Seminars in Cancer Biology 30 (2015) 7987

Contents lists available at ScienceDirect

Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

Modeling metabolism: A window toward a comprehensive

interpretation of networks in cancer
a,b ,
Osbaldo Resendis-Antonio a, , Carolina Gonzlez-Torres a , Gustavo Jaime-Munoz
a,c
a,b

Claudia Erika Hernandez-Patino

, Carlos Felipe Salgado-Munoz
a

Laboratory of Human Systems Biology, Instituto Nacional de Medicina Genmica (INMEGEN), Mxico, DF, Mexico
Facultad de Medicina-UNAM, Mexico
c
Undergraduate Program in Genomic Sciences-UNAM, Cuernavaca, Mexico
b

a r t i c l e

i n f o

Keywords:
Cancer metabolism
Mathematical models
Systems biology: Constraint-based
modeling
P4 medicine

a b s t r a c t
Given the multi-factorial nature of cancer, uncovering its metabolic alterations and evaluating their implications is a major challenge in biomedical sciences that will help in the optimal design of personalized
treatments. The advance of high-throughput technologies opens an invaluable opportunity to monitor
the activity at diverse biological levels and elucidate how cancer originates, evolves and responds under
drug treatments. To this end, researchers are confronted with two fundamental questions: how to interpret high-throughput data and how this information can contribute to the development of personalized
treatment in patients. A variety of schemes in systems biology have been suggested to characterize the
phenotypic states associated with cancer by utilizing computational modeling and high-throughput data.
These theoretical schemes are distinguished by the level of complexity of the biological mechanisms that
they represent and by the computational approaches used to simulate them. Notably, these theoretical approaches have provided a proper framework to explore some distinctive metabolic mechanisms
observed in cancer cells such as the Warburg effect. In this review, we focus on presenting a general
view of some of these approaches whose application and integration will be crucial in the transition from
local to global conclusions in cancer studies. We are convinced that multidisciplinary approaches are
required to construct the bases of an integrative and personalized medicine, which has been and remains
a fundamental task in the medicine of this century.
2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction
Multiple roads lead to cancer, it can emerge as the result of
mutations in regulatory or signaling proteins [1], as well as the
imbalance of oxidative stress and anti-oxidative mechanisms [2],
or by the continuous exposition of cells to a given stimulus [3].
There are a myriad of causes for cancer, and the compounds or
conditions that stop or delay its progress in some circumstances do
not work in others. A variety of factors contribute to this complex
behavior, including the heterogeneity in cancer cell populations,
even in tumors from the same patient, a fact that directly reduces
the effectiveness and reliability of the drugs for treating the disease
[4,5]. Furthermore, with the advent of high-throughput (HT) and
Next Generation Sequencing (NGS) technologies, new biological
mechanisms that are typical of cancer cells have been discovered

Corresponding author. Tel.: +52 01 55 5350 1900.

E-mail address: oresendis@inmegen.gob.mx (O. Resendis-Antonio).

[6]. This scenery has created the need to develop new ways to interpret these data and elucidate their role in human diseases in a
coherent and systematic fashion. At this stage, a biological system
can be considered an interactive set of networks with components
and relations at different biological levels that are the causes by
which certain phenotype, functional or dysfunctional, emerges, see
Fig. 1.
Currently, understanding how these biological networks
orchestrate their activities to support cancer phenotypes is a
great challenge in medical science to prevent, suggest and predict
strategies with direct implications in clinical stages. Despite this
astonishing complexity which involves biological processes such
as signaling, regulation and metabolic networks, hallmark traits
have been suggested to characterize key processes in all human
cancers, such as proliferation, invasion and metastasis [1,7,8].
Arguably the most fundamental trait of cancer cells is their ability to sustain chronic uncontrolled proliferation [1]. Although it is
well accepted that this dysfunctional state is accompanied by a
rewiring of metabolic activity in the cell [9], it is not completely

http://dx.doi.org/10.1016/j.semcancer.2014.04.003
1044-579X/ 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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Fig. 1. Mechanisms of metabolic regulation in cancer cells. Cancer cells display a variety of alterations in metabolic pathways for building the precursors that cells need
to proliferate and sustain the anomalous state. Glycolysis, the TCA cycle and glutaminolysis, are a few pathways that guide the malignant transformation by covering the
metabolic demand of nucleotides, amino acids, lipids and other building materials that cancer cells need to proliferate. Enzymes with an important role in cancer are depicted
in the upper level of the gure (gray ovals), and metabolites participating in anabolic pathways are depicted in pink and orange arrows. These metabolic alterations are
modulated by a variety of mechanisms that involve other molecules, such as oncogenes, tumor suppressors and microRNAs. Examples falling in the rst category are given by
c-MYC, HIF-1 and P53, with activities that directly affect metabolic activity (green circles). c-Myc and HIF act in complexes with other proteins to modulate the expression of
glycolytic genes or enzymes. c-Myc specically stimulates glutaminolysis. P53 regulates the suppression of glycolysis through TIGAR and increases mitochondrial metabolism
via SCO2 (yellow circle), as depicted by the dashed blue arrows. In turn, these regulators modulate the expression of other target genes to enhance the cancer phenotype.
c-MYC and HIF-1 promote the expression of cell cycle proteins, and mutations in P53, denoted as P53* , inhibit apoptotic genes, as depicted by the dashed green arrows.
Moreover, the transcription of oncogenes and tumor suppressors can be controlled by the up-regulation of oncogenic miRNAs (red) or inhibitory miRNAs, see green arrows.
Simultaneously, metabolites can play an important role in epigenetic regulation, see yellow arrow. Furthermore, the stromal cells induce important metabolic changes to favor
cancer proliferation thought metabolic cross-talk (cyan arrow). GLUT1 Glucose transporter 1, HK-hexokinase, GLC Glucose, G6P Glucose-6 phosphate, F6P Fructose
1,6phosphate, PFK Phosphofructokinase, G3P Glyceraldehyde-3phosphate, 3PG 3-Phosphoglycerate, PEP Phosphoenol pyruvate, LDH Lactate dehydrogenase, PYR
Pyruvate, LAC Lactate, MCT1 Monocarboxylate transporter 1, MCT4 Monocarboxylate transporter 4, SLC1A5 Glutamine transporter, GLNGlutamine, GLU Glutamate,
CIT Citrate, ICIT Isocitrate, -KG--Ketoglutarate, SuCoA Succinylcoenzyme A, SUC Succinate, FUM Fumarate, MAL Malate.

