cancer: principles and practice of oncology 9th edition - cap8 - metabolismo do câncer

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MATTHEW G. VANDER HEIDEN

CHAPTER 8 CANCER METABOLISM

One of the fi rst distinctions noted between cancer tissues and normal tissues was a difference in metabolism. In the 1920s, the biochemist Otto Warburg observed that when provided with glucose, cancer tissues generate large amounts of lactate regard-less of whether oxygen is present. This fi nding is in contrast to most normal tissues that only ferment glucose to lactate in the absence of oxygen. This metabolic difference between cancer cells and normal cells is referred to as the Warburg effect, and along with other metabolic alterations that characterize cancer cells, it remains an incompletely understood aspect of cancer biology. The metabolic phenotype of cancer cells has been exploited for cancer diagnostics and led to the development of some of the fi rst successful chemotherapies. However, despite the fact that altered metabolism is shared across many different cancer types, few therapies exist that exploit differences in cel-lular metabolism. Efforts to understand cancer metabolism are currently an active area of investigation and hold great promise as a source of novel targets for cancer treatment.

ALTERED METABOLISM IN CANCER CELLS

The regulation of metabolic pathways in tumor tissues is dif-ferent from that observed in most adult tissues.1 Rapidly divid-ing cells must balance energy production with macromolecular synthesis, while most nonproliferating adult tissues utilize a greater fraction of nutrients for energy production and require less nutrient uptake. Cancer cells rely primarily on glycolysis for their metabolism, while the majority of normal cells in adult tissues utilize aerobic respiration to completely catabolize glucose and generate cellular energy.2–5 Most differentiated cells primarily metabolize glucose to carbon dioxide in the presence of oxygen and only produce large amounts of lactate under anaerobic conditions. Warburg observed that cancer cells produce large amounts of lactate regardless of oxygen availability (Fig. 8.1).6,7 Because cancer cells use glycolysis to make lactate from glucose in the presence of oxygen, this form of metabolism observed in cancer cells is also called aerobic glycolysis.

The primary energy source for cells in most tissues is glu-cose. The concentration of glucose in the blood remains rela-tively constant at around 4–6 mM (72–110 mg/dL). Glucose uptake into cells is controlled most proximally by the expres-sion of glucose transport proteins on the cell surface (Fig. 8.2).8 Insulin-responsive tissues rely on the regulated delivery of Glut4 transporters to the cell surface to increase glucose uptake. Noninsulin responsive tissues, including most cancers, do not use Glut4, but instead use the homologous Glut1, Glut2, or Glut3 proteins to transport glucose into cells. All of these glu-cose transporters allow the diffusion of glucose across the plasma membrane. The transporters differ in their affi nity for

glucose and capacity for transport. Glut1 is responsible for the basal level of glucose uptake in most normal cells and is thought to be the transporter responsible for glucose uptake in most tumor cells. Expression of Glut3 and other less well character-ized glucose transporters have also been described in some cancers.9,10 How these transporters differ from Glut1 and whether these differences are important for tumor biology and metabolism remain active areas of investigation.

Glucose is trapped in the cytoplasm of cells by the addition of a phosphate group to form glucose-6-phosphate (Fig. 8.2).11 This reaction is catalyzed by the enzyme hexokinase, which also has several isoforms with different normal tissue distributions and enzymatic properties. The various isoforms of hexokinase can associate with the outer surface of mitochondria, and this proximity to a source of adenosine triphosphate (ATP) has been suggested to be important for the high rate of glucose uptake observed in many cancer cells.12 The association of hexokinase with mitochondria has also been implicated in the regulation of apoptosis such that hexokinase may constitute a molecular link between glycolysis and the cell death machinery.13

Once trapped in cells, glucose can be metabolized via glyco-lysis to generate pyruvate in the cytosol.11 The rate of glycolysis is controlled by glucose fl ux into cells, cofactor availability, and the activity of glycolytic enzymes (Fig. 8.3). Both the phospho-fructokinase and pyruvate kinase steps of glycolysis are highly regulated and have been implicated in the control of tumor cell metabolism (Figs. 8.3 and 8.4).14–16 Another major determinant of glucose metabolism by glycolysis is the availability of oxidized nicotinamide adenine dinucleotide (NAD) to serve as the elec-tron acceptor for the conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate. This reaction, catalyzed by glycer-aldehyde-3-phosphate dehydrogenase reduces NAD to NADH (reduced nicotinamide adenine dinucleotide). Because the size of the NAD/NADH cofactor pool in cells is small relative to the fl ux of glucose through glycolysis, continued cycling of NADH back to NAD is critical to permit continued glycolysis (Fig. 8.3). NADH can be reoxidized to NAD through a series of reactions that shuttle reducing equivalents into mitochondria for use in oxidative phosphorylation. This process is coupled to the fur-ther metabolism of pyruvate in the mitochondrial tricarboxylic acid (TCA) cycle and can result in the generation of large amounts of ATP. ATP is used as a source of free energy for cells to enable otherwise unfavorable biochemical processes. Mitochondrial oxidative phosphorylation requires the presence of oxygen (O2) as the fi nal acceptor of electrons from NADH and therefore is also referred to as aerobic respiration. Aerobic glycolysis also generates ATP; however, the ATP yield per mol-ecule of glucose is much less than for aerobic respiration. The metabolism of glucose to pyruvate without mitochondrial respi-ration requires the enzyme lactate dehydrogenase (LDH) to produce lactate and regenerate NAD from NADH.

