Molecular Biology of Cancer Translation to the Clinic
Translation to the Clinic
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10 11 12 13 10 9 8 7 6 5 4 3 2 1
Contents
Contributors..................................................................................... ix
Preface............................................................................................. xi
Introduction to the Molecular Biology of Cancer:
Translation to the Clinic . . . . . . . . . . . . . . . . . . . . . . . . 1
Raymond W. Ruddon
Molecular Biology and Anticancer Drug Discovery. . . . . 9
John S. Lazo
I. Introduction ................................................................................ 9
II. Phenotypic Targets........................................................................ 12
III. Molecular Targets ......................................................................... 16
IV. Other Contemporary Issues in Anticancer Drug Discovery ................... 26
V. Conclusions ................................................................................. 27
References .................................................................................. 27
Targeting Chemokine (C-C motif) Ligand 2 (CCL2) as an
Example of Translation of Cancer Molecular Biology
to the Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Jian Zhang, Lalit Patel, and Kenneth J. Pienta
I. Biology of CCL2........................................................................... 32
II. CCL2 in Prostate Cancer ............................................................... 37
III. CCL2 Development as a Therapeutic Target...................................... 41
IV. Conflicting Reports on the Roles of CCL2 in Cancer........................... 43
V. Conclusions ................................................................................. 43
References .................................................................................. 45
v
vi contents
Chromosomal Aberrations in Solid Tumors . . . . . . . . . . 55
Arul M. Chinnaiyan and Nallasivam Palanisamy
I. Introduction .............................................................................. 56
II. Historical Background: Discovery of Chromosome Aberrations
in Cancer .................................................................................. 57
III. Discovery of Gene Fusions in Cancer............................................. 58
IV. New Approaches for Gene Fusion Identification .............................. 61
V. Methods for the Characterization of Chromosome Aberrations
in Solid Tumors.......................................................................... 70
VI. Next-Generation Sequencing Technology........................................ 79
VII. Structural Classification of Gene Fusions ........................................ 82
VIII. Functional Classification of Gene Fusions ....................................... 83
IX. Mechanism of the Formation of Gene Fusions in Cancer................... 84
References ................................................................................ 86
Circulating Tumor Cells . . . . . . . . . . . . . . . . . . . . . . . 95
Daniel F. Hayes and Jeffrey B. Smerage
I. Introduction ................................................................................ 96
II. What Are the Technological Issues? ................................................. 96
III. What Are the Clinical Utilities of CTCs Detection and Enumeration? .... 100
IV. CTC Characterization ................................................................... 106
V. Summary .................................................................................... 107
References .................................................................................. 108
Stem Cells in Normal Development and Cancer . . . . . . 113
Rosemarie Chirco D’Angelo and Max S. Wicha
I. Introduction of Cancer Stem Cells and the Cancer Stem
Cell Hypothesis ........................................................................... 114
II. Comparison of Normal Stem Cells with Cancer Stem Cells ................. 115
III. Definition of Cancer Stem Cells and Identification of Cancer Stem
Cell Markers............................................................................... 117
IV. Identification of Cancer Stem Cells ................................................. 123
V. Activation of Signaling Pathways and Targeted Therapies for Cancer
Stem Cells.................................................................................. 129
VI. Therapeutic Implications for Targeting Cancer Stem Cells .................. 143
VII. Conclusions ................................................................................ 144
References ................................................................................. 145
contents vii
Bioinformatics and Systems Biology of Cancers . . . . . . . 159
Gilbert S. Omenn
I. Introduction .............................................................................. 160
II. The Cancer Biomedical Informatics Grid (caBIG) ............................ 162