clear how and which metabolic pathways differentially alters their

activities in cancer versus normal tissues [10,11].
The most studied metabolic alteration in cancer is the degradation of glucose via aerobic glycolysis, a less efcient pathway for
generating ATP compared with oxidative phosphorylation, despite

oxygen availability. This nding was reported almost a century ago

by Otto Warburg in his seminal studies of metabolism in cancer
cells [12]. Notably, studies in cancer biology have demonstrated
that cancer genes are intimately linked to the Warburg effect and
other metabolic alterations [13,14], see Fig. 1. There is evidence

O. Resendis-Antonio et al. / Seminars in Cancer Biology 30 (2015) 7987

that reprogramming signaling or regulatory networks in normal

cells induces the expression and activation of several enzymes that
form part of the metabolic pathways that promote proliferation
and survival in cancer cells [1517]. For instance, c-Myc regulates the expression of glycolytic genes, particularly enzymes such
as hexokinase (HK), phosphofructokinase (PFK), lactate dehydrogenase A (LDHA) and extracellular glucose transporter [1820].
Furthermore, c-Myc controls glutaminolytic pathways that promote the expression of glutamine transporters such as SLC1A5
and the expression of glutaminase (GLS) [21]. c-Myc has also been
implicated in the regulation of genes participating in mitochondrial
biogenesis [22]. Similarly, HIF-1 modulates the activity of some
enzymes involved in glycolytic metabolism at hypoxic conditions
[23,24]. Moreover, mutations in many types of cancer disrupt the
functional role of some tumor suppressors. For example, mutations
in P53 simultaneously promote glycolysis and inhibit mitochondrial respiration in cancer cells through genes such as TIGAR [25]
and SCO2 [26], see Fig. 1.c-Myc, HIF-1 and P53 are together involved
in other biological processes that sustain cancer. c-Myc and HIF1 form a complex with the protein MAX, and consequently, this
complex up-regulates the expression of cyclins (proteins involved
in of cell cycle). Conversely, mutated P53 promotes cancer by
down-regulating apoptotic genes [24,27]. In turn, the transcription
factors mentioned above are regulated by microRNAs (miRNAs),
small-noncoding RNAs of 1825 nucleotides in length [28]. miRNAs
typically reduce the translation and stability of target mRNAs by
specic base-pairing interactions, but in some cases, they can promote translation by indirect mechanisms [2830]. Some elements
of metabolic networks can affect other levels of regulation, which
adds another layer of complexity; for example, there is evidence
that metabolites can play an important role in epigenetic regulation [31], see Fig. 1. The above examples represent only a small
fraction of many cross-linking interactions at different biological
levels that are together responsible for cancer phenotype.
These different levels of biological information constitute one
aspect that determines metabolic capabilities in cancer cells, however the microenvironment also plays a relevant role in supporting
cancer phenotypes. Epithelial cancer cells have been shown to
induce a type of aerobic glycolysis in neighboring broblasts [32].
The proposed mechanism considers that cancer associated broblasts (CAF) produce high-energy metabolites such as lactate and
export them to the microenvironment. Then, epithelial cancer cells
can use these metabolites to fuel mitochondrial activity. This biochemical crosstalk between cell types is called the reverse Warburg
effect and induces a higher proliferative capacity in epithelial cancer cells [32]. These ndings reveal that the classical Warburg Effect
and the reverse Warburg effect are only the top of the iceberg on
metabolic alterations in cancer; there is thus an increased need
to understand how metabolic pathways in cancer can be altered
by environmental cells in a tissue specic context. To construct
a holistic view of this phenomenon, it is necessary to develop
systemic schemes capable of simultaneously: (1) representing biological knowledge in a mathematical language; (2) integrating HT
data; and (3) formulating and assessing metabolic predictions in
silico [33].
Signicant advances have been reported in understanding cancer metabolism through two parallel branches: experimentally
and computationally. A variety of biological assays in cancer
have discovered new metabolic changes that support growth and
proliferation [10,3437]. Additionally, new theoretical schemes
have been suggested to analyze, describe and predict cellular
metabolism at a genome scale level [38]. Although both branches
have been evolving, there remains a signicant challenge in
integrating them and improving our understanding of cancer
metabolism. In this review, we present some of the standard
formalisms to approach this problem. These methods represent

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a cornerstone for quantitatively interpreting and understanding

how cells alter their metabolism to acquire their malignant phenotype, an aim that could have strong implications for the design of
combined medical treatments in cancer that achieve more efcient
results [3941].
1.1. Conceptual schemes in cancer systems biology
Complexity in cancer is astonishing, and understanding the
metabolic mechanisms involved in this disease requires qualitative
and quantitative methods for systematically elucidating their principles [4245]. To this end, a variety of theoretical frameworks have
been suggested in the literature. These frameworks can be classied into a few categories: Topological, classical, stochastic, Boolean
and Constraint-based modeling, see Table 1. Although there is no
rule for the selection of the approach, it can be guided by at least
two criteria: (1) the type of biological question to be addressed;
and (2) the information that is available for the biological system.
In this section, we present some examples of different formalisms
that one can nd in the literature to analyze pathways in cancer.
This formalism represents schemes that are capable of uncovering
and highlighting some mechanisms in cancer at diverse levels of
detail and complexity.
2. Balancing complexity, biological detail and physiological
knowledge in cancer modeling
Given the complexity of biological systems, mathematical models are invaluable tool for integrating knowledge, understanding
mechanisms and predicting phenotypic behavior. In the construction of a model the balance between the degree of complexity and
the biological detail required should be addressed, Fig. 2. The strategy is guided by criteria such as the nature of the question and the
available data to validate the outputs and predictions of the model.
A variety of schemes have been applied to explore the behavior
of cancer cells in a broad spectrum of biological processes, such
as tumor growth, metabolism and treatment response [4549]. To
classify these schemes is not a trivial task, however they can be distinguished in terms of the mathematical formalisms used, the level
of its biological detail and the scopes of their predictions. Considering these items, we suggest the classication in Table 1 in which at
least six approaches are identied: Topological, Classical, Boolean,
Stochastic, Constraint-Based and Hybrid modeling.
2.1. Networks topology: unveiling structural organization in
metabolic networks
Cancer is a network disease resulting from alterations at diverse
biological levels, and topological analysis is a primary strategy to
survey the organization of the biological components and how
dysfunctional mechanisms can emerge. Thus, topological properties such as robustness, centrality, modularity, motif discovery or
minimal path-length provide clues concerning how organization
in biological networks can be associated with functional states
[5054].
Genome-scale metabolic reconstruction of human cells is a fastmoving area in which a framework can be established to distinguish
functional and dysfunctional states associated with diseases [38].
For instance, the most current version of the human metabolic
reconstruction (Recon) contains approximately 7400 reactions of
human metabolism, representing 123 metabolic pathways with
experimental and bioinformatics evidence in human cells [55,56].
Notably, this curated metabolic reconstruction constitutes a computational platform to explore in silico the metabolic phenotypes
that characterize human diseases, such as cancer, obesity, diabetes