Several hypotheses for why aerobic glycolysis appears to be selected for in cancer cells have been proposed. Warburg

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92 Molecular Biology of Cancer

hypothesized that cancer cells develop a defect in mitochon-dria that leads to impaired aerobic respiration and a subse-quent reliance on glycolytic metabolism.2 Although mutations in mitochondrial enzymes have been implicated in a subset of cancers (discussed in detail later in the chapter), subsequent studies demonstrated that mitochondrial function is not impaired in the majority of cancer cells.17 Nevertheless, despite his hypothesis being incorrect, Warburg’s original observation has held true with numerous reports describing that despite normally functioning mitochondria many cancer cells prefer-entially metabolize glucose via aerobic glycolysis.4,18

The growth of solid tumors is limited by the presence of an adequate blood supply to deliver oxygen and nutrients to sup-port cell metabolism. Therefore, angiogenesis is an important process for tumor growth, and targeting this process has been successful for cancer therapy.19 Because many tumors are

characterized by ineffi cient angiogenesis, cells must survive periods of relative hypoxia and nutrient deprivation during tumorigenesis.5 Therefore, it has been proposed that the rela-tive hypoxia of tumors selects for glycolytic metabolism.3 However, aerobic glycolysis is observed at the earliest stages of tumorigenesis. It is a characteristic feature of leukemia and lung cancers that arises under conditions of normal to high oxygen tensions and is found in normal rapidly proliferating tissues during embryogenesis and immune responses.1 Therefore, it is likely that aerobic glycolysis provides another benefi t to cancer cells that is selected for during tumorigenesis.1 Aerobic glycolysis may still facilitate tumor survival during periods of hypoxia. The same pathways that regulate angio-genesis also promote aerobic glycolysis, suggesting that impor-tant connections between these two processes exist.20,21

The selective pressure for aerobic glycolysis in cancer cells may be related to the reprogramming of metabolism to accom-modate rapid cell division. Cells metabolize glucose for pur-poses other than generating ATP.1 Intermediates derived from the metabolism of glucose are used in other metabolic pathways

Normal

Tissue

O2

Lactateproduction

No lactateproduction

O2

Tumor

Tissue

O2

Lactateproduction

Lactateproduction

O2

FIGURE 8.1 A graphic representation of Warburg’s experiment is shown. Most normal tissues produce lactate in large quantities only when oxygen (O2) is absent. In contrast, cancer cells tend to make lactate regardless of O2 availability. This tendency of cancer cells to metabolize glucose to lactate (aerobic glycolysis) is often referred to as the Warburg effect.

GlucoseFDG

G-6-P

Glut

HK

Insulin

Growth

Signals

P

P

P

FIGURE 8.2 Glucose uptake is controlled in mammalian cells by the presence of glucose transporters on the cell surface (Glut). These trans-port proteins allow the diffusion of glucose across the plasma mem-brane where it is phosphorylated by the enzyme hexokinase (HK) and trapped in the cell. Glucose transporter expression is controlled by insu-lin signaling in insulin responsive tissues. Glucose uptake is also regu-lated by cell growth signals. A positron emission tomography (PET) scan can be used to monitor glucose uptake in the clinic. This assay uses the positron-emitting fl uorine-18 (18 F)-conjugated glucose analogue fl uoro-2-deoxyglucose (FDG), which can be phosphorylated by hexoki-nase and trapped in the cell but cannot be metabolized further.

Lactate

Glucose

ATP/AMP

NAD

NAD

NADH

NADH

Glut

HK

PK

PDH

CO2

LDH

PFK

P

P

FIGURE 8.3 Cellular glucose metabolism is regulated at several steps. Uptake of glucose is regulated by glucose transporter expression (Glut). Glucose metabolism by glycolysis classically is considered to be regu-lated at three enzymatic steps: these include the reactions catalyzed by hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK). The PFK step in glycolysis is a major point of regulation. One major allosteric input to PFK activity is the adenosine triphosphate: adenosine monophosphate (ATP:AMP) ratio. PFK activity and glycoly-sis are activated when the ATP:AMP ratio is low and inhibited when the ATP:AMP ratio is high. Glycolysis is also controlled by the avail-ability of the cofactor nicotinamide adenine dinucleotide (NAD). NAD is reduced to NADH at the glyceraldehyde-3-phosphate dehydroge-nase step of the pathway, and NADH must be recycled back to NAD to allow continued glycolysis. NADH can be converted to NAD by lactate dehydrogenase (LDH)-mediated conversion of pyruvate to lac-tate. NAD regeneration can also be coupled to the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation. Entry of pyruvate into the TCA cycle is controlled by pyruvate dehydrogenase (PDH) and allows the complete catabolism of glucose to carbon diox-ide (CO2) and maximum ATP production.


Chapter 8: Cancer Metabolism 93

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in cells and ultimately provide much of the carbon necessary to produce biomass. The production of nucleic acids, amino acids, lipids, and carbohydrates needed to duplicate all the components of the dividing cell is the major metabolic require-ment that distinguishes rapidly proliferating cancer cells from most normal cells. If glucose is completely catabolized to car-bon dioxide (CO2), as occurs during oxidative metabolism, there are no metabolic intermediates available for biosynthetic reactions. Thus, aerobic glycolysis may refl ect how metabo-lism is altered to permit anabolic metabolism.1 Indeed, many micro-organisms grow by fermentation when nutrients are abundant and display a metabolic phenotype analogous to aerobic glycolysis.22

ENERGETICS OF CELL PROLIFERATION

There is evidence that the rate of aerobic glycolysis, including the accompanying increased rate of glucose utilization, is not elevated in cancer cells solely to satisfy ATP demand. It has been suggested that glycolysis in tumors cells is limited by the rate of ATP consumption.23,24 Cancer cells must balance the catabolism of nutrients to generate ATP with other metabolic needs to allow net biosynthesis and cell proliferation.1 To pro-duce a daughter cell, a proliferating cell must replicate the genome, duplicate the ribosomes and protein synthesis machin-ery, generate new organelles, and synthesize de novo enough lipids to duplicate cellular membranes. This imposes a large requirement of new nucleic acids, amino acids, and lipids for cell proliferation. While ATP hydrolysis provides free energy for many biosynthetic pathways, there are additional require-ments to carry out these anabolic reactions. Synthesis of lipids and nucleic acids both require specifi c metabolite precursors and reducing equivalents provided by nicotinamide adenine dinucleotide phosphate (NADPH) (Fig. 8.5). In fact the need for NADPH and carbon skeletons on a molar basis exceeds the requirement for ATP in many biosynthetic reactions.1 Aerobic glycolysis may allow cancer cells to balance the vari-ous metabolic requirements of proliferation.