III. TCGA: The Cancer Genome Anatomy Project ................................. 165
IV. Alternative Splicing: Discovery of a New Class of Protein Cancer
Biomarker Candidates ................................................................. 172
V. Concepts Tools for Systems Biology Analysis .................................... 181
VI. Determining the Activity of All 21,000 Protein-Coding Genes in the
Human Genome......................................................................... 183
VII. Bioinformatics and Systems Biology of Metastasis: The Case of
Lung Cancers ............................................................................ 184
VIII. Special Resources for Pharmacogenomics of Cancer Therapies ........... 185
IX. Conclusion ................................................................................ 187
References ................................................................................ 188
Progress in Cancer Nanotechnology. . . . . . . . . . . . . . . 193
Istvan J. Majoros, Brent B. Ward, Kyung-Hoon Lee,
Seok Ki Choi, Baohua Huang, Andrzej Myc, and
James R. Baker
I. Introduction and Historical Perspective .......................................... 194
II. Targeted Therapy........................................................................ 195
III. Computer Simulations as an Approach to Develop Nanotechnology
in Cancer .................................................................................. 196
IV. Nanomolecular Carriers for Drugs and Imaging Agents ..................... 200
V. Nanotechnology in Cancer-Targeted Delivery of Therapeutic Agents .... 207
VI. Targeted Imaging........................................................................ 216
VII. Apoptosis Sensors ....................................................................... 219
VIII. Future Direction in Research and Technology.................................. 227
References ................................................................................ 228
Applications of Molecular Imaging . . . . . . . . . . . . . . . . 237
Craig J. Galbán, Stefanie Galbán, Marcian E. Van Dort,
Gary D. Luker, Mahaveer S. Bhojani, Alnawaz Rehemtulla,
and Brian D. Ross
I. Optical Imaging............................................................................ 238
II. Magnetic Resonance Imaging.......................................................... 257
III. Nuclear Imaging........................................................................... 271
References .................................................................................. 286
viii contents
Cancer Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . 299
Wendell Weber
I. Introduction ................................................................................ 299
II. First, a Little History..................................................................... 300
III. Epigenetic Patterns in Normal Cells ................................................ 302
IV. Epigenetic Patterns in Cancer......................................................... 326
V. Epigenetic Therapies for Cancer ..................................................... 337
VI. Prospects for the Future of Cancer Epigenetics ................................. 342
References .................................................................................. 344
Molecular Targets and Clinical Cancer Risk Reductive
Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Madhuri Kakarala and Dean E. Brenner
I. Defining Cancer Risk Reductive Intervention (Chemoprevention) ....... 351
II. Cellular Transformational Molecular Events as Targets for CRRIs ....... 352
III. Inherited Genetic Mutations (Cancer Susceptibility Syndromes) ......... 352
IV. Special Features of CRRI Development ......................................... 355
V. Molecular Intermediates as Biomarkers for Cancer Risk
Reductive Efficacy ..................................................................... 356
VI. Future Approaches to Molecular Biomarker Applications to CRRI ...... 358
VII. Standards for Biomarkers as Endpoints for Cancer Risk
Reductive Efficacy ..................................................................... 358
VIII. Examples of CRRIs and Their Molecular Targets ............................. 358
IX. Nutritional Products ................................................................... 363
X. Multiagent CRRIs ...................................................................... 364
XI. Molecular Viral Targets for Cancer Risk Reduction ........................... 364
References ................................................................................ 366
Index ....................................................................................... 377
Contributors
Numbers in parentheses indicate the pages on which the authors’ contributions begin.
James R. Baker, Michigan Nanotechnology Institute for Medicine and
Biological Sciences, University of Michigan, Ann Arbor, Michigan, USA (193)
Mahaveer S. Bhojani, Department of Radiology, University of Michigan,
Center for Molecular Imaging, Ann Arbor, Michigan, USA (237)
Dean E. Brenner, University of Michigan Medical Center and VA Medical
