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CE Update
Autoantibody Biomarkers in Prostate Cancer
Xiaoju Wang, PhD
(Department of Pathology, Michigan Center for Translational Pathology, and Comprehensive Cancer Center, the University of Michigan
Medical School, Ann Arbor, MI)
DOI: 10.1309/AW0XDAV6KV4AVLRG
Abstract
Due to the low specificity of prostate-specific
antigen (PSA), there is great need for additional
serum biomarkers to supplement or replace
PSA for the detection of cancer in patients. Early
diagnosis and treatment of prostate cancer are
now becoming possible by employing the body’s
endogenous immune system as a biomarker,
which can serve as a natural “amplification
strategy” to respond to the low amount of
tumor-specific proteins by generating very-highaffinity T cells and antibodies.
The strength of using autoantibodies for the
detection of cancer lies in the sensitivity,
specificity, and efficiency of the immune
After reading this article, readers should be able to discuss the humoral
immune response to cancer and tumor-associated antigens eliciting
immune responses in the autologous host of prostate cancer patients.
Prostate cancer is the most commonly diagnosed malignancy, and the second leading cause of cancer-related deaths, in
men in the United States.1 Early diagnosis and treatment of prostate cancer can increase the possibility of curing the disease, especially for localized tumors, by avoiding tumor progression and
the development of micrometastasis. Currently, the prostate-specific antigen (PSA) blood test is widely relied upon for the early
detection of prostate cancer. Concurrent with the widespread use
of PSA screening, prostate cancer incidence has increased, while
mortality rates have decreased.2 In addition, the vast majority
of men are now diagnosed with localized disease in the absence
of symptoms.3 Despite these trends, however, the value of PSA
screening is still debated. Since the advent of PSA screening, the
improved detection of early disease has increased the lifetime risk
of a diagnosis of prostate cancer to 16%, whereas the lifetime risk
of death from prostate cancer is only 3.4%.4
A major limitation of the serum PSA test is its lack of specificity for prostate cancer, especially in the intermediate range of PSA
levels (4 to 10 ng/mL). In this range, the specificity of the PSA test
to detect prostate cancer has been reported to be only 20% at a
sensitivity of 80%.5 This poor specificity is, in part, associated with
the fact that serum PSA levels can be increased in patients with
nonmalignant conditions, such as benign prostatic hyperplasia or
prostatitis, and that PSA is highly expressed in both benign prostatic epithelia and prostate cancer cells. This has resulted in a surge
of equivocal prostate needle biopsies and men with the looming
threat of prostate cancer. On the other hand, recent evidence suggests that using the generally accepted value of 4.0 ng/mL as the
upper limit of normal actually fails to detect a significant percentage of cancers.6 These findings underscore the need for more accurate biomarkers that can not only detect prostate cancer but can
also distinguish indolent from aggressive disease.
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system. This article reviews the autoantibody
biomarkers that have shown to be clinically
useful in the diagnosis and prognosis of
prostate cancer. Ultimately, autoantibody
markers may provide information that can
be used to tailor the treatment of individual
patients.
Chemistry exam 20801 questions and corresponding answer form are
located after this CE Update article on page 172.
Because prostate cancer is such a common cancer, markers with a greater specificity rather than sensitivity are needed
to reduce unnecessary prostate biopsies or other invasive tests.
Moreover, it is unlikely that any single marker for prostate
cancer will have the desired high specificity and sensitivity,
making it important to develop a collection of markers that in
combination, could lead to accurate prostate cancer detection
and prognosis.
The search for new disease biomarkers entails characterizing 1 or more proteins produced by the body’s microenvironment and establishing assays with high sensitivity and
specificity. Most of these biomarkers, however, are expressed
at relatively low levels and are not secreted, thus making
them undetectable in serum. One approach to circumvent
the need to detect low abundant cancer biomarkers is to take
advantage of the body’s endogenous immune response to the
tumor. The idea that there is an immune response to cancer
in humans has been demonstrated by the identification of
autoantibodies against a number of intracellular antigens in
patients with various tumor types.7-10 This phenomenon is
known as the humoral response, and the detection of such
autoantibodies has been shown to be of great diagnostic and
prognostic value in the detection of cancer and the ability to
predict the course of the disease.11
This article will briefly introduce humoral immune response to cancer and discuss, in order of increasing sensitivity,
the tumor-associated antigens eliciting immune responses
in the autologous host of prostate cancer patients, as well as
highlight the recent cancer immunomic discoveries with the
potential to supplement or even replace PSA for the diagnosis
and prognosis of prostate cancer.
