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Metabolism of Cancers
Robert J. Gillies, Ian Robey, and Robert A. Gatenby
24S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 6 (Suppl) • June 2008
TABLE 1
Incidence of Cancers and Mortality in U.S. Adults and
Children (All Races, per 100,000)
Adults Children
Death Death
Cancer type Incidence (%) Incidence (%)
Breast 130 19 NR NR
Colorectal 58 31 NR NR
FIGURE 1. Sidney Weinhouse. Lung 71 86 NR NR
(Courtesy of the Office of Prostate 170 20 NR NR
NIH History, National Insti- Stomach 10 40 NR NR
tutes of Health.) Pancreatic 10 96 NR NR
Urogenital (female) 47 36 NR NR
Leukemia 11 64 4.2 27
iologic niches must be discussed. In adults, there are essen- Lymphoma 20 30 1.6 17
Central nervous system 6 68 2.8 36
tially 2 types of tissues: epithelia and stroma. These are Neuroblastoma NR NR 0.9 40
behaviorally distinct tissues in that epithelia are highly Soft-tissue sarcoma 2.9 37 0.8 36
polarized and will grow in monolayers along a single axis, Bone 0.8 46 0.6 39
whereas stromal cells are phenotypically plastic, highly
motile, and can grow in response to morphogenetic gradients NR 5 not reported.
in any direction. Neoplasia of epithelia gives rise to carci- Data are from Cancer Facts and Figures, 2007 (American Cancer
nomas, such as breast, lung, pancreatic, prostate, or mela- Society).
noma, which have a high prevalence in adults. Stromal
cancers include sarcomas, gliomas, and liquid cancers, which
are more prevalent in the young (Table 1). In mature organs, than their cell of origin (14). This plasticity has significance
epithelia and stroma are physically separated by a BM made to cancer, as epithelial cells undergo a transition to a mesen-
of laminin, collagen IV, proteoglycan, and various growth chymal phenotype (an epithelial-to-mesenchymal transition)
factors and proteases (13). On one side of the BM, epithelial concomitant with their adoption of an invasive phenotype
cells grow in a mono- or bilayer of polarized cells, forming (15).
a duct that is contiguous with the outside world. On the other Development of carcinomas proceeds through distinct
side of the BM lies a stroma of connective tissue containing stages, as shown for colorectal cancer in Figure 5. The initial
fibroblasts, muscle, blood, and lymphatic vessels, which are genetic changes result in hyperplasia that progresses into
constantly remodeling (Fig. 3). Epithelial and stromal com- dysplasia within the lumen of the ducts. The dysplastic
ponents are established during embryogenesis from the condition, known as carcinoma in situ (CiS), or adenoma in
3 primordial germ cell layers of ectoderm, endoderm, and the case of colorectal cancer (CRC), progresses through
mesoderm that give rise to skin and nervous system, epithe- early, middle, and late phases yet still remains separated from
lia, and mesenchymal tissues, respectively (Fig. 4). Epithelia the stroma by the BM. Once the BM is breached, the cells
are generally derived from endoderm and ectoderm (dermis),
and stromal components are generally derived from me-
soderm. However, there is significant plasticity, and cell
fates are more dependent on spatial and conditional factors
make contact with the stroma to become a locally invasive proliferation barriers that evolving tumor populations en-
cancer. Further evolution is then required to allow the counter during their progression through carcinogenesis.
avascular microscopic disease to ‘‘partner’’ with the stromal
cells to promote angiogenesis and extracellular matrix re- Early Carcinogenesis
modeling. The invasive tumor cells, either directly or indi- The initial steps in carcinogenesis result in the transfor-
rectly via lymphatics, enter the bloodstream (intravasation). mation of normal epithelium to epithelium that is hyperplas-
A small fraction of these are able to extravasate and colonize tic, which results in cellular proliferation away from the BM,
distant sites, forming metastatic cancer. forming multilayer growth. We argue that, whatever the
Although significant differences among cancers exist, mechanism, these steps have to involve a deregulation of
there are some phenotypic elements common to all cancers, cell–cell and cell–matrix growth inhibitory interactions that
which are known as the ‘‘hallmarks of cancer’’: evading maintain the epithelia in a monolayer (17). Despite the
apoptosis, self-sufficiency in growth signals, insensitivity to importance of this step, the molecular mechanisms of initi-
antigrowth signals, tissue invasion and metastasis, limitless ation and promotion have remained elusive. It is commonly
potential to replicate, and sustained angiogenesis (16). We assumed that this step requires genotoxic stress, as cancers
propose that all commonly observed traits must confer can be initiated by chemicals that form DNA adducts (18).