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Table 1
Modeling approaches in systems with applications in cancer systems biology. This table summarizes some properties associated with each approach. The square colors in
the rst column label approach classication in concordance with Fig. 2.
Approach

Description

Characteristics

Limitations

Examples

Network topology

Mathematical scheme to
uncover the organizing
principles in biological
network

This approach has been able to

elucidate organizing principles
in biology by taking into
account a large number of
biological entities

Topological analysis is
independent of time and
physiological context

ProteinProtein interaction
networks
Gene co-expression
networks

Classical models

Basic models based on ODE

or PDE for analyzing
biological systems with few
parameters

Consider few parameters of the

system generally macroscopic
properties. Those parameters
are related by simple equations

The resolution of the

information is restricted to
the scale used for the
calculations

LoktaVolterra
competition model
Gompertz growth rate

Boolean models

Biological networks whose

components can be in one of
two states (0,1) and whose
dynamic are given by logical
rules

It is a proper framework to
analyze biological circuits
where parameters are not well
characterized

The computational cost

may rise depending upon
the complexity of the
network

Transcriptional regulatory
networks
Signaling networks

Stochastic models

Models describing
phenomena in a probabilistic
approach due to signicative
uctuations in the system

Eliminate the deterministic view of

the system and consider that noise
is fundamental to drive the
phenotype of a biological circuit

Computational simulation is a
time consuming process, it
increases according the
number of component rises

Master equation systems

Constraint-based models

Models based on genomic

base information (omics
technologies) and
physiological information.

With the combination of the

omics information model can
be built for exploring the
relationship between genotype
with phenotype.

The quality of the results

depends of the metabolic
reconstruction, which in
turn depend on available
omics data and
physiological information.

Flux balance analysis

Flux variability analysis

Hybrid models

Combine two or more type of

models and mixes different
levels of information.

These models become more

detailed and will be more
accurate with the

Some limitations can be

solved mixing models, but
instead others can appear.

Novel agent base models

Multi-scale models

and mental disorders. Given the relevance of this reconstruction, community strategies have recently been accomplished for
improving data quality and, consequently, the predictive scope of
in silico models [55]. Although topology is independent of time
and physiological context, this approach can elucidate the organizing principles that govern biological functions in cells [57]. For
example, the presence of functional modules has been reported
at different levels of biological information, ranging from regulatory to metabolic networks [58,59]. The concept of modules has
a variety of connotations: in gene expression analysis a module is understood as a co-expressed set of genes, whereas in a
networks context, a module is a set of nodes that have strong

Cellular automaton models

Agent base models

interconnections among them, characterized by a high clustering

coefcient [60]. Notably, although these concepts arise from different criteria, there have been some efforts to combine them and
explore their relationships [42,57,59]. One such approach is based
on the reconstruction of co-expression networks that allows to
study how genes coordinate their expression to sustain a specic
biological state [42,6164]. These methods have been applied in
a variety of tissues to elaborate hypotheses and identify drug targets [6570]. Notable observations have been made with this type
of analysis, such as the nding that up-regulated genes in lung
cancer present a high degree of connection and centrality [71].
Although the representation of biological data through networks

Fig. 2. Theoretical approaches used in cancer modeling. This gure depicts some theoretical schemes that have been applied to analyze different aspects of cancer by
combining different levels of complexity and detail. Models that represent high biological complexity and a low level of detail (reduced number of variables) are located to
the left of the gure. Conversely, models that represent low biological level of complexity and a high level of detail are located on the right side. The colors of the examples
are in concordance with those in the classication proposed in Table 1.

Table 2
Algorithms used to reconstruct tissue-specic metabolic networks. Different strategies have been used in the literature to construction of metabolic networks. These computational methods use a genome-scale reconstruction
and high-throughput data for nding the most coherent sub-network and are more consistent with HT data. This table describes some distinctive properties associated with some of these methods (IMAT, INIT, mCADRE and
MBA). Global properties on input data, the algorithm used, its classication and some applications are listed in this table.
Input data

Algorithm

Method
classication

Biological reconstructions

MBA

Generic metabolic reconstruction

Human curated tissue specic
pathways
transcriptomic, proteomic,
metabolomic

Heuristic

Liver model General cancer

metabolism Hereditary
Leiomyomatosis and Renal-Cell

INIT

Generic metabolic reconstruction

Protein information
Optional
Metabolome
transcriptome

Mixed
integer-linear
problem (MILP)

16 cancer models like breast, cervical,

colorectal, prostate, thyroid, liver, lung.
70 normal tissue/cell type brain (3
structures each divided in different
kind of cells), stomach, skin, among
others

mCADRE

Generic metabolic reconstruction

Transcriptome
Optional
metabolome

Optimization
with topology

26 cancers including breast, lung,

ovary, pancreas, uterus, among others
100 normal tissue type including 30
distinct brain structures, kidney, ovary,
cervix, thyroid, among others