Cancer Cells Can Metabolize Nutrients Other Than Glucose

Although tumor cell metabolism is adapted to facilitate ana-bolic metabolism for rapid proliferation, it is not clear why many cancer cells excrete lactate. Each lactate excreted wastes three carbons that might otherwise be recycled to fulfi ll some need in building a new cancer cell. It has been hypothesized that the excretion of lactate, which accompanies aerobic glycolysis, may enable faster proliferative metabolism.1 In the early stages of tumorigenesis, cancer cells are not limited for nutrients. Cells

Lactate

Glutamine

Glucose Glycolysis

TCA

Cycle

Pentose

Phosphate

Pathway

Glutaminolysis

HK

Ras

PI3K/AKT

LKB1

AMPK

p53

Tyrosine

Kinase

Signaling

Myc

Glut

SDH

IDH

PDH

CoA

CoA

PK

LDH

PFKP

P

P

P P

P

PP P

P

P

PFH

FIGURE 8.4 A schematic of central carbon metabolism is presented to show how glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phos-phate pathway, and glutamine metabo-lism are interconnected in cells. The major points of enzymatic regulation, along with the enzymes discussed in the text that have been demonstrated to be important in cancer, are shown for orientation within the pathways, Glut, glucose transporter; HK, hexoki-nase; PFK, phosphofructokinase; PK, pyruvate kinase; LDH, lactate dehy-drogenase; PDH, pyruvate dehydroge-nase; IDH, isocitrate dehydrogenase; SDH, succinate dehydrogenase; FH, fumarate hydratase. The site of regula-tion within these pathways by some of the major oncogenes and tumor sup-pressor genes is also shown.

GlucoseRibose

Acetyl-CoA

ATP

NADPHNucleic Acids

LipidsCO

2

P P P

P P P

FIGURE 8.5 The generation of macromolecules requires several products of central carbon metabolism. In addition to adenosine triphosphate (ATP), the synthesis of nucleic acids and lipids both require reducing equivalents provided by nicotinamide adenine dinu-cleotide phosphate (NADPH) and carbon precursors that branch from different points of core metabolic pathways. Cancer cells must balance the production of specifi c macromolecular precursors such as ribose and acetyl-coA with the generation of enough NADPH and ATP to support proliferation.



that incorporate nutrients into biomass most effi ciently will proliferate faster. Lactate production may provide other advantages to a tumor as well. Acidifi cation of the tumor microenvironment has been shown to promote invasion and metastasis.3 Lactate can also act as a nutrient for some cells in the tumor.25 As tumors grow, cells in the less-well vascularized regions of a tumor can utilize lactate from neighboring cells as a carbon source to survive periods of cell stress.26

Despite an increased reliance on aerobic glycolysis, most tumor cells continue to metabolize at least some nutrients by oxidative phosphorylation. In fact, it is likely that in some cancer cells oxidative phosphorylation continues to generate much of the ATP required for biosynthetic reactions and cel-lular housekeeping functions.4 Attempts to quantitate ATP production experimentally in cancer cells have estimated that 80% of the ATP generated is derived from oxidative pathways, while 20% comes from glycolysis,27 and others report that up to 50% of the ATP in cancer cells can be derived from oxida-tive phosphorylation.28

Glucose is not the only substrate used by cancer cells for oxidative phosphorylation.27,29 In fact, some human cancers do not demonstrate elevated glucose uptake. It has been pro-posed that at least some of these cancers may be dependent on the amino acid glutamine as a primary source of carbon. Glutamine can be metabolized via two transamination reac-tions to the TCA cycle intermediate �-ketoglutarate (Fig. 8.4), and glutamine is required for proliferation of many cancer cells.30 In addition to glucose and glutamine, other nutrients have been shown to be important in some tumors. Several clinical studies have demonstrated that some human cancers show increased uptake of acetate by positron emission tomog-raphy (PET) scan using carbon-11 (11C)-acetate as a tracer

(see below).31 Acetate can be converted to acetyl-coA and serve as a precursor for lipid synthesis.32 When production of lipids from glucose is blocked by inhibiting ATP citrate lyase, an enzyme required to convert glucose to cytosolic acetyl-coA, acetate can completely rescue lipid synthesis and cell growth. Acetate is not thought to be a major nutrient available to can-cer cells in patients, but may refl ect an increased dependence of some cancer cells on lipid metabolism. Other enzymes involved in lipid metabolism have been linked with cancer progression,33,34 however, the exact mechanisms by which lipid metabolism promotes malignancy are not clear.

Nutrients such as amino acids and iron are also important for some tumors.35,36 Cachexia, or the loss of body mass that cannot be reversed by increased nutrition, is associated with the late stages of some cancers. Cachexia is poorly understood, but in cancer patients it is characterized by the loss of adipose tissue and muscle mass.37 This may refl ect a derangement in whole body metabolism to supply specifi c nutrients to the can-cer. Understanding how nutrients other than glucose contrib-ute to cancer biology remains an active area of investigation.