specific adaptive advantages to cancer cells as they progress. Hence, radiation damage or inflammation-derived reactive
In other words, the hallmarks of cancer can be viewed as the oxygen species, combined with deficiencies in DNA repair,
phenotypic adaptation necessary to overcome all of the could also be initiating events. The initiating events likely
26S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 6 (Suppl) • June 2008
involve mutational activation of proto-oncogenes to onco- genetic alterations such that, for example, the incidence of
genes. Proto-oncogenes are normal cellular constituents that mutated ras increased from ;7% in early adenoma to ;55%
are involved in regulation of cell cycle and proliferation that, in intermediate, ;60% in late, and ;45% in invasive carci-
when activated, can give rise to unregulated growth, a nomas. Thus, it can be proposed that this mutation caused
hallmark of cancers. These can be activated through chemical cells to be more aggressive but that it was not necessary once
carcinogens, and some have homologs in RNA viruses. cells metastasized. These data support a clonal, evolutionary
Fusion of these 2 approaches with characterization of the model of carcinogenesis, such as that diagrammed in Fig. 6.
src oncogene by Varmus and Bishop was awarded the Nobel Environmental or endogenous factors induce genotoxic
Prize in 1986 (19). Table 2 lists common classes of proto- stress, which is normally repaired. However, with relative
oncogenes and the incidence of their representative onco- frequency, genetic alterations can be fixed in a cell (green)
genes. that will render it more proliferative. These expand and ac-
Chronic activation of pro-proliferative pathways would cumulate successive mutations (blue, red) that each contrib-
normally be opposed by the action of proliferation suppressor ute to development of a more aggressive cancer phenotype.
gene products that include cell cycle checkpoint genes This model represents current thinking, which is decidedly
(20,21). Hence, carcinogenesis is also associated with loss genocentric.
of function of tumor suppressor genes, some of which are Although this model alludes to the clonal expansion of
listed in Table 2. Typically, humans that are heterozygous for tumor cells as an evolutionary process, it virtually ignores
tumor suppressor genes have increased susceptibilities to the altering environmental landscape that leads to selection.
cancers after loss of heterozygosity. This heritable loss of The interaction between gene products and their environ-
function can occur through genetic mutations, through chro- ment in carcinogenesis has been the subject of recent
mosomal loss, or through epigenetic mechanisms, such as models from our group and others.
DNA methylation (22).
Microenvironment During Cancer Progression
Genetic Models of Carcinogenesis As preinvasive cancers proliferate and evolve, their mi-
The developmental progression of many cancers can be croenvironment is altered, as shown in Figure 7. Normal
evaluated and predicted according to their complement of epithelia are single cell layers growing on a BM surface,
induced oncogenes and repressed tumor suppressor genes. surrounded by stroma. These cells are adjacent to blood
Fearon and Vogelstein were the first to document this for vessels on the other side of the BM and so are well perfused
colorectal cancer, CRC (23). In this work, they identified with serum growth factors and nutrients. Hence, the prolif-
distinct stages of CRC from normal epithelium to metastatic eration of normal epithelial cells into the lumen must be
disease (Fig. 5). In samples from each of these stages, they constrained through cell–cell and cell–BM interactions. If
identified chromosomal and genetic alterations associated epithelial cells die, they are sloughed off into the lumen. The
with each stage. As cancers progressed, they accumulated lack of cell–cell contact will induce an adjacent cell to divide
TABLE 2
Representative Oncogenes and Tumor Suppressor Genes
PDGF 5 platelet-derived growth factor; EGFR 5 epidermal growth factor receptor; GBM 5 glioblastoma multiforme; APC 5
adenomatosis polyposis coli; CML 5 chronic myelogenous leukemia; VHL 5 von Hippel–Lindau disease.
