Global Strategies for Disease Detection and Treatment: Proteomics
Disease Markers
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Global Strategies for Disease Detection and Treatment: Proteomics
0 Sudhir Srivastava
1 University of Michigan Medical Center , Ann Arbor, MI 48109 , USA
2 Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute , Bethesda, MD 20892 , USA
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The field of proteomics holds great promise for
identifying nontargeted, global molecular profiles
“signatures” of normal and diseased cells. While genomics
offers a wide array of tools for identifying mutated
or dysregulated genes, proteomics offers the ability to
measure post-translational modifications, protein
stability, phosphorylation state, protein-protein
interactions, and protein DNA-binding affinities. These
biological events play major roles in the pathogenesis
of disease and cannot be studied by DNA and mRNA
efforts alone. Recent studies have shown that there
is no specific correlation between mRNA abundance
and protein expression levels in a cell at a given time.
The discrepancy could arise from the control of mRNA
translation, and the stability of mRNAs and proteins.
Because almost all therapeutic intervention strategies
or early detection technologies target expressed
proteins, proteomic-based studies can provide
fundamental information to characterize disease progression at
the molecular level. Therefore, proteomics has
particular relevance to diagnostics and to the identification
of disease markers, as proteins can be assayed in serum
and other biological fluids.
Since the completion of human genome sequence,
the discipline of proteomics has taken a center stage
in defining the future of molecular diagnostics. This
is due, to some extent, to the fact that the sequencing
of the human genome and other important genomes
has opened the door for proteomics by providing a
sequence-based framework for mining the proteome.
The growth in proteomic tools and proteomics is in an
extraordinary growth phase. As a consequence,
proteomics is witnessing an extraordinary growth in the
number of new investigators and biotechnology
companies that are taking an active interest in the field.
Proteomics is evolving at a fast pace, as is evident from
this special issue. Strategies for protein fractionation
prior to analysis are increasingly being relied upon.
Selective enrichment for a subset of proteins of interest
can be achieved using a variety of techniques from
centrifugation procedures to affinity capture. In addition to
reducing sample complexity and increasing sensitivity,
strategies based on the separate analysis of subcellular
compartments provide the means to determine protein
location in a cell. There is clearly interest in
developing robust “industrial strength” proteomic platforms to
achieve high-throughput and high sensitivity.
During the lean years of proteomics, the field was
largely dominated by a single approach, namely
twodimensional (2-D) gels, backed up by an assortment
of related tools, ranging from software for image
analysis to mass spectrometry. Several technologies for
protein profiling are emerging that are not 2-D gel
based, including direct profiling by mass
spectrometry and the use of protein microarrays. High
throughput technologies, such as Surface-Enhanced Laser
Desorption/Ionization Time-of-Flight (SELDI-TOF) and
Matrix-Assisted Laser Desorption/Ionization
Time-ofFlight (MALDI-TOF) technologies, are providing us
with a non-biased, global discovery approach using
patient serum, plasma, urine or other sources of
secretions, to identify – in a single run – the expression
patterns in thousands of small molecular mass proteins
(< 20 kDa) based on their molecular mass and charge,
offering a tool to determine which proteins are secreted
from tumor cells or are measurable in the bodily fluids
of patients. However, it is likely that no one technology
platform will meet the needs of the wide spectrum of
applications encompassed by proteomics. Diagnosing
disease through proteomics may well require all the
tools at our disposal to identify and validate the most
promising markers.
S. Srivastava and S. Hanash / Global Strategies for Disease Detection and Treatment: Proteomics
While the emergence of proteomics brings hope to
disease detection and therapeutic intervention, it poses
several analytical challenges. Analyzing voluminous
data generated by high-throughput proteomics arrays is
a fairly new endeavor for statisticians for which there
is not extensive literature. Another complexity to these
analyses is how to analyze proteomics data in reference
to disease outcomes. The maturation of proteomics
technology, with its global, non-directed ability to
analyze serum proteins, will add to the markers or
patterns of markers that are able to predict the presence
of ovarian cancer. For example, if the protein products
of the amplified DNA or RNA are secreted from tumor
cells and migrate to serum, plasma, urine, or other
accessible fluids, proteomics will offer a rapid advance
in the identific (...truncated)