IMAGING CANCER METABOLISM IN PATIENTS

The characteristic increased glucose uptake of cancer cells has been exploited to image cancer in the clinic. The glucose analogue 2-deoxyglucose is permeable to glucose transport-ers and trapped in cells when phosphorylated by hexokinase (Fig. 8.2). The 2-deoxyglucose-6-phosphate is unable to be further metabolized,38,38 and thus 2-deoxyglucose-6-phosphate

A B

FIGURE 8.6 Early metabolic changes on 18F-fl uro-2-deoxyglucose position emission tomography/computed tomography (FDG-PET/CT) are highly predictive of fi nal treatment response. Fused coro-nal FDG-PET/CT images in a 44-year-old woman with stage IIA Hodgkin’s lymphoma at presenta-tion (A) and after two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemo-therapy (B). The tumor seen in the mediastinum and bilateral neck shows intense avidity for the glucose analogue FDG prior to therapy consistent with increased glucose uptake in (A). Although a residual tumor mass is still seen on CT after two cycles of ABVD chemotherapy (B), it is no longer FDG-avid, and the patient has been in remission for over 2 years since completion of therapy. Normal FDG uptake and excretion is seen in the stomach, heart, and urinary tract, respectively. (Image cour-tesy of Tricia Locascio, Katherine Zukotynski, and Annick D. Van den Abbeele, Department of Imaging, Dana-Farber Cancer Institute.)



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accumulation can be used to assess the rate of glucose uptake into cells. By conjugating the positron emitting isotope fl uo-rine-18 (18F) to 2-deoxyglucose, the uptake of glucose can be measured in patients using PET.40 18F-fl uro-2-deoxyglucose (FDG)-PET is used widely in the clinic to visualize tumors. The current use of FDG-PET is primarily as a staging tool for cancers, however, it is also sometimes used to characterize lesions observed by other imaging modalities. FDG-PET is also increasingly being used as a marker of response to ther-apy (Fig. 8.6). At least for some treatments, there is mounting evidence that decreased uptake of FDG by PET scan following therapy is a predictor of clinical effi cacy.41,42

In the clinic, FDG-PET scan can be used to classify tumors. Although many tumors are visible by FDG-PET scan, some tumors do not display elevated FDG uptake. This illustrates that different tumors can display distinct metabolic phenotypes related to their genetic background or site of origin. As dis-cussed above, some tumors rely on nutrients other than glucose. For instance increased 11C-acetate uptake has been observed by PET in prostate tumors that do not demonstrate elevated signal on FDG-PET scan.43 However, increased uptake of 11C-acetate is also seen in some benign prostate conditions, so whether 11C-acetate uptake defi nes a characteristic of some prostate cancers or refl ects the underlying biology of the prostate gland remains to be determined.44 New methods to image tumor metabolism by PET or magnetic resonance imaging (MRI) are being devel-oped. If successful, such efforts will better defi ne distinct meta-bolic phenotypes in patient tumors.

GENETIC EVENTS IMPORTANT FOR CANCE R INFLUENCE

METABOLISMHuman cancer occurs as a consequence of genetic events that promote the inappropriate proliferation of cells.45 These events lead to the expression of oncogenes or the loss of tumor suppressor genes that contribute to tumor formation and progression. Although alterations involving specifi c onco-genes or tumor suppressor genes are hallmarks of specifi c malignant phenotypes, many of these genetic events are found in numerous types of cancer. These genetic changes occur in

diverse cellular signaling and transcriptional pathways, and it is unclear how the various mutations converge to allow inap-propriate cell growth and proliferation. One common down-stream consequence of these genetic changes is altered cellular metabolism.

Efforts to understand the predisposition to malignancy dis-played by von Hippel-Lindau (VHL) syndrome patients identi-fi ed a link between cancer genetics and the regulation of cell metabolism.46 VHL syndrome results when patients inherit one mutated copy of the VHL gene, leading to a spectrum of benign and malignant tumors including clear cell carcinoma of the kid-ney. In these patient’s tumors, the normal VHL allele is lost, con-sistent with VHL acting as a tumor suppressor gene. Subsequent work demonstrated that the VHL gene product is also com-monly lost in sporadic renal clear cell carcinomas. Although the exact mechanism by which VHL loss leads to renal cell carci-noma and other tumors is not known, loss of VHL has a pro-found impact on metabolic gene regulation, and these effects are thought to be important in the pathogenesis of these cancers.

The VHL gene encodes the substrate recognition compo-nent of a ubiquitin E3 ligase.46 As an E3 ligase, the VHL protein-containing complex facilitates the transfer of ubiquitin to spe-cifi c target proteins to effect their degradation. Among the targets of the VHL protein is the hypoxia-inducible transcrip-tion factor-1� (HIF-1�) (Fig. 8.7). HIF-1� levels are regulated by oxygen tension.21,47 In the presence of oxygen HIF-1� is hydroxylated. The hydroxylated form of HIF-1� is recognized by VHL, leading to ubiquitination and degradation of the pro-tein. When oxygen is absent, or when VHL is lost, HIF-1� protein accumulates, dimerizes with HIF-1�, and promotes the transcription of a number of hypoxia inducible genes. These genes include factors that promote angiogenesis to improve tissue blood supply as well as glucose transporters and most of the enzymes in glycolysis. Thus, inappropriate HIF-1� activation leads to the characteristic increased glucose uptake and glycolysis that is observed in cancer. HIF-1� accu-mulation is a direct consequence of VHL loss, providing a link between the loss of a tumor suppressor gene and the altered metabolic phenotype of malignant cells.