iMAT

Generic metabolic reconstruction

Proteome, transcriptomic

The human curated tissue specic pathways reactions are classied as high
probability core reaction (CH ),and those reported by omics data as medium
probability core reactions (CM ).The idea behind it is to nd a model that has all
the CH , a maximal CM with minimal amount of extra reactions to ll the gaps.
These characteristics are represented in a score. Reactions are removed from a
generic model unless its exclusion prevent the activation of Chor reduces the
score. Given that the order in which reactions are removed might affect the
reconstruction, multiple candidate models are made. Then the reactions are
ranked according to the fraction of candidate models in which they were
present. Then a new model is made adding reactions accordingly to this rank
until a consistent model is reached
The proteome and/or transcriptome data is transformed to weights. Evidence
of expression will give a positive weight while absence will give a negative
weight.
This enable to make a constraint based model optimization where the number
of ux-carrying reactions associated with highly expressed enzymes is
maximized.
Unlike the others method If the metabolite is present in the tissue it allows a
small positive net accumulation
The expression data is used to infer genes (reactions) that are present or
absent. Those reactions that are constantly present in the samples form a core
that should be able to carry ux. The rest of the genes then are ranked
according to a combination of expression data and topology. For example if a
reaction is connected to a highly expressed reaction with few others
connections it probably should be included in the model. Then the generic
network is pruned given that ranking, unless its exclusion inactive a core
reaction or doesnt allow the cell to create key metabolites from glucose
The proteome and/or transcriptome data is transformed to numerical weights.
Evidence of expression will give a positive weight while absence will give a
negative weight. This enable to make a constraint based model optimization
where the number of ux-carrying reactions associated with highly expressed
enzymes is maximized. This algorithm assumes steady state, unlike INIT

Mixed
integer-linear
problem (MILP)

10 healthy tissues brain, heart, kidney,

liver, lung, pancreas, prostate, spleen,
skeletal muscle and thymus

O. Resendis-Antonio et al. / Seminars in Cancer Biology 30 (2015) 7987

Method

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has contributed to understanding the organization of dysfunctional pathways in cancer, some elements require more attention
to ensure proper interpretations. For instance, the topological analysis of metabolic networks is usually performed with only one
type of element as node, i.e. either reactions or metabolites, as a
consequence, there is a loss of information in these approaches.
To overcome this fact, the representation of metabolism through
bipartite networks and the development of methods to explore
their architecture are needed to uncover more general organizing
principles [72]. In a more general context, the proper networks representation and coherent interpretation of heterogeneous HT data
is a major challenge in the eld, achieving that will advance our
understanding of cancer in at least two ways: (1) uncovering organization principles by which cancer cells response and evolve in
tissues, and (2) applying this knowledge to contribute to the design
of optimal treatments for cancer. Both goals are closely linked to
the purposes of P4 medicine: predictive, preventive, personalized,
and participatory [46].
2.2. Classical mathematical models
In classical models of cancer, ordinary differential equations
(ODE) or partial differential equations (PDE) play important roles
in describing processes in cancer. A myriad of ODE models have
analyzed cancer from different points of view that range from
modeling the growth rate to calculating radiation doses in therapy [45]. In this classication, we include all those models whose
description is characterized by simplifying the biological system
through a reduced number of mathematical variables associated
with biological macroscopic properties (such as cell growth). A
seminal example falling into this classication is the Gompertz
model that reproduces growth rate measurements of cancer cells
in vitro [73]. Some other models based on ODE focus on analyzing drug responses in cancer cultures, which is an essential point
for the optimal design of therapeutic strategies [74]. A detailed
description of these methods and a broader number of examples
can be found in the literature [45]. Although these schemes have
contributed signicantly to understanding global mechanisms in
cancer such as growth rate, angiogenesis or metastasis they do
not include detailed information regarding specic alterations in
signaling, regulatory or metabolic networks underlying the phenotype. To integrate this latter information one necessary step is to
move toward genome-scale modeling, which allows us to explore
the relationship among topology, dynamic and biological functionality [42,75,76].
2.3. Boolean models
Another option for mathematical modeling in cancer is the
Boolean formalism, a proper scheme for analyzing the dynamic
behavior of transcriptional regulatory (TRN) or signaling networks
without the need to include kinetic parameters of the processes
involved. Given a network, this approach assumes that the expression of each biological element can be in one of two states (zero
or one) whose selection depends on a set of Boolean rules dened
by the state of the elements that regulate it. Hence, with network
topology and Boolean rules, the dynamic behavior of genes can be
obtained by applying the rules at discrete intervals of time in a synchronic or asynchronic fashion. As a result, the state of the entire
network changes at a discrete interval of time until it reaches a
xed or cyclic state associated with a phenotype state, known as an
attractor [77,78]. To ensure a proper simulation, one should dene
Boolean rules in terms of physiological knowledge [79]; however,
this information is often absent, and the combinatory effects of
the possible mechanisms signicantly increase as a function of the
number of regulators involved. Nevertheless, this approach is an

appealing formalism when one desires to explore global questions

about the dynamic organization of the network without an accurate
knowledge of mathematical parameters. In cancer studies, Boolean
networks have an important role to elucidate the mechanisms that
can sustain the cancer phenotype [8183]. Hence, to characterize
the biological prole in cancer, some methods applying a Boolean
scheme have explored the physiological states of transcriptional
regulatory networks (TRN) and its transition between normal and
dysfunctional states [80,81]. For instance, Fumi et al. constructed
a regulatory protein network integrating signaling pathways relevant in cancer and characterized its phenotypes through Boolean
states. The dynamic behavior of this network was such that the
attractors identied were associated with one of these physiological states: proliferative, quiescent or apoptotic. Furthermore,
gene mutation analysis carried out in silico evaluate the stability of
cancers attractors, and their simulations concluded that perturbations in some nodes elicit transitions among physiological states.
Notably, this nding suggest the possibility of controlling the disease evolution through the proper selection of targets along the
network [82].
2.4. Stochastic models
Biological processes in cells are constantly subject to internal
uctuations that are induced by the fact that concentrations of
some reacting species, such as transcriptional factors or metabolites, are extremely low inside the cell. Notably, biological circuits
have the ability to control this noise to favor certain phenotypic
states in cells according to the environmental conditions [83].
Noise functions at many levels of biological complexity, including
genetic regulatory mechanisms, metabolism and cell populations
[5,84,85]. Cancer cells are not excluded from this fundamental
effect, and a clear consequence is observed at a population level
where subspecies of cancer cells in a tumor coexist to potentially
favor and sustain the malignant phenotype [5]. To describe the consequences that noise has on cell activity, a stochastic approach is
more convenient than a deterministic one is more convenient to
elucidate the cellular mechanism by which noise is controlled [86].
For simplicity, we subdivided stochastic models into two types:
those that involve master equations; and those based on computational techniques such as cellular automaton or Monte Carlo
simulations. The rst scheme is frequently used to investigate analytically the statistical properties of biological circuits with a low
number of components in a homogenized mixture [86], where
as the second scheme overcomes these limits by computationally simulating interacting cells and biological networks subjected
to diffusion and population effects. Thus, cellular automaton has
been a central piece of the in silico models developed to simulate
heterogeneities in tumors by considering vascularization, genetic
mutations, metabolism and other biological processes [87]. For
instance, computational models have simulated tumor growth in
a set of interacting cancer cells in three dimensional space, where
gradient effects of key metabolites, such as glucose or oxygen, play
important factors in determining the disease. Overall, computational and mathematical models are complementary strategies for
understanding the mechanisms by which cells regulate intrinsic
and extrinsic noise and exploring how these biological mechanisms
contribute to the cancer phenotype.
2.5. Constraint-based modeling
New HT technologies have contributed signicantly to move
toward the integration and coherent interpretation of biological data. To this end, constraint-based modeling is a paradigm
in systems biology that uses a biochemical, genetic and genomic
(BiGG) knowledge base to explore the metabolic capabilities in