28S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 6 (Suppl) • June 2008
acid production, and the effect of this on acidification of the
interstitial pH can be exacerbated by reduced perfusion in the
periluminal volume of in situ lesions (34,35). Acid pH has
been shown to increase invasive behavior (36–42). Thus, one
mechanism of cancer progression may involve elevated
glycolysis leading to acidosis that leads to invasion. How-
ever, although it is often observed, according to the equiv-
alence principle, elevated glucose consumption need not be a
prerequisite for cancers to transition from a CiS to an invasive
carcinoma. Alternative mechanisms can be envisioned
whereby cells can acquire an invasive phenotype without
glycolysis and acidosis.
Transitioning to an invasive cancer involves breaking
through the BM, giving epithelial cells direct access to the
vasculature and the stroma for the first time in their natural
history (vide supra). It is at this time, through unknown
FIGURE 8. Periodic acid–Schiff staining of hepatic colorectal
mechanisms, that these cancer cells undergo an epithelial-to- metastasis.
mesenchymal transition. These mesenchymelike cells are more
highly motile than their epithelial precursors and can be char-
acterized by expression of stroma-specific markers (43–45). produce H1. As these H1 are glucose-derived, then it follows
With direct access to the stroma, cancer cells can disperse that successful metastatic cancers consume high amounts of
through the heme or the lymphatic vasculature. Migration of glucose, to produce acid. This appears to be the case, as
these cells through lymphatic vessels results in colonization evidenced from 18F-FDG PET.
of the draining lymph nodes in a characteristic pattern. Thus, 18F-FDG
PET OF AEROBIC GLYCOLYSIS IN
in breast cancer, the draining axillary lymph nodes are
METASTASES
generally the first to become involved and are thus known
as sentinel nodes. Either directly or indirectly via lymphatics, Perhaps no other imaging test has had as much impact on
invasive cancer cells eventually find themselves in the the fundamental understanding of human cancer as has 18F-
bloodstream. It has been estimated that a 1-cm3 tumor will FDG PET. Although 18F-FDG avidity can be highly vari-
shed as many as 106 cancer cells per day into the blood (46). able in primary cancers, it has an extremely high sensitivity
Through specific endothelial cell interactions, cancer cells and specificity for metastases. This was comprehensively
will lodge in ectopic sites that are specific for different reviewed in 2001 (51) and discussed within the context of
cancers. The occurrence of metastases in specific organs led drug development in 2005 (52). Table 3 shows a recapitu-
to Paget’s ‘‘seed–soil’’ hypothesis, wherein the host organ lation of data from Gambhir et al. (51). Although the ranges
provides factors necessary for the growth of the metastatic are broad, the average sensitivity and specificity are high.
lesion (47). Despite intensive study for more than a century, Generally speaking, once a cancer progresses to distant
these factors remain unknown. metastases beyond lymph nodes, the sensitivity and spec-
In order to form successful metastases, the cancer cells ificity are greater than 90% (except for prostate cancers).
must survive, colonize, and grow in the host tissue. Survival These data are mirrored in Table 4, which includes studies
is a rare event, estimated at less than 1 cell per 1,000, although that are more recent than the 2001 review. Note that the
this may be dependent on the relative population of cells with sensitivity of cervical and prostate lymph node metastases
‘‘stemlike’’ properties (48). Colonization results in micro- are not high, but most other metastatic carcinomas have
metastases, which can be abundant and are less than 1.0 mm sensitivities and specificities of greater than 90%. As dis-
in diameter. The switch from micro- to macrometastases is in- cussed in previous publications, reductions in sensitivity are
completely understood but likely involves neoangiogenesis primarily caused by small lesions with motion, and reduc-
(49). tions in specificity can be due to local inflammation (53).