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The Humoral Immune Response to Cancer
Not all tumor markers are secreted into the circulation
in concentrations high enough to be detected easily. Whereas
other detection methods may be unable to recognize low levels of cancer proteins, the immune system is well-equipped to
detect very low levels of tumor-associated antigens that may
originate in only a few neoplastic cells,12 and it responds to
these minute amounts of markers by generating very-highaffinity T cells and antibodies. This response is then displayed
in the circulation, where it can be easily measured. The
strength of using autoantibodies for the detection of cancer
lies in the sensitivity, specificity, and efficiency of the immune
system. Therefore, with the goal of developing a noninvasive
serum-based test, it is possible to employ the body’s endogenous immune system as a natural “amplification strategy” to
detect prostate cancer (Figure 1).
The finding that cancer patients produce autoantibodies to tumor antigens13-16 suggests that the detection of such
autoantibodies can have diagnostic and prognostic value. For example, it has been shown that somatic alterations in the p53 gene
elicit a humoral response in 30% to 40% of affected patients.17
The detection of anti-p53 antibodies can predate the diagnosis of
the cancer. In other work, 60% of patients with lung adenocarcinoma exhibited a humoral response to glycosylated annexins I
and/or II, whereas none of the noncancerous standards exhibited
such a response. In addition, it has been shown that the majority
of antigens from tumor cells that elicit this response are not just
products of mutated genes. These proteins are often differentiation antigens or other proteins overexpressed in cancer.
The use of autoantibodies as serological markers for cancer
diagnosis is feasible because of the general absence of particular
autoantibodies in normal individuals and in noncancer conditions. Therefore, the search for human tumor antigens eliciting immune responses in the autologous host has identified a
number of attractive molecules for diagnosis, monitoring, and
therapy, including immunotherapy, of cancer.
Figure 1_Illustration of autoantibody as cancer biomarker. In vivo, small amounts of tumor-associated antigens (TAA), released by prostate
cancer (PCa), are engulfed by an antigen-presenting cell (APC), and their component proteins (antigens) are cut into pieces and displayed on
the cell’s surface. Pieces of the antigens bind to the major histocompatibility complex (MHC) proteins, also known as human leukocyte antigen
(HLA) molecules, on the surface of the APCs. This complex then binds to a T-cell receptor on the surface of another type of immune cell, the
CD4 helper T cell. This complex enables these T cells to focus the immune response to a specific protein. The antigen-specific CD4 helper T
cells divide and multiply while secreting substances called cytokines, which cause inflammation and help activate other immune cells. One of
the activated cells is the antigen-specific B cell, which can produce and release antibodies into the circulating system to neutralize and help
eliminate the antigens from the body. Therefore, the body’s endogenous immune system can serve as a natural “amplification strategy” to
respond to the low amount of tumor antigens (in vitro).
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CE Update
Table 1_List of Tumor-Associated Antigens (TAAs) Used for Profiling Antoantibody Signature in Prostate Cancer
TAA
Properties/Functions
Prevalence of Immune Response
(Samples, # Tested)
Reference
LEDGF
PARIS-1
P90
VAMP3
FLJ23438
PSA
HER2/neu
HIP1
GRP78
AMACR
ECPKA
Prostasomes
Multiplex TAA
Autoantibody signature
18.4% (n=207)
20% (n=10)
30.8% (n=133)
7.4% (n=27)
37% (n=27)
11% (n=200)
15.5% (n=200)
24% (n=97)
35.7% (n=108)
61.6% (n=151)
86% (n=35)
88% (n=218)
79% (n=206)
81.6% (n=60)
19
20
21
22
22
25
25
38
8
43
58
60
62
64
Lens-epithelium-derived growth factor
New TBC domain-containing, immunogenic tumor antigen
Novel tumor cytoplasmic autoantigen
Vesicle-associated membrane protein
Novel immunogenic tumor antigen
Prostate-specific antigen
Transmembrane oncoprotein
Huntingtin-interacting protein 1
Heat shock protein
Alpha-methylacyl CoA racemase
Cyclic AMP–dependent protein kinase
Prostate-derived secretory granules
A panel of 7 antigens
22 phage-derived epitopes
Tumor-Associated Antigens (TAAs)
The serum autoantibody repertoire from cancer patients is
currently being actively exploited to identify tumor-associated
antigens (TAAs) for noninvasive biomarkers. Tumor-associated
antigens are recognized by the patient’s immune system, which
