In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.For unicellular organisms such as microbes, there is evolutionary pressure to reproduce as quickly as possible when nutrients are available. Their metabolic control systems have evolved to sense an adequate supply of nutrients and channel the requisite carbon, nitrogen, and free energy into generating the building blocks needed to produce a new cell. When nutrients are scarce, the cells cease biomass production and adapt metabolism to extract the maximum free energy from available resources to survive the starvation period (Fig. 1). Reflecting these fundamental differences in metabolic needs, distinct regulatory mechanisms have evolved to control cellular metabolism in proliferating versus non-proliferating cells.In multicellular organisms, most cells are exposed to a constant supply of nutrients. Survival of the organism requires control systems that prevent aberrant individual cell proliferation when nutrient availability exceeds the levels needed to support cell division. Uncontrolled proliferation is prevented because mammalian cells do not normally take up nutrients from their environment unless stimulated to do so by growth factors. Cancer cells overcome this growth factor dependence by acquiring genetic mutations that functionally alter receptorinitiated signaling pathways. There is growing evidence that some of these pathways constitutively activate the uptake and metabolism of nutrients that both promote cell survival and fuel cell growth (1,2). Oncogenic mutations can result in the uptake of nutrients,

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation and the tumor microenvironment. In this Review, we have organized known cancer-associated metabolic changes into six hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite-driven gene regulation, and (6) metabolic interactions with the microenvironment. While few tumors display all six hallmarks, most display several. The specific hallmarks exhibited by an individual tumor may ultimately contribute to better tumor classification and aid in directing treatment.

This Article demonstrates that tumour-associated IDH1 somatic mutations result in a gain of enzyme function that causes the accumulation of R(-)-2-hydroxyglutarate (2HG). We proposed that accumulation of 2HG might drive oncogenesis, and referenced work demonstrating 2HG accumulation in patients with 2-hydroxyglutaric aciduria 1 . As a plausible mechanism of oncogenesis, we proposed that R(-)-2HG induces redox stress owing to impairment of the respiratory chain. This hypothesis suggests that R(-)-2HG may promote cancer mutations, and is consistent with the latency observed in glioma development and the fact that gliomas increase in incidence with age. Nonetheless, we do appreciate that there are other possible mechanisms by which R(-)-2HG may promote tumour formation. Further work has identified that the abnormal production of 2HG is associated with tumours bearing a mutation in either IDH1 or IDH2 and supports a link between 2HG accumulation and cancer. So far, we have not found any tumour samples containing IDH1 or IDH2 mutations that do not have increased 2HG levels. Determining the mechanistic link between 2HG accumulation and cancer formation, and how each stereoisomer of 2HG may drive malignancy by the same or distinct mechanism is the subject of continuing investigation by our group and others. Hum Genet. 2005; 76:358-360. [PubMed: 15609246] NIH Public Access

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