Cancer metabolism can be viewed as the sum of a large but finite number of interdependent biochemical pathways, each of which provides a specific function for the cell [1,2
]. Many of these pathways, particularly glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and the synthesis of nucleotides and lipids, either are required to support the intense biosynthetic demands of cell proliferation or are subject to alternative regulation in cancer. Below, we outline six concepts that illustrate the important links between tumor biology and metabolism.
Historically, the first important concept was that tumor metabolism differs from that of the surrounding tissue. In the 1920s, Otto Warburg demonstrated that tumors had high rates of glucose consumption and lactate production compared with the normal tissue [3,4
]. This seminal observation created the field of tumor metabolism, which has been dominated largely by the study of glycolysis ever since [5
]. Enhanced fluxes in other pathways including lipid synthesis, amino acid transport, and nucleotide transport have also been observed in aggressive tumors and are being investigated for diagnostic purposes [6
] or as therapeutic targets [7–9
Regulation of tissue pH is also abnormal in cancer. Most tumors have an acidic extracellular pH compared with normal tissue, and this can be correlated with prognosis and response to treatment [10–12
]. Secondary changes in malignant tissue such as inflammation and ischemia are among the pathologic states associated with an altered acid-base balance [13–16
]. Despite the importance of pH and its relationship to the disease, there is currently no clinical tool available to image the spatial distribution of pH in humans.
More recently, it has been shown that tumor suppressors and oncogenes regulate nutrient uptake and metabolic flux. Thus, tumor metabolism is linked mechanistically to the mutations that cause cancer. As early as the 1980s, it was determined that overexpressing the oncogenes ras
in fibroblasts was sufficient to drive glucose uptake [17
], and numerous subsequent studies have documented the metabolic effects of various mutations or aberrant signaling activities. Many of these studies have focused on glucose uptake, but others suggest wider influence involving either the specific fates of glucose carbon within the cell or the ability to orchestrate multiple pathways simultaneously. For example, the oncogenic transcription factor c-Myc seems to regulate cellular handling of both glucose and glutamine, which, together, feed the metabolic pathways required for cell growth and proliferation [18 19–20
]. Deletion of the tumor suppressor gene TP53
can stimulate glucose uptake and suppress the oxidation of pyruvate, both of which are hallmarks of the metabolic phenotype described by Warburg [16,21
]. Together, these observations support the notion that alterations in metabolism are common downstream indicators of the transformed state.
A fourth and perhaps surprising principle is that mutations in metabolic enzymes may cause a small number of cancers. Pheochromocytoma and paraganglioma can be caused by mutations in subunits of succinate dehydrogenase, an enzyme complex that [16,21
] functions in both the TCA cycle and electron transport [13,22,23
]. Similarly, mutations in the TCA cycle enzyme fumarate hydratase occur in a familial form of leiomyomatosis and renal cell cancer [13,22,23
]. In both of these diseases, affected patients inherit one mutant allele and their tumors exhibit loss of the other, resulting in a severe deficiency of enzyme activity in the tumor. The mechanism for tumorigenesis in these diseases is unknown but may be mediated by accumulations of succinate and fumarate, both of which have been demonstrated to elicit effects normally brought on by hypoxia [24
]. More recently, mutations in the two isoforms of isocitrate dehydrogenase, IDH1 and IDH2, were identified in glioblastoma, low-grade gliomas, and acute myelogenous leukemia [25–27
]. Although the mutant enzymes lack the canonical IDH enzymatic activity, the genetics of these tumors pointed to a more complex mechanism of tumorigenesis than simple loss of function. In particular, the fact that these somatically acquired mutations were confined to a single codon and were not accompanied by loss of heterozygosity suggested that the mutant alleles functioned as oncogenes. Consistent with this idea, mutant IDH1 proteins were recently shown to possess a new enzymatic activity, the production of the metabolite 2-hydroxyglutaric acid from alpha-KG [28
]. It should be noted that several other inborn errors of metabolism, including glycogen storage disease type 1 and tyrosinemia type 1, are also associated with cancer. These findings together indicate that the detection of abnormal metabolic fluxes or the accumulation of unusual metabolites could be used to monitor the predisposition to cancer in humans.
Some aspects of metabolism may predict disease severity or outcomes in cancer. For example, the enzyme transketolase-like 1 (TKTL1), which catalyzes transfer reactions between glycolysis and the nonoxidative branch of the pentose phosphate pathway, is overexpressed in a number of tumor types. A large study involving more than 1000 primary tumor samples determined that a high expression of TKTL1 predicted early mortality in colon and urothelial cancers [29
]. Another study demonstrated a similar connection between TKTL1 expression and distant metastases in ovarian carcinoma [30
]. These observations raise the appealing possibility that methods to monitor the activity of TKTL1, fatty acid synthase (FAS), and other enzymes in vivo
would provide novel biomarkers of disease severity, enabling clinicians to tailor treatment regimens.
Finally, clinical oncologists have long known that tumor growth can be suppressed by modifying metabolic activity in some instances. For example, l
-asparaginase, an important component of treatment regimens in pediatric leukemias, operates on the principle that the demand for asparagine in rapidly proliferating tumor cells exceeds what can be supplied through endogenous de novo
asparagine synthesis. Infusion of l
-asparaginase reduces the availability of asparagine from the blood supply, thereby specifically limiting the growth of the tumor cells. Antimetabolite therapies such as methotrexate suppress de novo
nucleotide synthesis in proliferating cells. More recent studies have demonstrated that genetic or pharmacological manipulations of other metabolic activities are effective in limiting the growth of xenografts [31–34
]. These studies have generated excitement about developing related approaches in human cancer.