Increased expression of HIF-1�-regulated genes is found in many different types of cancer and correlates with poor patient prognosis.48 Expression profi ling of transformed cells demon-strates that metabolic genes are among the most strongly

PI3KLow Oxygen

VHL Loss

Increased Succinate

Glucose Uptake/

Metabolism &

Angiogenesis

Proteasome

VHLUB

UB

UB

OH

HIF-1α HIF-1α HIF-1β

HIF-1α

HIF-1α

α-ketoglutarate

Succinate

HIF-1α HIF-1β

O2

CO2

OH

FIGURE 8.7 Transcription of many genes related to metabolism and angiogenesis is con-trolled by hypoxia-inducible transcription factor-1� (HIF-1�). HIF-1� levels are regulated by translational control downstream of phos-phatidylinositol-3-kinase (PI3K) signaling and by the rate of proteosomal degradation. HIF-1� is marked for degradation by hydroxylation. This hydroxylation is sensitive to O2, �-ketoglu-tarate, and succinate levels. The von Hippel-Lindau (VHL) protein facilitates ubiquitination and degradation of hydroxylated HIF-1�. Thus, PI3K signaling, hypoxia, succinate levels, and the presence of VHL all infl uence transcription of HIF-1a target genes. (Figure courtesy of Brooke J. Bevis, Whitehead Institute.)



up-regulated groups of genes.49 Loss of expression of the HIF-1� target genes correlates with response to therapy in at least some models of cancer, suggesting that these genes are important for malignant cell proliferation and survival. Importantly, increased expression of glucose transporters and glycolytic enzymes under the control of HIF-1� are seen even in non-hypoxic tumors expressing VHL.49,50 HIF-1� also drives expression of pyruvate dehydrogenase kinase, a nega-tive regulator of the pyruvate dehydrogenase complex that catalyzes pyruvate entry into mitochondria.51,52 Thus HIF-1� expression can promote aerobic glycolysis in cancer cells.

Transcription factors other than HIF-1� can promote the expression of metabolic enzymes. Expression of ChREBP-1, mondoA, and SREBP-1 has also been shown to be important in some cancers. ChREBP-1 is a key regulator of glycolytic enzyme expression and can promote anabolic metabolism.53 MondoA is a key regulator of metabolic gene expression and coordinates glucose and glutamine metabolism.54 Enzymes involved in cho-lesterol and lipid metabolism are controlled by the SREBP tran-scription factor,55 and SREBP is induced as a result of oncogenic signaling.56 Finally, increased HIF-1�−mediated gene transcrip-tion is observed in many cancers in the absence of hypoxia or VHL loss.48 This has been attributed to increased production of HIF-1� that results from aberrant signaling downstream of phosphatidylinositol-3-kinase (PI3K), as discussed below.

Many Genetic Drivers of Cancer Increase Nutrient Uptake

Highlighting the central role that altered cellular metabolism plays in tumor biology, one shared consequence of many genetic events that promote cancer is increased glucose uptake and metabolism. Transformation is associated with elevated glucose uptake.57,58 Activation of the PI3K signaling pathway is a common event in human cancer, and PI3K has a well-described role in glucose metabolism through its action as a proximal mediator of insulin signaling that leads to glucose uptake.59 However, even in noninsulin dependent tissues, PI3K signaling can regulate glucose uptake and utilization and appears to drive this process in many cancers.

PI3K is activated downstream of receptor tyrosine kinases and transfers a phosphate to the membrane lipid phosphatidylinositol.59,60 When phosphorylated on the 3-posi-tion (to generate phosphatidylinositol-3,4,5-triphosphate), the phosphorylated inositol species can recruit other kinases to the membrane, including the protein kinase AKT (also known as protein kinase B). Activation of AKT leads to increased expression of glucose transporters such as Glut1 and enhances the proximal steps in glycolysis by increasing hexokinase and phosphofructokinase activity (Fig. 8.4). Point mutations that result in growth-factor independent activation of PI3K are found in many human cancers, including a sig-nifi cant percentage of breast, ovarian, and colon cancers.60 Loss of phosphatases that degrade the phosphatidylinositol species, leading to activation of signaling downstream of PI3K, are also common events in human cancer. Loss of the phosphatidylinositol-3,4,5-triphosphate-3-phosphatase PTEN is frequently observed in human cancer, including a sizable fraction of prostate cancer, breast cancer, glioblas-toma, and melanoma.60 Similarly, loss of INPP4B, a phos-phatidylinsolitol-3,4-bisphosphate-4-phosphatase, is seen in breast and ovarian cancers.61

In addition to regulating glucose uptake and capture through activation of AKT, PI3K activation also leads to increased expres-sion of enzymes in glucose metabolism via increased production of HIF-1�.62 Activation of the mTOR kinase, an event down-stream of PI3K signaling, induces expression of HIF-1� target

genes at least in part through increased translation.63–65 This activation of glucose metabolism results in the propensity for tumors with PI3K activation to be FDG-avid on PET scan. Small molecules that disrupt PI3K signaling lead to decreased glucose uptake by the tumors as measured by FDG-PET, and the ability to inhibit tumor FDG uptake correlates with tumor regression in PI3K-driven animal models of cancer.66

Increased glucose uptake and metabolism are also charac-teristic features of tumors with activated RAS signaling. RAS activation is frequently observed across human cancers. Glucose deprivation has been shown to drive the emergence of cells harboring an activating mutation in the KRAS gene.67

This has led to the hypothesis that increased glucose uptake via Glut1 expression is a major downstream mediator of RAS signaling that contributes to tumorigenesis. In addition to increasing glucose transporter expression, RAS activation leads to increased phosphofructokinase activity and stimulates the proximal metabolism of glucose (Fig. 8.4).14 Though less well studied, activating mutations in B-Raf, a kinase down-stream of RAS, also result in increased nutrient uptake.67

Mutations in receptor tyrosine kinases cause increased signal-ing through both the RAS and PI3K signaling pathways and also cause increased nutrient uptake.

Increased MYC expression is another frequent event in human cancer. MYC is a transcription factor, and many of the transcriptional targets of MYC include metabolic genes.50 MYC regulates the transcription of enzymes involved in glucose uptake and metabolism, including LDH, the enzyme responsi-ble for production of lactate. MYC-dependent tumors are sen-sitive to LDH inhibition.68 MYC also directly and indirectly regulates the uptake of glutamine,30,69 and MYC-dependent cancer cells are particularly sensitive to glutamine withdraw-al.70 Genetic alterations that lead to activation of MYC, PI3K, RAS, Raf, and receptor tyrosine kinases are among the best-understood driver events in human cancers. These seemingly disparate genetic alterations that promote cancer and occur across cancer types all lead to a converging metabolic pheno-type characterized by enhanced cell autonomous nutrient uptake (Fig. 8.8).