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microorganism and human tissues [8890]. Constraint-based modeling integrates computational methods that contribute to link
the fundamental relationship between the genotype and the
phenotype such as the identication of gene essentiality in
microorganisms [90]. One of the most applied methods is ux balance analysis (FBA) that calculate the ux through a metabolic
networks that ensure an optimal production of a specic physiological objective function, such as biomass production in a cell [91,92].
FBA has been successful in exploring the metabolic capacities of
cancer cell lines and identifying potential enzymes with therapeutic applications [33,93]. Given that most human diseases have
consequences in metabolic activity, constraint-based modeling is
considered a useful paradigm for understanding the mechanisms
involved in human diseases [56].
2.6. Hybrid models
Computational or mathematical models based on previous
schemes have guided our understanding of cancer at different levels of descriptions [44]. However, each approach has limits and to
move toward more realistic models, there is an interest in combining more than one scheme simultaneously. In most cases, this
integrative effort is propelled by the type of biological question to
be explored and the experimental technologies that can be used to
assess the conclusions. Currently, some strategies have been proposed to model metabolism in solid tumors by integrating different
levels of complexity, such as metabolism and tumor development
[94,95]. Advances in these types of modeling will create the opportunity to analyze the behavior of cancer cells with a greater level of
detail, including additional processes such as cell cycle, angiogenesis, metastasis and the effect of metabolite gradients during the
growth of solid tumors [95,96].
Overall, these paradigms constitute a valuable conceptual platform to characterize, understand and identify the mechanisms
sustaining cancer [43,97]. As soon as these approaches increase
their capacity to integrate biological information and heterogeneous high-throughput data, their role for moving toward an
integrative analysis of diseases and the development of personalized, preventive and predictive medicine will become evident in
clinical areas.
3. Tissue specic metabolism in cancer
Metabolic alterations are important avenues to propitiate
tumorigenesis and sustain cancer, these changes are heavily inuenced by the physiological and microenvironmental conditions
in human tissues. The human body integrates tissues with cells
that are specialized in several processes, such as storing fat, transforming carbohydrates, creating hormones and covering energetic
demands, among others functions. Tissues have physiological purposes, and when a disease emerges, its evolution is strongly
inuenced by tissue-specic metabolic ambiance [32,46,96,98]. For
instance, prostate cancer appears to prefer fatty acid metabolism
as a source of acetyl-CoA synthesis, whereas breast cancer appears
to prefer the consumption of glucose as a main carbon source to
sustain malignant phenotype [99,100]. Undoubtedly, the characterization of specic metabolic states in each tissue will contribute
to improve the descriptive and predictive capacities of computational models in different types of cancer. To address this
valuable and fundamental topic, there have been efforts to create manually curated networks (bottom-up scheme) for a couple
of human tissues [101104]. This type of reconstruction has the
advantage of including high-quality curated information regarding
biological networks. In recent years there has also been increased
interest in implementing computational algorithms that integrate

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high-throughput data to reconstruct tissue-specic metabolic

networks (top-down scheme). In the latter case, these computational methods start from a generic non-tissue-specic human
metabolic reconstruction such as Recon [55,56,100], EHMN [105]
or HumanCyc [106] and then select the subnetwork that better ts available biological data, such as microarrays, proteomics
or metabolomics. Currently, a variety of methods are available in
the literature, some of which have been applied to reconstruct the
tissue-specic metabolism in cancer [38,107]. Conceptual foundations and properties of some of these methods are briey
described in Table 2. Some differences can be highlighted among
them, for instance, INIT (Integrative Network Inference for Tissues) allows for a small net accumulation in the metabolic ux
to have a network able to synthesize molecules such as NADH,
rather than only being able to use such molecules as cofactors
[108]. Although the nal tissue-specic metabolic reconstruction
in mCADRE (context-specicity assessed by deterministic reaction evaluation) is constrained to produce universally important
metabolites from simple precursors such as glucose, INIT allows
the model to use precursors that the cell is known to take up [109].
Remarkably, the achievements of these methods constitute a rst
step toward a human metabolic atlas that will serve as a platform
to understand the metabolic alterations in cancer and potentially
design drugs and more effective treatments for patients.

4. Outlook
Mathematical models represent a simplied version of reality whose essential purpose is to help us handle and understand
the complexity of biological phenomena. Systems biology enables
the systematic analysis and coherent interpretation of highthroughput data, and this paradigm is fundamental to achieve a
better understanding of metabolic mechanisms involved in cancer in a coherent and systematic fashion. The implications of this
perspective should be reected in practical aims oriented toward
basic questions in biomedical sciences and clinical areas, such
as the uncovering of metabolic alterations in cancer, discovering
possible therapeutic targets or properly designing personalized
treatments. However, these aims are not trivial tasks, and one
important piece in the puzzle is the development of computational
modeling methods that are capable of integrating information
with HT data and physiological behavior in cancer. In this review,
we present some theoretical schemes that have contributed to
the understanding of key mechanisms in cancer. Each approach,
whether mathematically or computationally, has its own scopes
that are distinguished by their levels of complexity and the number of variables used to model the phenotype. Thus, systems biology
schemes are a paradigm to advance our knowledge of how cancer emerges in tissues and how to design novel drugs treatments.
Although there have been some important advances in this area, the
practical implication of these ndings for cancer therapy remains
a challenge in systems biology. This challenges addresses additional problems, such as the building of a common language to
communicate between the clinical and theoretical scientists and
preparing a new generation of scientists with skills in mathematics,
genomic and computational sciences. In our opinion, these strategies are required to move toward a quantitative description of
cancer phenotype that contributes to the advent of a systemic and
personalized medicine.