Center, Ann Arbor, Michigan, USA (351)
Arul M. Chinnaiyan, Michigan Center for Translational Pathology, and
Department of Pathology, and Howard Hughes Medical Institute, Maryland,
and Department of Urology; and Comprehensive Cancer Center, University
of Michigan, Ann Arbor, Michigan, USA (55)
Seok Ki Choi, Michigan Nanotechnology Institute for Medicine and
Biological Sciences, University of Michigan, Ann Arbor, Michigan, USA
(193)
Rosemarie Chirco D’Angelo, Department of Internal Medicine, Division of
Hematology and Oncology, University of Michigan Comprehensive Cancer
Center, University of Michigan, Ann Arbor, Michigan, USA (113)
Craig J. Galbán, Department of Radiology, University of Michigan, Center
for Molecular Imaging, Ann Arbor, Michigan, USA (237)
Stefanie Galbán, Department of Radiation Oncology, University of Michigan,
Center for Molecular Imaging, Ann Arbor, Michigan, USA (237)
Daniel F. Hayes, Breast Oncology Program, University of Michigan
Comprehensive Cancer Center, Ann Arbor, Michigan, USA (95)
Baohua Huang, Michigan Nanotechnology Institute for Medicine and
Biological Sciences, University of Michigan, Ann Arbor, Michigan, USA
(193)
Madhuri Kakarala, University of Michigan Medical Center and VA Medical
Center, Ann Arbor, Michigan, USA (351)
John S. Lazo, Department of Pharmacology and Chemical Biology, University
of Pittsburgh Drug Discovery Institute and Cancer Institute, University of
Pittsburgh, Pittsburgh, Pennsylvania, USA (9)
Kyung-Hoon Lee, Michigan Nanotechnology Institute for Medicine and
Biological Sciences and Department of Chemistry, University of Michigan,
Ann Arbor, Michigan, USA (193)
Gary D. Luker, Department of Radiology, University of Michigan, Center for
Molecular Imaging, Ann Arbor, Michigan, USA (237)
ix
x contributors
Istvan J. Majoros, Michigan Nanotechnology Institute for Medicine and
Biological Sciences, University of Michigan, Ann Arbor, Michigan, USA (193)
Andrzej Myc, Michigan Nanotechnology Institute for Medicine and
Biological Sciences, University of Michigan, Ann Arbor, Michigan, USA
(193)
Gilbert S. Omenn, Department of Internal Medicine, Department of Human
Genetics, School of Public Health, Center for Computational Medicine and
Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA (159)
Nallasivam Palanisamy, Michigan Center for Translational Pathology, and
Department of Pathology; and Comprehensive Cancer Center, University of
Michigan, Ann Arbor, Michigan, USA (55)
Lalit Patel, Department of Medicine; and Department of Urology, Michigan
Center for Translational Pathology and the University of Michigan Comprehen-
sive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA (31)
Kenneth J. Pienta, Department of Medicine; and Department of Urology,
Michigan Center for Translational Pathology and the University of Michigan
Comprehensive Cancer Center, University of Michigan, Ann Arbor,
Michigan, USA (31)
Alnawaz Rehemtulla, Department of Radiation Oncology, University of
Michigan, Center for Molecular Imaging, Ann Arbor, Michigan, USA (237)
Brian D. Ross, Department of Radiology, University of Michigan, Center for
Molecular Imaging, Ann Arbor, Michigan, USA (237)
Raymond W. Ruddon, Department of Pharmacology, University of Michigan
Medical School, Ann Arbor, Michigan, USA (1)
Jeffrey B. Smerage, Breast Oncology Program, University of Michigan
Comprehensive Cancer Center, Ann Arbor, Michigan, USA (95)
Marcian E. Van Dort, Department of Radiology, University of Michigan,
Center for Molecular Imaging, Ann Arbor, Michigan, USA (237)
Brent B. Ward, Oral and Maxillofacial Surgery, University of Michigan
Hospitals, Ann Arbor, Michigan, USA (193)
Wendell Weber, Department of Pharmacology, University of Michigan
Medical School, Ann Arbor, Michigan, USA (299)
Max S. Wicha, Department of Internal Medicine, Division of Hematology and
Oncology, University of Michigan Comprehensive Cancer Center, University
of Michigan, Ann Arbor, Michigan, USA (113)
Jian Zhang, Department of Medicine; and Department of Urology, Michigan
Center for Translational Pathology and the University of Michigan Comprehen-
sive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA (31)
Preface
The purpose of this volume in the Progress in Molecular Biology and Transla-
tional Science series is to explore some of the most exciting recent advances in
basic research on the molecular biology of cancer and how this knowledge leads
to advances in the diagnosis, treatment, and prevention of cancer.
The chapter topics include introduction to the molecular biology of cancer
(Ruddon), molecularly targeted approaches to the development of anticancer
drugs (Lazo), targeting chemokine ligands and their role in cancer metastasis
(Pienta), discovery of cancer cell fusion genes in solid cancers (Chinnaiyan),
role of circulating tumor cells in cancer diagnosis, disease progression and
response to therapy (Hayes), cancer stem cells (WIcha), bioinformatics and
systems biology of cancers(Omenn), progress in cancer nanotechnology
(Baker), molecular imaging (Ross), cancer epigenetics (Weber), and cancer
prevention (Brenner).