generates humoral and cellular immune responses against these
antigens. Although factors leading to the production of such
autoantibodies are not clear, emerging data indicates that cancerassociated autoantibodies can be used as a reporter identifying
aberrant cellular mechanisms in tumorigenesis.18
The list of candidate TAAs in prostate cancer is growing
rapidly. While the general frequency and titers of autoantibodies in prostate cancer patients were relatively similar to those in
matched controls, significant differences could be detected between the 2 groups in the autoantibody response to an individual
antigen. For example, anti-LEDGF/p75 antibodies were detected
by ELISA in 18.4% of prostate cancer patients (n=207) and
5.5% of matched controls (n=166; P<0.001) but not in patients
with benign prostatic hyperplasia (BPH).19 Using serological
identification of antigens by recombinant expression cloning
(SEREX), a novel gene PARIS-1 was identified, and the autoantibody was detected in 20% of prostate cancer patient sera but
not in normal sera.20 P90 autoantibodies were detected in 30.8%
of 133 prostate cancer patients versus 1.5% of sera from patients with BPH (P=0.0085). Antibodies to p62 also occurred in
22.6% of prostate cancer sera but not in BPH samples.21 Pontes
and colleagues demonstrated 37% (10/27) and 7.4% (2/27) of
prostate cancer plasma samples presented autoantibodies against
FLJ23438 and VAMP3, respectively. Only 8.3% (1/12) of BPH
plasma samples were reactive for both autoantibodies, while none
(0/12) of the healthy controls were reactive.22
The autoantibody response to TAAs in certain prostate cancer patients suggests that the immunogenicity of these proteins
might be increased in prostate tumors, possibly as a consequence
of increased expression combined with proteolytic cleavage in
tumor cells dying under a proinflammatory environment. The
prevalence of autoantibodies in prostate cancer sera suggests that
humoral immune response against this antigenic determinant
could be a potential serum marker for this cancer (Table 1).
Prostate-Specific Antigen (PSA)
Prostate-specific antigen (PSA) is a serine protease that is secreted by the prostatic epithelium, as well as the epithelial lining
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of the periurethral glands, and functions in the liquefaction of
seminal fluids. Since its approval by the Food and Drug Administration (FDA) in 1986, PSA remains the only serum biomarker
recommended by the American Cancer Society for use in the
screening of malignancies.23
As a well-characterized TAA in prostate cancer, antibody
immunity to PSA was demonstrated in BPH and various stages
of the disease.24-26 Anti-PSA antibody titers were significantly
higher in the BPH group than in the controls and prostatitis
group (P<0.0005). Accordingly, 59% of BPH patients could be
defined as responders to PSA compared with none among the
controls (P<0.0005). Another study, using 200, patients with
various stages of prostate cancer and male controls demonstrated
that antibody immunity to PSA was significantly different between the patient (11%; 22 of 200) and control populations
(1.5%; 3 of 100; P=0.02), and high antibody titers were particularly prevalent in the subgroup of patients with androgenindependent disease (11%; 6 of 56).
These findings imply that prostate cancer is an immunogenic tumor. Moreover, the prevalence of PSA autoantibody was
higher in patients with androgen-independent disease, indicating that even patients with advanced stage prostate cancer can
have an immune response to their tumor. This also suggests that
immune tolerance to the tumor-associated protein might be circumvented in vivo.
HER2/neu
The human epidermal receptor 2 (HER2) proto-oncogene
(HER2/neu, c-erb-2) encodes a transmembrane tyrosine kinase
growth factor receptor that has fundamental roles in development,
proliferation, and differentiation.27 Overexpression of the HER2
receptor protein and amplification of the HER2 gene has been
implicated in the development and progression of tumors and has
been associated with a poor prognosis in several types of cancer.28
In prostate cancer, HER2 is overexpressed in 25% to 40%
and 60% to 80% of cases of localized and metastatic cancer,
respectively.29-35 Immunoassay demonstrated that serum HER2/
neu has a significant difference between patients with and without clinical metastases (P=0.006). Increased serum HER2/neu
correlates with the presence of metastatic disease, thus indicating
an increased risk of death in patients with metastatic prostate
cancer (P=0.001). Therefore, increased serum HER2/neu has a
negative affect on prognosis.