Funding
The authors thank the nancial support from the Research Chair
on Systems Biology-INMEGEN-FUNTEL Mexico.

86

O. Resendis-Antonio et al. / Seminars in Cancer Biology 30 (2015) 7987

Competing interests
The authors have declared that no competing interests exist.

References
[1] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell
2011;144(5):64674.
[2] Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals: metals
and antioxidants in oxidative stress-induced cancer. Chem Biol Interact
2006;160(1):140.
[3] De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grnberg H, Drake CG, et al. Inammation in prostate carcinogenesis. Nat Rev Cancer 2007;7(4):25669.
[4] Yap TA, Gerlinger M, Futreal PA, Pusztai L, Swanton C. Intratumor heterogeneity: seeing the wood for the trees. Sci Transl Med 2012;4(127):127ps10.
[5] Swanton C. Intratumor heterogeneity: evolution through space and time.
Cancer Res 2012;72(19):487582.
[6] Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I,
Pugh TJ, et al. Landscape of genomic alterations in cervical carcinomas. Nature
2014;506:3715.
[7] Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and nononcogene addiction. Cell 2009;136(5):82337.
[8] Shaw RJ, Cantley LC. Decoding key nodes in the metabolism of cancer cells:
sugar & spice and all things nice. F1000 Biol Rep 2012;4:2.
[9] DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab
2008;7(1):1120.
[10] Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt
stimulates aerobic glycolysis in cancer cells. Cancer Res 2004;64(11):38929.
[11] Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even
Warburg did not anticipate. Cancer Cell 2012;21(3):297308.
[12] Warburg O. On the origin of cancer cells. Science 1956;123(3191):30914.
[13] Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell
2008;134(5):7037.
[14] Kroemer G, Pouyssegur J. Tumor cell metabolism: cancers Achilles heel. Cancer Cell 2008;13(6):47282.
[15] Elstrom RL, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res
2004;64(11):38929.
[16] Dang CV. Links between metabolism and cancer. Genes Dev
2012;26(9):87790.
[17] Icard P, Lincet H. A global view of the biochemical pathways involved in
the regulation of the metabolism of cancer cells. Biochim Biophys Acta
2012;1826(2):42333.
[18] Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, et al. Deregulation of
glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem
2000;275(29):21797800.
[19] Dang CV, O Donnell KA, Zeller KI, Nguyen T, Osthus RC, Li F. The c-Myc target
gene network. Semin Cancer Biol 2006;16(4):25364.
[20] Shim H, Dolde S, Lewis BC, Wu C-S, Dang G, Jungmann RA, et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl
Acad Sci U S A 1997;94(13):665863.
[21] DeBerardinis RJ, Cheng T. Qs next: the diverse functions of glutamine in
metabolism, cell biology and cancer. Oncogene 2010;29(3):31324.
[22] Wonsey DR, Zeller KI, Dang CV. The c-Myc target gene PRDX3 is required for
mitochondrial homeostasis and neoplastic transformation. Proc Natl Acad Sci
U S A 2002;99(10):664954.
[23] Dang CV, Semenza GL. Oncogenic alterations of metabolism. Trends Biochem
Sci 1999;24(2):6872.
[24] Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control
of cancer cell metabolism and proliferation. Cancer Cell 2007;12(2):10813.
[25] Bensaad K, Tsuruta A, Selak MA, Vidal MNC, Nakano K, Bartrons R,
et al. TIGAR: a p53-inducible regulator of glycolysis and apoptosis. Cell
2006;126(1):10720.
[26] Matobsa S, Kang J-G, Patino WD, Wragg A, Boehm M, Gavroliva O, et al. p53
regulates mitochondrial respiration. Science 2006;312(5780):16503.
[27] Berge EO, Huun J, Lillehaug JR, Lnning PE, Knappskog S. Functional characterisation of p53 mutants identied in breast cancers with suboptimal responses
to anthracyclines or mitomycin. Biochim Biophys Acta 2013;1830(3):27907.
[28] Hatziapostolou M, Polytarchou C, Iliopoulos D. miRNAs link metabolic reprogramming to oncogenesis. Trends Endocrinol Metab 2013;24(7):36173.
[29] Rottiers V, Naar AM. MicroRNAs in metabolism and metabolic disorders. Nat
Rev Mol Cell Biol 2012;13(4):23950.
[30] Farazi TA, Hoell JI, Morozov P, Tuschl T. MicroRNAs in human cancer. Adv Exp
Med Biol 2013;774:120.
[31] Wellen KE, Thompson CB. A two-way street: reciprocal regulation of
metabolism and signalling. Nat Rev Mol Cell Biol 2012;13(4):2706.
[32] Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz
AK, Frank PG, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated broblasts and the tumor stroma. Cell Cycle
2009;8(23):39844001.
[33] Resendis-Antonio O, Checa A, Encarnacion S. Modeling core metabolism in
cancer cells: surveying the topology underlying the Warburg effect. PLoS ONE
2010;5(8):e12383.