Tumor Suppressor Gene Products Also Influence Cellular Metabolism

Many tumor suppressor gene products also regulate metabo-lism (Fig. 8.8). Loss of p53 function is among the most frequent genetic events in human cancer, and p53 expression infl uences metabolism (Fig. 8.4).71 TIGAR, a gene induced by p53 expres-sion, redirects glucose fl ux from glycolysis to the pentose phos-phate pathway and promotes apoptosis.72 Phosphoglycerate mutase, a glycolytic enzyme negatively regulated by p53, inhib-its cell senescence.73 Excess production of reactive oxygen spe-cies also promotes cellular senescence and apoptosis, and many of the genes induced by p53 are involved in adaptation to oxi-dative stress and regulation of mitochondrial metabolism.74,75

The tumor suppressor LKB1 is also involved in the adaptive response to cell stress. LKB1 is a kinase that is required for acti-vation of adenosine monophosphate (AMP)-activated protein kinase (AMPK).76–78 AMPK responds to cellular energy stress (by sensing a low ATP/AMP ratio) and initiates a signaling cas-cade that promotes increased ATP production and decreased ATP consumption.79 AMPK also inactivates the mTOR protein kinase that acts as an important integrator of cell growth sig-nals with nutrient availability to regulate cell growth.80,81 In addition to AMPK, mTOR is regulated by PI3K signaling through the TSC1/TSC2 complex.82,83 TSC1 and TSC2 are tumor suppressor genes that indirectly infl uence metabolism via effects on mTOR signaling.84 mTOR is also regulated by amino



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acids such that the mTOR growth promoting activity is turned off under conditions of poor nutrient availability.85 The response to cell stress also includes the induction of autophagy to catabo-lize existing cellular material for energy production and removal of damaged organelles.86,87 Both mTOR signaling and nutrient stress regulate autophagy induction,88 but the role of autophagy in cancer remains unclear. The use of mTOR inhibitors is gain-ing increasing use in the clinic to treat various cancers, yet the relationship between mTOR, autophagy, metabolic stress, and cancer is incompletely understood.

Other genetic changes may be important to promote ana-bolic metabolism in cancer cells. For instance, all cancer cells appear to express the M2 isoform of the glycolytic enzyme pyruvate kinase (PK-M2).16,89 PK-M2 is normally expressed during embryonic development and is unique among the human pyruvate kinase isoforms in that it is regulated by tyrosine kinase signaling.15 This regulation of PK-M2 by growth factor signaling promotes aerobic glycolysis in cells89 and may consti-tute a molecular switch that allows cancer cells to metabolize glucose in a manner conducive to proliferation only when growth signals are present.

Mutations in Metabolic Enzymes Can Lead to Cancer

Altered cell metabolism can directly contribute to transforma-tion as mutations in metabolic enzymes can promote cancer. Inherited loss of function mutations in genes that encode pro-teins involved in the proper assembly or function of the mito-chondrial succinate dehydrogenase complex account for the subtypes of hereditary paraganglioma.90–94 Succinate dehydro-

genase (SDH) is an enzyme complex in the TCA cycle that catalyzes the oxidation of succinate to fumarate and supplies electrons to the mitochondrial electron transport chain.11

These mutations lead to decreased activity of SDH and succi-nate accumulation. The enzymes that carry out the oxygen-dependent hydroxylation of HIF-1� also convert �-ketoglu-tarate to succinate as part of their catalytic mechanism.95 Thus, accumulation of succinate leads to a decrease in HIF-1� hydroxylation, less HIF-1� degradation, and increased expres-sion of HIF-1� target genes (Fig. 8.7). Loss-of-function SDH mutations that cause this “pseudohypoxia” account for some cases of renal cell carcinoma expressing normal amounts of VHL, supporting the notion that HIF-1� expression is an important event in some cancers.93,95 Mutations in the TCA cycle enzyme fumarate hydratase (FH), which further metabo-lizes the fumarate produced by the succinate dehydrogenase complex, have also been described in renal cell carcinoma, leiomyomas, and other rare cancers.95–97

Isocitrate dehydrogenase (IDH) is another metabolic enzyme that is mutated in cancer.98–100 All reported cases of IDH muta-tion occur in only one allele, with preservation of wild-type enzyme expression from the other allele (Fig. 8.9).101 These mutations are frequent events in low-grade gliomas and second-ary glioblastomas.98,99,102

Interestingly, IDH-mutant gliomas

appear to have a better prognosis,98 suggesting that gliomas har-boring these mutations represent a distinct subset of glioma with a different response to therapy or natural history. IDH muta-tions are also found in patients with acute myelogenous leuke-mia (AML) and myelodysplastic syndrome (MDS) and defi ne a distinct clinical subset of these patients without other cytoge-netic abnormalities.100,103–105 IDH mutations have been proposed to be an early event in the pathogenesis of both AML and glioma.101,105,106 Sporadic mutations in other cancers have also been reported. A summary of IDH mutations in human cancer is shown in Table 8.1, and the frequency of IDH1 or IDH2 muta-tions in specifi c cancer subsets is shown in Table 8.2.