The acid-mediated invasion hypothesis proposes that suc- The common observation of enhanced 18F-FDG uptake
cessfully invasive tumor lesions export glucose-derived H1, indicates that it is a fundamental property of metastases
which leads to degradation of the extracellular matrix, (vide infra). This could suggest a commonality of mecha-
thereby allowing more efficient invasion of the cancer into nisms, yet this does not appear to be the case, as described
a host organ. This has been shown both theoretically (11) and later in this article.
empirically using window chambers (50). Figure 8 shows
periodic acid–Schiff staining of a biopsy from an invasive MOLECULAR MECHANISMS REGULATING GLUCOSE
metastatic colon cancer in the liver, showing a ‘‘halo’’ of less UPTAKE
dense extracellular matrix surrounding the lesion. Hence, we Glucose metabolism is essential to generate both catabolic
propose that successful metastatic cancers are those that can and anabolic precursors. Thus, it is not surprising that there
Sensitivity Specificity
No. of No. of
Cancer metastasis patients Range Average patients Range Average
are a multitude of pathways that activate glucose metabolism. cancers continue to consume glucose at high rates, even in the
It has long been assumed that the primary function of glucose presence of adequate oxygen, an effect first described by
is to provide energy to the cell in the form of ATP as an Warburg (Fig. 10) in 1930 (59).
alternative to mitochondrial respiration. Hence, a major Hence, ‘‘aerobic glycolysis’’ can be described as a cancer
regulator of glucose consumption is the availability of oxy- hallmark (60). Elevated rates of 18F-FDG uptake are strongly
gen, which was first described by Pasteur (Fig. 9) in 1856 negatively correlated to patient outcome in many cancers
(54,55). Thus, glucose consumption is higher in hypoxic (51,61), as are elevated lactate levels (62,63). Hence, ele-
tissues (55,56). Although 18F-FDG uptake can be elevated in vated glucose consumption may play an essential role in
response to hypoxia, seminal studies comparing 18F-FDG cancer progression. Genes of glycolysis are ubiquitously
uptake with retention of hypoxic markers (18F-misonidazole, overexpressed in cancers (64) (65). Thus, it is of fundamental
18F-pimonizaole) have shown little correlation between hy- importance to understand the molecular mechanisms regu-
poxia and 18F-FDG uptake in humans (57,58), indicating that lating the metabolic switch to aerobic glycolysis. The bio-
TABLE 4
Detection of Metastases by 18F-FDG PET
30S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 6 (Suppl) • June 2008
messengers such as cAMP (75,76). The HK-2 isoform is
notable because it is reversibly bound to mitochondria and is
a key regulator of glycolysis and survival in multiple cancers,
where it is a poor prognostic indicator (77–79). When bound
to mitochondria, HK-2 preferentially uses mitochondrion-
generated ATP to phosphorylate glucose very efficiently
(80). Drugs, such as clotrimazole, can induce a dose-
dependent detachment of hexokinase from mitochondria and
inhibit glycolysis (81). Notably, the binding site for HK-2 on
the mitochondrial membrane is the voltage-dependent anion
channel (VDAC), a mitochondrial protein (porin) involved
FIGURE 9. Louis Pasteur. in exchange of metabolites for oxidative phosphorylation,
as well as the release of cytochrome c during intrinsic apo-
chemical uptake mechanisms of 18F-FDG were reviewed by ptosis cascade (82). This is one of many instances wherein
elevated glycolysis is correlated to apoptosis resistance,
Pauwels et al. in 2000 (66). As discussed later in this article,
although delineation of a function relationship between these
there does not appear to be a single mechanism for control of
aerobic glycolysis in all cancers. A conceptual framework for 2 processes has been elusive.
interpreting this observation is discussed at the end of this
Mitochondrial Defects
section.