[34] Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, et al.
PKM2 isoform-specic deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 2013;155(2):397409.
[35] Vander Heiden MG, Lunt SY, Dayton TL, Fiske BP, Israelsen WJ, Mattaini
KR, et al. Metabolic pathway alterations that support cell proliferation. Cold
Spring Harb Symp Quant Biol 2011;76:32534.
[36] Herling A, Kning M, Bulik S, Holzhtter H-G. Enzymatic features of the glucose metabolism in tumor cells. FEBS J 2011;278(14):243659.
[37] Sharma AK, Konig R. Metabolic network modeling approaches for investigating the hungry cancer. Semin Cancer Biol 2013;23(4):22734.
[38] Lewis NE, Abdel-Haleem AM. The evolution of genome-scale models of cancer
metabolism. Front Physiol 2012;4:237.
[39] Csermely P, Korcsmros T, Kiss HJM, London G, Nussinov R. Structure and
dynamics of molecular networks: a novel paradigm of drug discovery: a
comprehensive review. Pharmacol Ther 2012;138(3):333408.
[40] Kim HU, Sohn SB, Lee SY. Metabolic network modeling and simulation for
drug targeting and discovery. Biotechnol J 2012;7(3):33042.
[41] Asgari Y, Salehzadeh A, Schreiber F, Masoudi-Nejad A. Controllability in cancer metabolic networks according to drug targets as driver nodes. PLoS ONE
2013;8(11):e79397.
[42] Resendis-Antonio O, Hernndez M, Mora Y, Encarnacion S. Functional modules, structural topology, and optimal activity in metabolic networks. PLoS
Comput Biol 2012;8(10):pe1002720.
[43] Fisher J, Henzinger TA. Executable cell biology. Nat Biotechnol
2007;25(11):123949.
[44] Barillot E, Calzone L, Zinovyev A. Systems biology of cancer. Med Sci (Paris)
2009;25(67):6017.
[45] Barillot E, Calzone L, Hup P, Vert J-P, Zinovyev A. Computational Systems
Biology of Cancer. In: Chapman & Hall/CRC Mathematical and computational
Biology Series. CRC Press; 2013.
[46] Hood L, Auffray C. Participatory medicine: a driving force for revolutionizing
healthcare. Genome Med 2013;5(12):110.
[47] Araujo RP, McElwain DL. A history of the study of solid tumour growth:
the contribution of mathematical modelling. Bull Math Biol 2004;66(5):
103991.
[48] Deisboeck TS, Zhang L, Yoon J, Costa J. In silico cancer modeling: is it ready
for prime time? Nat Clin Pract Oncol 2009;6(1):3442.
[49] Batchelor E, Mock CS, Bhan I, Loewer A, Lahav G. Recurrent initiation: a
mechanism for triggering p53 pulses in response to DNA damage. Mol Cell
2008;30(3):27789.
[50] Barabasi AL, Oltvai ZN. Network biology: understanding the cells functional
organization. Nat Rev Genet 2004;5(2):10113.
[51] Alon U. Network motifs: theory and experimental approaches. Nat Rev Genet
2007;8(6):45061.
[52] Lacroix V, Cottret L, Thbault P, Sagot MF. An introduction to metabolic
networks and their structural analysis. IEEE/ACM Trans Comput Biol Bioinform 2008;5(4):594617.
[53] Almaas E. Biological impacts and context of network theory. J Exp Biol
2007;210(Pt 9):154858.
[54] Jeong H, Mason SP, Barabsi A-L, Oltvai N. Lethality and centrality in protein
networks. Nature 2001;411(6833):412.
[55] Thiele I, Swainston N, Fleming RMT, Hoppe A, Sahoo S, Aurich MK, et al.
A community-driven global reconstruction of human metabolism. Nat Biotechnol 2013;31(5):41925.
[56] Duarte NC, Becker SA, Jamshidi N, Thiele I, Mo ML, Vo TD, et al. Global reconstruction of the human metabolic network based on genomic and bibliomic
data. Proc Natl Acad Sci U S A 2007;104(6):177782.
[57] Hartwell LH, Hopeld JJ, Leibler S, Murray AW. From molecular to modular
cell biology. Nature 1999;402(6761 (Suppl.)):C4752.
[58] Ravasz E, Somera AL, Mongru DA, Oltvai ZN, Barabsi A-L. Hierarchical organization of modularity in metabolic networks. Science 2002;297(5586):15515.
[59] Resendis-Antonio O, Freyre-Gonzlez JA, Menchaca-Mndez R, GutirrezRos RM, Martinez-Antonio A, vila-Snchez C, et al. Modular analysis of the
transcriptional regulatory network of E. coli. Trends Genet 2005;21(1):1620.
[60] Segal E, Friedman N, Koller D, Regev A. A module map showing conditional
activity of expression modules in cancer. Nat Genet 2004;36(10):10908.
[61] Hanisch D, Zien A, Zimmer R, Lengauer T. Co-clustering of biological networks
and gene expression data. Bioinformatics 2002;18(Suppl. 1):S14554.
[62] Patil KR, Nielsen J. Uncovering transcriptional regulation of metabolism
by using metabolic network topology. Proc Natl Acad Sci U S A
2005;102(8):26859.
[63] Kharchenko P, Church GM, Vitkup D. Expression dynamics of a cellular
metabolic network. Mol Syst Biol 2005;1, 0016.
[64] Ihmels J, Levy R, Barkai N. Principles of transcriptional control in the metabolic
network of Saccharomyces cerevisiae. Nat Biotechnol 2004;22(1):8692.
[65] Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, et al. Analysis of
oncogenic signaling networks in glioblastoma identies ASPM as a molecular
target. Proc Natl Acad Sci U S A 2006;103(46):174027.
[66] Dudley JT, Schadt E, Sirota M, Butte AJ, Ashley E. Drug discovery in a multidimensional world: systems, patterns, and networks. J Cardiovasc Transl Res
2010;3(5):43847.
[67] Wu G, Stein L. A network module-based method for identifying cancer prognostic signatures. Genome Biol 2012;13(12):R112.
[68] Xu M, Kao M-CJ, Nunez-Iglesias J, Nevins JR, West M, Zhou XJ. An integrative
approach to characterize disease-specic pathways and their coordination: a
case study in cancer. BMC Genomics 2008;9(Suppl. 1):S12.