The IDH mutations associated with cancer involve point mutations in the active site of either IDH1 or IDH2.98–100,105 Other less frequent mutations involving residues in IDH1 have been reported in rare cases,105,107–109 however, whether these represent driver mutations or polymorphisms remains unclear. IDH1 mutations involve R132, and mutations in the analo-gous active site residue (R172) are found in IDH2. This argin-ine (R132 in IDH1, R172 in IDH2) coordinates the CO2 group that is lost during oxidative decarboxylation of isocitrate to �-ketoglutarate.110 The other mutated residue in IDH2 (R140) makes contacts with the same CO2 group in the IDH2 active

P

P

Glucose

Glutamine

Catabolic

Metabolism

PI3K

RTK

Ras

Raf

Myc

p53

LKB

Autophagy

Anabolic

Metabolism

FIGURE 8.8 Many of the oncogenic events thought to drive cancer development infl uence metabolism by increasing glucose or glutamine uptake. Other genetic events and processes associated with cancer also infl uence metabolism but do not necessarily cause elevated nutrient uptake. Rather, these events appear to be involved in reprogramming of metabolism away from catabolic metabolism and promote the ana-bolic pathways necessary for cell growth and proliferation. Both the increase in nutrient uptake and the reprogramming of metabolism to support anabolism are required for cancer cells to proliferate. RTK, receptor tyrosine kinase.

R132VR132SR132LR132CR132H

IDH1

OR

IDH2

R172WR172GR172SR172MR172K

R140WR140LR140Q

FIGURE 8.9 Mutations in isocitrate dehydrogenase-1 or -2 (IDH1 or IDH2) reported in human cancer are all monoallelic and involve a single residue in IDH1 or one of two residues in IDH2. (Figure adapted from Lenny Dang and Shengfang Jin, Agios Pharmaceuticals.)



TA B L E 8 . 1

MUTATIONS IN IDH1 AND IDH2 REPORTED IN HUMAN CANCERS

Cancer Type IDH1 (Ref.) IDH2 (Ref.)

Glioma R132H (98,102,150–153) R172K R132C (98,154,155) R172M (99) R132S (98,99) R172G R132G (99) R172S (155) R132L R132V (102)

Acute myeloid leukemia (AML) R132H (103) R140Q (103,105) R132G (105) R140W (105) R132C (107) R140L R172K (107)

Myelodysplastic syndrome (MDS) R132H (156) R140Q) R132C R140L (104) R132L (104) R172K R132G

Acute lymphoblastic leukemia (ALL) R132C (153)

Prostate cancer R132H (153) R132C

Colorectal cancer R132C (98)

Paragangliomas R132C (157)

Thyroid cancer R132H (109)

Table provided by Lenny Dang and Shengfang Jin, Agios Pharmaceuticals. IDH, isocitrate dehydrogenase.

TA B L E 8 . 2

FREQUENCY OF IDH1 AND IDH2 REPORTED IN HUMAN CANCERS

Tumor Classification IDH1 Mutated (%) IDH2 Mutated (%)

GLIOMASecondary glioblastoma (grade IV)Diffuse astrocytoma (grade II)Oligodendroglioma (grade II)Oligoastrocytoma (grade II)Anaplastic astrocytoma (grade III)Anaplastic oligodendroglioma (grade III)Anaplastic oligoastrocytoma (grade III)Primary glioblastoma (grade IV)Primitive neuroectodermal tumor (grade IV)Giant cell glioblastoma (grade IV)Pediatric glioblastoma (grade IV)Pilocytic astrocytoma (grade I)Pleomorphic xanthoastrocytoma (grade II)Compiled from references: (98, 99, 102, 106, 150, 153, 155, 158–161)

HEMATOLOGIC MALIGNANCIESAcute myeloid leukemia (AML), allAML, normal cytogeneticsAML, abnormal cytogeneticsMyelodysplastic syndrome/myeloproliferative neoplasmB-acute lymphoblastic leukemiaCompiled from references: (100, 104, 105, 107, 108, 162–164)

*,Less than 50 cases reported, too few to determine percentage mutated.IDH, isocitrate dehydrogenase; — indicates no reported cases.Table provided by Patrick S. Ward and Craig B. Thompson, University of Pennsylvania.

73–8859–8868–8250–9452–7860–8643– 78 3–16 6–33

***—

4.4–9.1 7.1–16.2

0–5.41.1

2.0

—0.92.31.30.93.43.4—————*

15.419.3–19.4

—5.8

—



MO

LE

CU

LA

R B

IOL

OG

Y O

F C

AN

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R

site.105 All three mutations result in an alteration of enzyme activity that decreases the enzyme’s ability to oxidatively decarboxylate isocitrate to �-ketoglutarate, but increases enzyme activity to reduce �-ketoglutarate. In the mutant enzymes, this reduction does not lead to incorporation of CO2 to make isocitrate, but instead produces 2-hydroxyglutarate (2HG).105,107,110 Because IDH mutations are monoallelic and the neomorphic activity acquired by the mutant enzyme is slow relative to the normal wild-type enzyme in these cells, the normal interconversion of isocitrate and �-ketoglutarate is not dramatically altered, and the main consequence of these muta-tions is 2HG production (Fig. 8.10).105,107,110 The 2HG is pro-duced in low levels in normal cells as an error product of vari-ous TCA cycle enzymes; however, in IDH mutant tumors 2HG accumulates to very high levels and has been linked with the pathogenesis of the disease.110 Accumulation of 2HG has been demonstrated in rare patients with hereditary loss of the enzyme that degrades 2HG,111 and gliomas have been described in a subset of these patients.112 Mutations in IDH1 have been reported to result in HIF-1� accumulation,113 how-ever, the relationship among IDH mutation, 2HG accumula-tion, and HIF-1� accumulation remains unclear.

Recurrent mutations in yet another metabolic enzyme have recently been reported in colon cancer.114 These are inactivating mutations of an enzyme involved in glucosamine metabolism, and signaling involving glucosamine-based protein modifi cations has been suggested to be important in cancer.115 The exact mech-anism by which the shunt from glucose to glucosamine impacts cellular metabolism and cancer remains to be determined.