Given the importance of glucose in energy metabolism, it
is perhaps not surprising that mitochondrial defects would
GLUT and HK result in increased ‘‘aerobic’’ glycolysis (83). Thus, even
The 2 major proteins that are unequivocally associated under normoxic conditions, the cell machinery sensing the
with increased 18F-FDG uptake in cancers are the glucose presence of oxygen would be ineffective. Indeed, Warburg’s
transporter, primarily GLUT-1, and hexokinase, primarily original hypothesis stated that increased aerobic glycolysis
HK-2 (67–69). Thus, insights can be obtained by examining was due to a deficiency in respiration (84). Despite elegant
the molecular controls over the expression and activity of and sophisticated methods (at the time), he was not able to
these proteins. Given the physiologic importance of glucose prove his hypothesis during his lifetime. However, with more
uptake, it is not surprising that GLUT-1 expression is modern molecular techniques, mitochondrial defects have
regulated by several hormones, both extracellular, such as been correlated with increased aerobic glycolysis. For
insulin, prolactin, follicle stimulating hormone, noradrena- example, increased 18F-FDG uptake in vivo and glucose
line, and vasopressin, and intracellular, such as testoster- consumption in vitro correlate strongly to a loss of mito-
one, estrogen, progesterone, glucocorticoids, retinoic acid, chondrial markers, such as the F1-ATPase, in lung cancers
and thyroxin (70,71). Some of these effects are likely me- (85). Mitochondrial impairment is often seen in clear cell
diated via activity of the SP1 transcription factor (72,73) or renal carcinomas (86). In colorectal cancers, transcriptome
cyclic adenosine monophosphate (cAMP) levels (74), both and proteome analyses have observed that expression of gly-
of which can be dysregulated in cancers. colytic and tricarboxylic acid cycle proteins were inversely
In addition to control by glucose levels, HK-2 expression proportional (87–89). Also, in breast cancer, the metabolic
can be affected by hormones such as insulin, and second proteome undergoes a pronounced shift toward an enhanced
glycolytic phenotype concurrent with a profound reduction
in the F1-ATPase levels with a classification sensitivity of
approximately 97% to overall and disease-free survival (90).
Notably, the expression of F1-ATPase alone allowed identi-
fication of a subgroup of breast cancer patients with signif-
icantly worse prognosis. In more empiric studies, directed
depletion of mitochondrial DNA resulted in reduced electron
transport activity and increased glycolysis (91), or accumu-
lated mutations in the NADH dehydrogenase subunit 2, ND2,
led to increased HIF-associated aerobic glycolysis (92).
The molecular signals between mitochondria and glycol-
ysis are likely identical to the ‘‘retrograde signaling’’ in-
volved in the Pasteur effect. A central mechanism appears to
involve the activity of pyruvate dehydrogenase (PDH), which
is responsible for importing pyruvate into the mitochondria
as a substrate for the tricarboxylic acid cycle (also known as
FIGURE 10. Otto Warburg. the Krebs cycle or the citric acid cycle). The mammalian
32S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 6 (Suppl) • June 2008
translocate to the inner leaflet of the plasma membrane (150). F26bP increases the rate of glycolysis by allosterically
(132). The PTEN (phosphatase and tensin homolog deleted activating phosphofructokinase. F26bP levels are regulated
on chromosome 10) tumor suppressor is a PIP3 phospha- by a family of bifunctional phosphofructo-2-kinase/fructose-
tase that acts to reconvert PIP3 back to PIP2. It is inactive 2,6-bisphosphatases (PFKFB1–PFKFB4). Especially rele-
through deletion or mutation in many cancers, resulting in vant is isozyme 3, PFKFB3, which is activated by mitogenic
constitutively high levels of PIP3. stimuli and steroid hormones, and is constitutively expressed
Akt (protein kinase B) is a 57-kDa Ser/Thr kinase that by several human tumor cells, possibly through activation by
exists in 3 isoforms, with Akt-1 being most associated with the oncogene, Ras (151,152). The gene for PFKB3 is also
epithelium-derived cancers (133). Akt contains a plekstrin HIF-induced (153) and is found to be markedly elevated in
homology domain and preferentially binds to PIP3, which multiple aggressive primary neoplasms, including colon,
translocates it to the plasma membrane where it is phos- breast, ovarian, and thyroid carcinomas (154). Once tran-
phorylated on Thr308 and Ser473 by membrane kinases, such scribed, the protein can be activated by phosphorylation
as the phosphoinositide-dependent kinase, PdK-1 (134,135). (155). Inhibition of inducible PFK-2 protein expression
In breast cancers, the Akt pathway is activated in late DCIS decreases 5-phosphoribosyl-1-pyrophosphate, a product of
and in the majority of invasive breast cancers, and this is the pentose phosphate pathway (PPP) and an important
moderately correlated to PTEN loss (136,137). precursor for nucleic acid biosynthesis (156).