The senior investigators represented here are all University of Michigan
faculty, with the exception of John Lazo, from the University of Pittsburgh, but
even he has a U of M genealogy, having received his Ph.D. in Pharmacology
from the Ruddon lab at U of M. However, all of these scientists are leaders in
their fields of research. Thus, this is not just a parochial concatenation of
narrowly focused local research, but it is, in fact, representative of the most
advanced research in the fields discussed here.
R. W. RUDDON, ANN ARBOR
xi
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Introduction to the Molecular
Biology of Cancer: Translation
to the Clinic
Raymond W. Ruddon, M.D., Ph.D.
Department of Pharmacology, University of
Michigan Medical School, Ann Arbor,
Michigan, USA
Advances in molecular biology over the last several decades are being steadily
applied to our understanding of the molecular biology of cancer, and these
advances in knowledge are being translated into the clinical practice of oncology.
Many examples can be cited to demonstrate this. Some of them are listed
below. Everyone has their favorite list, of course; however, everyone would
probably agree that the items on this list should be included in any such list of
advances.1
1. Techniques of modern molecular biology: These include PCR, DNA
microarrays, proteomics, molecular imaging, identification of cancer
stem cells, and the analysis of DNA methylation in cancer epigenetics.
Other advances are in methods for metabolomic measurements, nano-
technology, systems biology, cancer immunology and monoclonal anti-
body production, and bioinformatics. Many of these advances will be
discussed in this volume.
2. Cancer susceptibility genes: In the early 1900s, it was known that familial
clustering of some cancers occurred, for example, with colon cancer and
breast cancer, but the genes involved in this were not known. The APC,
BRCA-1, BRCA-2, and p53-inherited mutations, for example, were not
known until more recently. Research in this area has identified a number
of genes involved in cancer susceptibility, and with modern cloning
techniques, more are identified every few months.
3. Genes involved in cancer initiation and promotion: It has been known
for a long time that chemicals and irradiation could damage DNA and
initiate cancer in animals and humans, but what genes were altered was
almost completely unknown until the advances in molecular biology
were applied. We now know a lot about what genes are involved at
various stages of a number of cancers. For example, the work of Bert
Vogelstein and his colleagues have defined a pathway, sometimes called
the ‘‘Vogelgram,’’ for the progression of colon cancer.2 We knew that
Progress in Molecular Biology Copyright 2010, Elsevier Inc.
and Translational Science, Vol. 95 1 All rights reserved.
DOI: 10.1016/S1877-1173(10)95001-1 1877-1173/10 $35.00
2 RAYMOND W. RUDDON
DNA repair was important and that heritable conditions of defective
DNA repair (e.g., xeroderma pigmentosum) could lead to cancer, but
the ideas about the mechanisms of DNA repair were primitive until
fairly recently.3
4. The identification of oncogenes: This did not really take off until the early
1980s. The src gene was identified in 1976 by Stehelin et al. and erb,
myc, and myb oncogenes in the late 1970s, but this was about the limit of
our knowledge (reviewed in Ref. 4).
5. Tumor suppressor genes: The term ‘‘tumor suppressor gene’’ was not
even coined until the early 1980s, although their existence had been
implied from the cell fusion experiments of Henry Harris, who showed
that if you fused a normal cell with a malignant cell, the phenotype was
usually nonmalignant (reviewed in Ref. 5). The RB gene was the first
one cloned, in 1986 by Friend et al.6 P53 was originally thought of as an
oncogene. It was not realized until 1989 that wild-type p53 could
actually suppress malignant transformation. A number of tumor
suppressor genes have, of course, been identified since.
6. Cell cycle checkpoints: These were identified in yeast starting in the
1970s by Lee Hartwell and colleagues, but the identification of many of
the human homologs of these genes did not occur until the late 1980s.
7. Tumor immunology: The mechanism of the immune response and the
ability to manipulate it with cytokines, activated dendritic cells, vaccines,
and drugs was not in the treatment armamentarium until recently.
Advances in identification of tumor antigens and in the techniques to
produce monoclonal antibodies are now leading to newer treatment
modalities.