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Immune response to HER2/neu was evaluated in 200
patients with various stages of disease and male controls. The
antibody immunity is significantly higher in patients with prostate cancer (15.5%; 31 of 200) compared with controls (2%; 2
of 100; P=0.0004), and high antibody titers were most prevalent
in the subgroup of patients with androgen-independent disease
(16%; 9 of 56). These findings indicate that immunomic studies
against HER2/neu may lead to the development of prognosis
biomarkers of prostate cancer.
Huntingtin-Interacting Protein 1 (HIP1)
Huntingtin-interacting protein 1 (HIP1) was originally
identified as a protein that interacts with huntingtin, the product of the gene mutated in Huntington disease.36 It is a clathrinbinding protein involved in growth factor receptor trafficking
that transforms fibroblasts by prolonging the half-life of growth
factor receptors. Huntingtin-interacting protein 1 is frequently
overexpressed in prostate cancer and is significantly associated
with prostate cancer progression and metastasis.37 Using a prostate mouse model (TRAMP), Bradley and colleagues discovered
that HIP1 plays an important role in mouse tumor development.38 In addition, autoantibodies to HIP1 were developed
in the sera of TRAMP mice with prostate cancer. A test with
autoantibody to HIP1 in humans yielded a specificity of 97%
when combined with the anti-AMACR test. This data suggests
that HIP1 plays a functional role in tumorigenesis and that a
positive HIP1 autoantibody test may be an important serum
marker of prostate cancer.
Glucose-Regulated Protein-78 (GRP78)
Autoantibody to GRP78 was first identified through profiling the circulating antibodies from cancer patients using phage
display. By screening combinatorial peptide libraries, Mintz
and colleagues identified 1 such glucose-regulated protein family member, glucose-regulated protein-78 kDa (GRP78), as a
tumor antigen through epitope mapping of the humoral immune response from cancer patients. The percentage of positive
reactivity was demonstrated in a large population of prostate
cancer patients (n=108) to increase as the disease progressed.
Interestingly, significantly less reactivity was observed in the
serum from patients with metastatic non−small-cell lung cancer
(P<0.001), metastatic breast cancer (P<0.001), and advanced
ovarian cancer (P<0.001). More intriguingly, a Kaplan-Meier
survival curve showed that positive reactivity to GRP78 was associated with a trend towards a shorter overall survival (log-rank
test, P=0.07). This data strongly suggests that reactivity against
GRP78 is a serological marker of prostate cancer relative to
other malignant tumors.
Glucose-regulated proteins (GRPs), localized in the endoplasmic reticulum (ER), are a family of proteins related to
the heat-shock protein family. The best-characterized GRP is a
78-kDa protein referred to as GRP78. GRP78 has been shown
to function as a molecular chaperone, thus stabilizing proteins in
the ER.39,40 It appears to have antiapoptotic properties that may
be a key component in the resistance of some cancers to cytotoxic treatment. Since its discovery in 1977, GRP78 expression
has been documented in a variety of tumors, such as breast and
hepatocellular carcinoma,41,42 and more recently in human prostate cancer. It was found that GRP78 protein is highly expressed
in bone metastases and weakly expressed in normal prostate. The
intensity of expression is significantly associated with survival
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and clinical recurrence. GRP78 has considerable potential not
only as a prognostic indicator but also as a therapeutic target.
Alpha-Methylacyl CoA Racemase (AMACR)
Recently, the identification of a test that discovers autoantibodies to the prostate tumor marker, a-methylacyl CoA racemase (AMACR), provided hope that use of cytoplasmic tumor
markers in addition to secreted antigens could lead to blood
screening tests.43 AMACR was identified by differential display
analysis and expression array analysis as a gene specifically upregulated in prostate cancer epithelia relative to benign prostatic
epithelia.44-48 Studies using prostate tissue specimens demonstrated that AMACR protein is a highly specific and sensitive
marker for cancer cells in the prostate gland.49-51 Immunohistochemical staining using monoclonal antibodies to AMACR is
now commonly used in many institutions to assist in the pathologic diagnosis of prostate cancer. A recent multi-institutional
study52 of 807 prostatic specimens showed sensitivity and specificity of 97% and 92%, respectively, for the detection of prostate
cancer using immunohistochemistry specific for AMACR. With
respect to its use in differentiating between indolent prostate
cancers versus potentially metastatic cancer, AMACR expression
has been found to be subject to the state-of-tumor differentiation.53 While potentially useful in the tissue diagnosis of prostate
cancer, AMACR as a tumor marker would have considerably
more use if it could be detected in serum.