Activated P-Akt phosphorylates several targets involved
in aerobic glycolysis and antiapoptosis. Phosphorylated Akt Ras
stimulates glucose consumption in transformed cells with- The Ras superfamily of low-molecular-weight GTP-
out affecting the rate of oxidative phosphorylation (138). binding proteins includes H-Ras, K-Ras, and N-Ras, which
When the BAD protein is phosphorylated by Akt, it is are all active in human cancer (157). Ras activation in tu-
prevented from inhibiting the antiapoptotic BCL-2 and mors is frequently the result of a point mutation in the Ras
BCL-XL proteins (139). The activation of Akt by trans- gene (158), which leads to constitutive activation of down-
forming mutations, such as the amplification of HER-2/neu stream effector enzymes that regulate cell cycle progression,
in breast cancer and the formation of the BCR/ABL fusion survival, and migration. One of the most studied signaling
gene in chronic myelogenous leukemia, seems to be essen- pathways is through serine/threonine kinase Raf, which
tial for the transforming activity of these oncogenes (140). phosphorylates and activates a cascade of mitogen-activated
High expression of Akt activity makes cells more suscep- protein kinases (MAPKs) and cell cycle regulatory proteins
tible to death after glucose withdrawal, causing this to be (159,160). Additionally, Ras interacts directly with the cat-
termed ‘‘glucose addiction’’ (141). alytic subunit of type I PI3k (161,162), which stimulates the
activity of Akt (163).
p53/TIGAR/PFKB3 Among their many functions, Ras proteins have been
p53 is a tumor suppressor transcription factor that is implicated in the regulation of aerobic glycolysis (164–167).
mutated in up to 80% of cancers (142). Its physiologic Pharmacologic inhibition of Ras (164,168) with farne-
function is to produce cell cycle arrest or apoptosis in re- sylthiosalicylate or dominant-negative expression (169) result
sponse to DNA damage (143,144). It is dysfunctional in in the inhibition of Ras signaling to both the Raf/MEK/ERK
mutated forms and hence fails to induce checkpoint arrest in and the PI3k pathways (170), which result in a substantial
response to genotoxicity, thus increasing the accumulation of downregulation of glycolytic enzymes, including Glut-1.
potentially carcinogenic mutations (145). It has only recently Likewise, stable transfection with H-Ras promotes increased
been recognized that wild-type p53 plays a key role in regu- glucose uptake and lactate production (171–173). In these
lating glucose consumption (146). For example, p53-induced cases, H-Ras upregulated 6-phosphofructo-1-kinase (PFK-1)
apoptosis involves the systematic activation of multiple activity through induction of F26bP (171,173). Increased
pathways, including those involved in glucose metabolism PFK-1 activity in rat kidney cells stably transfected with Ras
(147). Wild-type p53 can repress GLUT1 transcription, and and human papillomavirus type 16 E7 oncoprotein leads to
mutations within the DNA-binding domain of p53, which are higher levels of fructose-1,6-bisphosphate, which allosteri-
usually associated with malignancy, impair this repressive cally activates the tetramerization of pyruvate kinase type
effect, thereby resulting in increased glucose metabolism and M2 (174). This results in increased AMP levels, which
cell energy supply (148). Like MYC, p53 also directly affects suppressed DNA synthesis and cellular proliferation, prob-
mitochondrial biogenesis. For example, wild-type p53 af- ably though activation of AMPK (165,175,176). Similar
fects the synthesis of cytochrome c oxidase 2, which has been results were observed in mouse fibroblasts bearing K-Ras
ascribed to being responsible for aerobic glycolysis in p53- codon-specific mutations (167).
deficient tumors (149).