8. The viral etiology of cancer: This was still being widely debated in the
1980s. The involvement of Epstein–Barr virus in Burkitt’s lymphoma
and of hepatitis B virus in liver cancer was becoming accepted, but the
role of viruses in these diseases and in cervical cancer, Kaposis’ sarcoma,
and in certain T-cell lymphomas became clearer much later.
9. Growth factors that affect cancer: Even though growth factors that
stimulate cell replication, such as IGF-1 and 2, FGF, NGF, PDGF,
and EGF, have been known for a long time, knowledge about their
receptors and signal transduction mechanisms have been greatly
expanded. Importantly, it is now known that the signal transduction
mechanisms that cancer cells use are overlapping and redundant.
Thus, cancer cells can become resistant to anticancer drugs by
upregulating alternate pathways.
INTRODUCTION TO THE MOLECULAR BIOLOGY OF CANCER 3
The explosion of knowledge about signal transduction mechanisms and
how these pathways interact have also been a tremendous boon to our
understanding of how cells respond to signals in their microenvironment and
communicate with one another.
10. Regulation of gene expression: Current information on the packaging of
chromatin, transcription factors, coinducers and corepressors, inhibi-
tory RNA (siRNA), and micro RNA is expanding our knowledge of how
gene expression is regulated in cancer.
Several decades of advances in cancer cell molecular biology have led to a
rich pipeline of anticancer agents aimed at membrane-bound receptor protein
kinases, intracellular signaling kinases, epigenetic abnormalities, as well as to
agents that affect protein folding and degradation, tumor vasculature, and the
tumor cell microenvironment (reviewed in Ref. 7).
The history of chemotherapy has seen its ups and downs since the intro-
duction of nitrogen mustard after World War II.8 The focus until recently has
been almost exclusively on toxic chemicals that somewhat nonselectively kill
dividing cells. Now, however, there is a large focus on what has been called
‘‘molecularly targeted agents.’’ Two successful examples are trastuzumab
(Herceptin) and imatinib (Gleevec). The number of successes for this approach
to date is small, however, and the success of imatinib in treatment of chronic
myelogenous leukemia (CML) may be the exception rather than the rule,
arguing for the need to continue to search for agents that are toxic to dividing
cells (albeit, hopefully, more selectively toxic ones).9
The other school of thought argues that targeted therapies can be devel-
oped against specific targets that are selectively overexpressed or mutated in
cancer cells and thus be less toxic to normal tissues.10 To this end, a detailed
understanding of the target’s structure and function will be necessary to
identify a targeted drug’s mechanism of action and the mechanisms of
resistance development to the drug. In addition, the use of cytotoxic drugs in
combination with targeted drugs will most likely continue to be the most
efficacious approach to treating cancer.
In Chapter 2 of this volume, John Lazo expands on these concepts.
Of course, all successful approaches to new cancer treatment depend on
the adaptation of molecular findings into the clinic, so-called translational
research. In Chapter 3, Ken Pienta et al. describe a beautiful example of how
this is done. They have shown how the monocyte chemoattractant protein
MCP-1 (CCL2) is involved in the lethal phenotype of prostate cancer cells,
that it is increased in prostate cancer bone metastases, and that it is a
4 RAYMOND W. RUDDON
pro-survival and pro-angiogenic factor that leads to metastasis.11 They have
also shown that monoclonal antibody targeted to CCL-2 inhibits bone
metastasis and increases survival.
In Chapter 4, Nallasivam Palanisamy and Arul Chinnaiyan discuss the
recent discovery of gene fusions in ‘‘solid cancers’’ such as prostate, breast,
and lung cancers. Up until this research, it was generally believed that gene
fusion events occurred typically in hematologic malignancies and rare bone and
soft-tissue tumors, but not in tumors such as prostate, lung, breast, and colon.
Novel gene fusions were discovered utilizing integrative analysis of high
throughput long- and short-read transcriptome sequencing of cancer cells.