TARGETING METABOLISM TO TREAT CANCER

The mechanisms by which cancer metabolism is regulated and how this regulation is impacted by genetic alterations known to be critical for cancer survival suggest cellular metabolic depen-dencies that could be exploited for cancer treatment. In fact, one of the fi rst successful chemotherapies targeted folate metabo-lism. The observation that folate could enhance blood cell prolif-eration ultimately lead to the development of antifolates as che-motherapeutics.116 Other active chemotherapeutics target purine metabolism. Although these agents are now thought of as “cyto-toxic,” they target metabolic dependencies of tumor cells and continue to play an important role in modern cancer therapy.

New therapies are being explored that directly or indirectly target cancer metabolism. A large fraction of human cancer is dependent on aberrant signaling through the PI3K/AKT path-way, and agents that target this pathway are being actively tested in the clinic.117 The growing evidence that cancer cells depend on elevated glucose metabolism suggests that targeting key metabolic control points important for aerobic glycolysis might also be effective cancer therapies. Recent evidence sug-gests that drugs developed to treat metabolic diseases such as diabetes may provide a benefi t to patients with cancer. A num-ber of retrospective clinical studies have found a benefi t to the widely used diabetic drug metformin (Glucophage) both in the primary prevention of cancer as well as improved outcomes when used with other cancer therapies.118–120 The exact mech-anism by which metformin lowers blood glucose levels is not completely understood; however, metformin decreases gluco-neogenesis in the liver. Recently, metformin was discovered to be an activator of AMPK, and this effect was shown to be critical for inhibiting gluconeogenesis in the liver.121 In addi-tion, metformin has been shown to inhibit mitochondrial complex I and impair oxidative phosphorylation in cells.122,123 Inhibition of oxidative phosphorylation and the subsequent decrease in energy charge (ATP:AMP ratio) is likely how met-formin activates AMP kinase.

Recently, two separate clinical studies have shown a reduc-tion in cancer-related mortality with metformin use.118,119 This effect appears to be independent of blood glucose level as patients with similar glucose levels treated with insulin do not derive the same benefi t as patients taking metformin. Another study reported that diabetic patients on metformin had a higher pathological complete response to neoadjuvant therapy for breast cancer than diabetic patients receiving other glucose lowering therapies.120 Studies exploring metformin use for cancer therapy in numerous preclinical cancer models have suggested that these compounds may be selectively toxic to cancer cells with specifi c genetic backgrounds,123–125 however, these compounds may also infl uence cancer therapy via their systemic effects on glucose metabolism. Increased insulin-like growth factor-1 (IGF1) levels, which accompany poor glucose control, may promote cancer growth.126,127 Particularly in tumors with mutations that lead to activation of the PI3K pathway,128 at least one effect of metformin may be to decrease the effect of IGF1 on cell growth.129

The success of FDG-PET scans as a diagnostic and predic-tive tool for treatment response in many cancers has lead some

Glutamine

Glucose

Pyruvate

Acetyl-CoA

IDH3

NADH NADPH

NADP+ NADP+

NADPH

NAD+ 2HG 2HG

IDH2

WT

IDH1

WT

IDH2

mutant

IDH1

mutant

Citrate

Isocitrate

α-ketoglutarate α-ketoglutarate

Citrate

Isocitrate

CO2 CO

2CO

2

FIGURE 8.10 Human cancer associ-ated mutations in isocitrate dehydroge-nase-1 or -2 (IDH1 or IDH2) results in the neomorphic production of the metabolite 2-hydroxyglutarate (2HG). Because a wild-type version of both IDH1 and IDH2 remain even in IDH mutant cells, the normal activities of these enzymes persist despite the activ-ity of the mutant enzyme to produce 2HG. The subcellular localization and enzymatic activities for all of the IDH isoforms is shown. (Figure courtesy of Patrick S. Ward and Craig B. Thompson, University of Pennsylvania.)



to suggest that targeting enzymes involved in metabolism may be an effective therapy.130 Specifi c therapies may be possible for patients with mutations in metabolic enzymes that contribute directly to tumorigenesis.130,131 In addition, metabolism may be suffi ciently different in some cancers to target pathways such as glycolysis. 2-deoxyglucose is a competitive inhibitor of proxi-mal glucose metabolism.38,39 Cells exposed to suffi cient amounts of 2-deoxyglucose undergo growth arrest or apoptosis,132–134 and preclinical models show 2-deoxyglucose may potentiate standard cytotoxic chemotherapy.135 2-deoxyglucose can be administered to patients,136 but when given in combination with radiation therapy to glioblastoma patients at doses suffi -cient to limit glucose metabolism in cancer cells signifi cant toxicity is observed.137–139 However, other agents to block glu-cose metabolism are being investigated. 67,130,140–146 Whether a sufficient therapeutic window exists to target glycolysis directly remains to be determined.

It is possible to alter cellular metabolism in a tumor with-out causing unacceptable toxicity in patients. Dichloroacetate has been used to treat lactic acidosis in non-cancer patients with rare inborn errors of mitochondrial metabolism. 147,148

Dichloroacetate reduces lactate production by inhibiting pyru-vate dehydrogenase kinase (PDK),149 a negative regulator of the mitochondrial pyruvate dehydrogenase complex (PDH). PDH catalyzes the fi rst step in mitochondrial metabolism of pyruvate (Fig. 8.4).11 Thus, PDK inhibition that leads to acti-vation of PDH diverts pyruvate away from lactate production. Because lactate production is the hallmark of aerobic glycoly-sis, it has been proposed that dichloroacetate might be a useful agent to target cancer metabolism.148,149 Dichloroacetate is tolerated by cancer patients at dosages that can alter mito-chondria in patient tumor samples. Studies are ongoing to understand the impact of these metabolic alterations on tumor biology and clinical outcome.

Selected References

The full list of references for this chapter appears in the online version.

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