The effects of p53 on glycolysis may be mediated by a Teleology
recently characterized protein, the TP53-induced glycolysis The aforementioned observations are consistent with the
and apoptosis regulator (TIGAR), which inhibits glycolysis unsurprising conclusion that uptake and use of glucose can
by modulating fructose-2,6-bisphosphate (F26bP) levels be controlled by a multitude of factors, all of which have
Bioenergetics
The dominant perception of energy metabolism in cancer
has been that ATP production is fueled by oxidative metab-
olism of glutamine and glucose and by the anaerobic metab-
olism of glucose through the Embden–Meyerhof pathway
(EMP) of glycolysis, and that this ATP is needed to support
a high level of oncogene-induced proliferation. However,
the available data are equivocal. In a careful review of the
available data from careful mass balance studies, it was
FIGURE 11. Regulation of glycolysis. Kinase reactions are
shown in purple, dehydrogenases are shown in red, and concluded that, on average, cancers derive 17% of their ATP
regulatory elements are shown in blue. Abbreviations are as in turnover from EMP glycolysis, whereas normal tissues de-
text. e- Xport 5 electron transport. rive around 20% (185). The total ATP turnover in MCF-7
34S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 6 (Suppl) • June 2008
breast cancer cells is 80% oxidative and 20% glycolytic and equivalent in terms of their ability to maintain an oxidizing
the entire contribution from glucose (glycolysis and oxida- cytoplasm in the face of anaerobiosis (196). NADPH can be
tion) to total ATP turnover was about 23%, or twice that of used for reducing glutathione for antioxidant defenses and
glutamine (186). Uterine, lung, breast, liver, and skin cancers there is evidence that PPP activity makes cells more resistant
all derive a significant amount of energy from oxidative to reactive oxygen species–induced apoptosis (197). NADPH
phosphorylation (187). A review of the mass balance of the is also a necessary cofactor for fatty acid synthesis and,
end products of metabolism (lactate and CO2) showed that indeed, increased rates of fatty acid synthesis have been
acid loads were approximately equally split between oxida- observed in many cancers (198,199). NADH can be used to
tive and nonoxidative products (188). The mole stoichiom- reduce pyruvate to lactate or to make ATP via mitochondrial
etries are 1 ATP per lactate and 5–6 ATP per CO2, suggesting oxidative phosphorylation (200). Entry into the upper (oxi-
that approximately 15% of the ATP turnover was derived dative) part of the PPP is regulated by glucose-6-phosphate
from glycolysis. Thus, although the role of glycolysis in dehydrogenase (201). The lower, nonoxidative part of the
providing ATP is often invoked as a rationale for its increase PPP is controlled by transketolase enzyme reactions. A
in cancers, such a claim is not substantiated by available mutated transketolase transcript (TKTL1) has been detected
evidence. Hence, if increased ATP production is not the in human malignancies and correlated to poor patient out-
reason for selection of a glycolytic phenotype, other sequelae come in CRC (202). Thus, the PPP-derived metabolites
of glucose metabolism might be. include antioxidants, nucleic acid precursors, and substrates
for fatty acid synthesis, any one of which could be selected to
PPP enhance cancer cell survival.
It has been alternatively proposed that some cancers,
notably colorectal cancers, upregulate the PPP to convert Acidosis
glucose to pyruvate (189–194). Figure 13 illustrates the Whether glucose is metabolized aerobically or anaerobi-
relationship between the PPP and EMP, which differ primar- cally, the secreted end products are acids: CO2 and lactate,
ily in their redox products. The EMP produces NADH, respectively. CO2 is hydrated to (HCO321H1) in a reaction
whereas the PPP produces NADPH as well as ribose-5- catalyzed by CA. An extracellular CA isozyme, CA-IX, is
phosphate (195). The production of ribose-5P for nucleic upregulated by HIF and promotes this hydration to contribute
acid biosynthesis had been proposed as a rationale for the to extracellular acidification (203–205). Although the end-
increase in the PPP by Warburg. NADPH and NADH are product lactate is an acid, the H1 is actually produced at the
36S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 6 (Suppl) • June 2008
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