The humoral response to AMACR was evaluated as a possible biomarker for the detection of prostate cancer. By measuring
circulating autoantibodies to AMACR in the serum, Sreekumar
and colleagues were able to distinguish prostate cancer patients
from controls more accurately than by using PSA. Immunoreactivity against AMACR was statistically significantly higher in
sera from patients with prostate cancer than in control. Highthroughput immunoblot analysis revealed that, in subjects with
intermediate PSA levels (4 to 10 ng/mL), the immune response
against AMACR was more sensitive and specific than PSA in
distinguishing sera from prostate cancer patients relative to control subjects (sensitivity and specificity of 77.8% and 80.6% versus 45.6% and 50%, respectively; area under the curve of 0.789
versus 0.492; P<.001), indicating humoral immune response
against AMACR may have the potential to supplement PSA
screening in identifying patients with clinically-significant prostate cancer, especially those with intermediate PSA levels.
Extracellular Protein Kinase A (ECPKA)
In normal mammalian cells, cyclic AMP-dependent protein
kinase (PKA) is present strictly intracellularly.54 Intriguingly,
however, cancer cells of various types excrete PKA into the conditioned medium. This PKA, designated as extracellular PKA
(ECPKA), was found to be markedly up-regulated in the serum
of patients with cancer,55,56 and surgical removal of tumors led to
a decrease in ECPKA levels in patients.57 The ECPKA autoantibodies were analyzed in the sera samples from 295 patients with
various cancers, 155 normal controls, and 55 patients without
cancer, and the presence of autoantibody was highly correlated
with cancers. Particularly, in the subset of prostate cancer patients
(n=35), high anti-ECPKA antibody titers (frequency=86%;
mean titer=2.95) were detected, whereas low or negative titers
(frequency=12%; mean titer=1.0) were in the control group. This
indicates autoantibody ECPKA is a universal serum biomarker
for various cancer types including prostate cancer.58
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CE Update
Glossary
Antibody: A Y-shaped protein secreted by B cells in response to an antigen. An antibody binds specifically to the antigen that induced its
production. Antibodies directed against antigens on the surface of infectious organisms help eliminate those organisms from the body.
Antigen: A substance (often a protein) that induces the formation of an antibody. Antigens are commonly found on the surface of infectious
organisms, transfused blood cells, and organ transplants.
Autoantibody: An antibody that reacts with antigens found on the cells and tissues of an individual’s own body. Autoantibodies can cause
autoimmune diseases.
Autoantibody signature: A molecular “fingerprint” of autoantibodies produced against a disease state.
Epitope: A molecular region site on the surface of an antigen capable of eliciting an immune response and of combining with the specific
antibody produced by such a response. The epitope is also known as an antigenic determinant.
Humoral immune response: An immune response in which the body recognizes and defends itself against microorganisms, viruses, and
substances recognized as foreign and potentially harmful to the body. The defense involves antibodies which are secreted by B cells. The
B cells are activated when a specific antigen binds to the antibody, which is located on the surface of the B cells. Plasma B cells release
antibodies specific for the antigen.
Phage display: A technique in which bacteriophages are engineered to fuse a foreign peptide or protein with their capsid proteins and, hence,
expose or display it on their external surfaces. The immobilized phages may then be used as a screen to see which ligands bind to the expressed
fusion protein exhibited (displayed) on the phage surface.
Phage-peptide protein microarray: Phage lysates expressing diverse peptide fusion proteins spotted in an arrayed format onto a coated
substrate. These phage-peptides can then serve as “bait” to capture specific autoantibodies in serum.
Tumor-associated antigens (TAAs): Antigens predominately displayed on the surface of tumor cells or released by tumor cells.
These molecules can elicit an immune response by hosts.
Prostasomes
Prostasomes are small secretory granules synthesized by normal and neoplastic human prostate epithelial cells and released
with prostate secretions into prostate gland ducts.59 Normally,
the prostate cells and the excretory ducts form a closed system
and the balance among the various immune cells impedes destructive immunological reactions in the prostate. Highly-differentiated prostate cancer cells and larger tumors produce more
prostasomes. The derangement of the normal prostate tissue by
the tumor will interfere with the excretion of prostasomes. In
combination with the growth of the tumor into blood vessels
and the release of prostasomes into the circulation, this will increase the amount of prostasomal antigens exposed for the patient’s immune system. Since the prostate antigens are hidden or
do not appear until puberty, the immunological system regards
them as foreign and creates autoantibodies against them if they
escape the immunological barriers.