O. Resendis-Antonio et al. / Seminars in Cancer Biology 30 (2015) 7987

[69] Goh WW, Lee YH, Zubaidah RM, Jin J, Dong D, Lin Q, et al. Network-based
pipeline for analyzing MS data: an application toward liver cancer. J Proteome
Res 2011;10(5):226172.
[70] Higareda-Almaraz JC, Enriquez-Gasca MR, Hernndez-Ortz M, ResendisAntonio O, Encarnacion-Guevara S. Proteomic patterns of cervical cancer cell
lines, a network perspective. BMC Syst Biol 2011;5:96.
[71] Wachi S, Yoneda K, Wu R. Interactome-transcriptome analysis reveals the
high centrality of genes differentially expressed in lung cancer tissues. Bioinformatics 2005;21(23):42058.
[72] Montanez R, Medina MA, Sol RV, Rodriguez-Caso C. When metabolism
meets topology: reconciling metabolite and reaction networks. Bioessays
2010;32(3):24656.
[73] Laird AK. Dynamics of tumor growth. Br J Cancer 1964;13:490502.
[74] Lankelma J, Luque RF, Dekker H, Van den Berg J, Kooi B. A new mathematical
pharmacodynamic model of clonogenic cancer cell death by doxorubicin. J
Pharmacokinet Pharmacodyn 2013;40(4):51325.
[75] Jamshidi N, Edwards JS, Fahland T, Church GM, Palsson BO. Dynamic simulation of the human red blood cell metabolic network. Bioinformatics
2001;17(3):2867.
[76] Resendis-Antonio O. Filling kinetic gaps: dynamic modeling of metabolism
where detailed kinetic information is lacking. PLoS ONE 2009;4(3):e4967.
[77] Aldana M, Balleza E, Kauffman S, Resendiz O. Robustness and evolvability in
genetic regulatory networks. J Theor Biol 2007;245(3):43348.
[78] Zhang R, Shan MV, Yang J, Nyland SB, Liu X, Yun JK, et al. Network model of
survival signaling in large granular lymphocyte leukemia. Proc Natl Acad Sci
U S A 2008;105(42):1630813.
[79] Alvarez-Buylla ER, Chaos A, Aldana M, Bentez M, Cortes-Poza Y, EspinozaSoto C, et al. Floral morphogenesis: stochastic explorations of a gene network
epigenetic landscape. PLoS ONE 2008;3(11):e3626.
[80] Huang S, Kauffman S. How to escape the cancer attractor: rationale and limitations of multi-target drugs. Semin Cancer Biol 2013;23(4):2708.
[81] Srihari S, Raman V, Leong H, Ragan M. Evolution and controllability of cancer networks: a Boolean perspective. IEEE/ACM Trans Comput Biol Bioinform
2013;99:1.
[82] Fumia HF, Martins ML. Boolean network model for cancer pathways:
predicting carcinogenesis and targeted therapy outcomes. PLOS ONE
2013;8(7):e69008.
[83] McAdams HH, Arkin A. Its a noisy business! Genetic regulation at the
nanomolar scale. Trends Genet 1999;15(2):659.
[84] Eldar A, Elowitz MB. Functional roles for noise in genetic circuits. Nature
2010;467(7312):16773.
[85] Almendro V, Kim HJ, Cheng Y-K, Gonen M, Itzkovitz S, Argani P, et al.
Genetic and phenotypic diversity in breast tumor metastases. Cancer Res
2014;74(5):1.
[86] Paulsson J. Summing up the noise in gene networks. Nature
2004;427(6973):4158.
[87] Gevertz J, Torquato S. Growing heterogeneous tumors in silico. Phys Rev E
Stat Nonlin Soft Matter Phys 2009;80(5 Pt 1):051910.
[88] Schellenberger J, Park JO, Conrad TM, Palsson BO. BiGG: a Biochemical Genetic
and Genomic knowledgebase of large scale metabolic reconstructions. BMC
Bioinformatics 2010;11:213.

87

[89] Feist AM, Palsson BO. The biomass objective function. Curr Opin Microbiol
2010;13(3):3449.
[90] Lerman JA, Hyduke DR, Latif H, Portnoy VA, Lewis NE, Orth JD, et al. In silico
method for modelling metabolism and gene product expression at genome
scale. Nat Commun 2012;3:929.
[91] Orth JD, Thiele I, Palsson BO. What is ux balance analysis? Nat Biotechnol
2010;28(3):2458.
[92] Price ND, Reed JL, Palsson BO. Genome-scale models of microbial cells:
evaluating the consequences of constraints. Nat Rev Microbiol 2004;2(11):
88697.
[93] Vazquez A, Liu J, Zhou Y, Oltvai ZN. Catabolic efciency of aerobic glycolysis:
the Warburg effect revisited. BMC Syst Biol 2010;4:58.
[94] Chignola R, Milotti E. A phenomenological approach to the simulation of
metabolism and proliferation dynamics of large tumour cell populations. Phys
Biol 2005;2(1):822.
[95] Milotti E, Vyshemirsky V, Sega M, Stella S, Chignola R. Metabolic scaling in
solid tumours. Sci Rep 2013;3:1938.
[96] Yang HM. Mathematical modeling of solid cancer growth with angiogenesis.
Theor Biol Med Model 2012;9:2.
[97] Savage N. Modelling: computing cancer. Nature 2012;491(7425):S623.
[98] Shlomi T, Cabili MN, Herrgard MJ, Palsson BO, Ruppin E. Networkbased prediction of human tissue-specic metabolism. Nat Biotechnol
2008;26(9):100310.
[99] Liu Y. Fatty acid oxidation is a dominant bioenergetic pathway in prostate
cancer. Prostate Cancer Prostatic Dis 2006;9(3):2304.
[100] Suburu J, Chen YQ. Lipids and prostate cancer. Prostaglandins Other Lipid
Mediat 2012;98(12):110.
[101] Gille C, Blling C, Hoppe A, Bulik S, Hoffmann S, Hbner K, et al. HepatoNet1:
a comprehensive metabolic reconstruction of the human hepatocyte for the
analysis of liver physiology. Mol Syst Biol 2010;6:411.
[102] Jamshidi N, Wiback SJ, Palsson BB. In silico model-driven assessment of the
effects of single nucleotide polymorphisms (SNPs) on human red blood cell
metabolism. Genome Res 2002;12(11):168792.
[103] Lewis NE, Schramm G, Bordbar A, Schellenberger J, Andersen MP, Cheng JK,
et al. Large-scale in silico modeling of metabolic interactions between cell
types in the human brain. Nat Biotechnol 2010;28(12):127985.
[104] Sahoo S, Thiele I. Predicting the impact of diet and enzymopathies on
human small intestinal epithelial cells. Hum Mol Genet 2013;22(13):
270522.
[105] Hao T, Ma H-W, Zhao X-M, Goryanin I. Compartmentalization of the Edinburgh Human Metabolic Network. BMC Bioinformatics 2010;(11):393.
[106] Romero Pet al. Computational prediction of human metabolic pathways from
the complete human genome. Genome Biol 2005;6(1):R2.
[107] Blazier AS, Papin JA. Integration of expression data in genome-scale metabolic
network reconstructions. Front Physiol 2012;3:299.
[108] Agren R, Bordel S, Mardinoglu A, Pornputtapong N, Nookaew I, Nielsen J.
Reconstruction of genome-scale active metabolic networks for 69 human
cell types and 16 cancer types using INIT. PLoS Comput Biol 2012;8(5):
e1002518.
[109] Wang Y, Eddy JA, Price ND. Reconstruction of genome-scale metabolic models
for 126 human tissues using mCADRE. BMC Syst Biol 2012;6:153.