The finding in human prostate cancers that a fusion (TMPRSS2-ERG) occurs
between an oncogene and an androgen regulated gene was a seminal observa-
tion. Subsequently, gene fusion events have been found in a variety of other
human solid cancers, including breast, lung, and pancreatic cancers.12
In the Chapter 5, Dan Hayes and Jeffrey Smerage discuss the technique to
isolate cancer cells from the blood of cancer patients and how the monitoring of
serial changes in circulatory breast cancer cells can be used as an index of
cancer progression in both murine xenograft models of human breast cancer13
and in patients with breast cancer.14
In this method, an iron-tagged (ferrofluid) monoclonal antibody to epithe-
lial cell surface markers is used to isolate epithelial cells from red and white
blood cells. Since epithelial cells do not normally circulate, these cells are often
of tumor origin. Hayes et al.14 have shown that the number of circulatory tumor
cells (CTCs) obtained before treatment is an independent predictor of pro-
gression-free survival and overall survival in patients with metastatic breast
cancer.
The concept that cancer stem cells (discussed in chapter 6 by D’Angelo and
Wicha) are the most aggressive cell type in a tumor cell population is an area of
evolving research. The concept is based on studies that indicate that only a very
small subset of cells (often less than 0.1%) of cells in a tumor have the ability to
generate a new tumor from an implanted human cancer cell population in
immunodeficient (SCID) mice.15 The stem cells in a human breast cancer cell
population have a specific stem cell population phenotype: CD44þ/CD24/
aldehyde dehydrogenase 1þ. These findings have important diagnostic and
therapeutic implications. For example, as noted earlier, currently available
chemotherapeutic drugs were developed largely on the basis of their ability
to shrink a tumor mass in experimental models and clinical trials. This essen-
tially predicts the ability of a drug to kill the bulk of cells in a cancer population,
potentially leaving the more aggressive, drug-resistant cells behind. Thus,
drugs more specifically targeted to the cancer stem cell population would
most likely result in more effective and durable responses.
INTRODUCTION TO THE MOLECULAR BIOLOGY OF CANCER 5
As more is learned about the phenotype and genotype of cancer cells, it is
becoming apparent that cancer cells are extremely complex. They not only
utilize many of the same genes and proteins that normal cells express but can
up- or downregulate functions in order to survive extraordinary environmental
threats such as toxic drugs or radiation therapy. They have redundant and
overlapping signal transduction pathways that enable them to circumvent
many challenges to their viability. The relatively new science of systems biology
is beginning to unravel much of this complexity.
Systems biology is a conceptual framework to quantify and integrate the
types of biological information contained in cells, tissues, organisms, and popu-
lations of individuals. It is these interacting networks that modulate and regulate
life. This includes the study of genomics, transcriptomics, proteomics, metabo-
lomics, and most other ‘‘-omics’’ that have yet to be so named. Systems biology
attempts to delineate and integrate the dynamic relationships between DNA as
it is packaged in chromalin, RNA (including mRNA, rRNA, siRNA, and micro-
RNA), gene regulatory networks, protein–protein interactions, and cellular
communication systems as well as interactions at the tissue and organ levels.
This is a tremendously complicated business and requires the analysis and
integration of enormous data sets. Thus, the science of bioinformatics is playing
a crucial role in this new way to look at cancer cell biology. For example, even in
lower organisms, such as yeast, Caenorhabditis elegans, and Drosophila, the
interactions of gene and protein networks are high (reviewed in Ref. 16).
The global mapping of a yeast genetic interaction network containing 1000
genes revealed over 4000 interactions. A single large network of 1548 proteins
showed 2538 interactions. In C. elegans, more than 5500 protein–protein
interactions were identified. In Drosophila, a total of 10,623 gene transcripts
produced a map of 7048 proteins with 20,405 predicted interactions.
Some of the issues of determining the complicated interactions in cells and
the use of bioinformatics in solving these puzzles are described by Gil Omenn
in Chapter 7.
Studies in the relatively new field of metabolomics are beginning to reveal a
lot about the cancer cell phenotype. Metabolomics is at the same time less
complicated and more complicated than its ‘‘-omics’’ cousins genomics, tran-
scriptomics, and proteomics. It is less complicated in the sense that whereas
there are 25,000–30,000 genes in the human genome, 100,000 transcripts, and
1,000,000 proteins, there are only about 1800 compounds that constitute the
metabolome. It is more complicated in that these 1800 compounds are in a
constant, rapid state of flux depending on absorption of dietary substances,
hormone levels, drug intake, exercise, body temperature, and the presence of
disease states such as diabetes, infections, or cancer. NMR and mass spectrom-
etry are the typical tools used in the study of metabolomics.17
