stressed cellular microenvironment by maintaining proper redox homeostasis. Myc oncogenes regulate multiple aspects of tumor metabolism, enabling tumor cells to avidly take up both glucose and glutamine (Dang, 2013). The Myc family contains three members, C-Myc, L-Myc, and Mycn; they encode C-MYC, L-MYC, and N-MYC, respectively (Adhikary and Eilers, 2005). Although C-Myc is broadly deregulated in many human tumors, Mycn expression is more restricted to neural tumors, and L-Myc is predominantly found in small-cell lung cancer (Adhikary and Eilers, 2005). The unleashed Myc oncogene frequently produces abundant MYC protein, which activates genes involved in ribosome and mitochondrial biogenesis, glucose and glutamine metabolism, and lipid and nucleotide biosynthesis, enabling rapid generation of building blocks to sustain uncontrolled tumor cell proliferation (Dang, 2013; Morrish and Hockenbery, 2014; van Riggelen et al., 2010). Mammalian cells, whether they are cancerous or not, have to obtain essential amino acids (EAAs) from the extracellular milieu because they are unable to produce EAAs de novo (Payne and Loomis, 2006). EAAs not only provide fundamental building blocks for macromolecular biosynthesis but also serve as signaling molecules to induce mammalian target of rapamycin (mTOR) activation (Hosios et al., 2016; Jewell et al., 2013). There are a total of nine amino acids (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) that are essential in humans. Except for histidine, lysine, methionine, and threonine, the remaining five are EAAs with large branched or aromatic side chains, collectively called LNEAAs (large neutral essential amino acids). Compared with their normal counterparts, tumor cells frequently exhibit an increased demand for EAAs (Hattori et al., 2017; Sheen et al., 2011). However, it is not quite clear how EAA uptake is elevated in human cancers and, in particular, how elevation of EAA incorporation reprograms cells to promote the cancer state.