Several groups observed that prostasome autoantibody
in serum can be a novel marker for prostate cancer. In a pilot
study, antiprostasome antibodies were detected in all 13 patients
with PSA levels ≥50 ng/mL, while 39 healthy controls with low
PSA were negative. Another independent assay also identified
the autoantibody existing in 191 (88%) of 218 patients with
verified prostate cancer.60 This antibody titer did not correlate to
PSA values in patient sera. Significant inverse relationships were
observed for antiprostasome antibody titer with skeletal or nodal
metastases (P=0.035) and tumor stage (P=0.025), implying that
a high antiprostasome antibody titer is compatible with a lessaggressive tumor. This could reasonably be explained by the fact
that highly differentiated prostate cancers produce more prostasomes, thereupon producing a stronger antibody challenge.
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Multiplex Autoantibody Biomarkers
Cancer sera contain antibodies that react with a unique
group of TAAs, but the low frequency of positive reactions
against any individual antigen has precluded use of autoantibodies as useful diagnostic markers. It was shown that autoantibody
reactivity to individual TAAs rarely exceeds 20% to 30% in a
population of cancer patients61,62; however, successive addition
of TAAs to a panel of antigens results in a dramatic increase in
the number of positive antibody reactions in cancer patients,
but not in normal healthy controls. Koziol and colleagues demonstrated the presence of serum autoantibodies to a panel of
known TAAs in various human cancers, including prostate cancer. In this study, 7 TAAs (c-myc, cyclin B1, IMP1, Koc, p53,
p62, and survivin) were examined for the antibody frequencies
in 527 cancer patients (64 breast cancer patients, 45 colorectal
cancers, 91 gastric cancers, 65 hepatocellular carcinomas, 56
lung cancers, and 206 prostate cancers), and 346 normal controls. Recursive partitioning resulted in the selection of subsets of
the 7-panel TAA, which differentiated between tumors and controls, and these subsets were unique to each cancer cohort. Antibody frequency to any individual TAA was variable but rarely
exceeded 15% to 20%. With the successive addition of TAAs to
a final total of 7 antigens, there was a stepwise increase of positive antibody reactions up to a range of 44% to 68%. This study
shows that multiple antigen assay can provide accurate and valuable tools for cancer detection and diagnosis.
Recently, Zhong and colleagues63 measured antibodies
against 5 phage-expressed proteins to identify antigens that
could be used as markers of non-small-cell lung cancer. No
single antibody response measured showed overwhelming sensitivity and specificity (estimated using ROC curves). They were
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able to increase significantly both sensitivity and specificity only
by combining data from the 5 proteins. They concluded that
multiple antibody measurements improve predictive accuracy
even if further work would be necessary to improve the statistical
power and to validate autoantibody measurements as a clinically
reliable approach.
Autoantibody Signature in Prostate Cancer
Multiplex immune assay strongly suggested that uniquelyconstituted antigen panels provide an alternative approach for
discriminating autoantibody reactivity between cancer patients
and control individuals, thus significantly improving upon the
sensitivity and specificity with which prostate cancer is detected.
Therefore, identifying additional antigens targeted by the immune
system in prostate cancer patients is essential for profiling autoantibody signatures in prostate cancer populations and for defining
targets of novel strategies for the treatment of this cancer type.
Recently, Wang and colleagues64 reported the use of a
technique that combines phage display technology with protein
microarrays to identify and characterize new autoantibodybinding peptides derived from prostate cancer tissue. This novel
approach, termed “cancer immunomics,” allows a global analysis
of the humoral response against specific antigens in neoplasm.
Samples from PCa patients and healthy controls were initially
tested on a 2,304-phage peptide microarray, which allowed
identification of 186 phage peptides with the highest level of differentiation between cancers and controls. These candidate peptides were then used to develop focused microarrays for analyses
in the subsequent training and validation phase. As a final result,
a 22-phage peptide detector was designed from the training set
capable of discriminating 68 prostate cancer serum samples from
60 healthy controls with 88.2% specificity and 81.6% sensitivity
(AUC=0.93), whereas PSA was 80% accurate (AUC = 0.80).
Most impressively, this “autoantibody signature” performed
significantly better than PSA, particularly in those men with
PSA levels between 2.5 and 10 ng/mL. It was concluded that
autoantibodies against peptides derived from prostate cancer
tissue could be used as the basis for improving a screening test
for serum biomarkers for prostate cancer. Further studies are
currently underway to validate this elaborate detection tool on a
larger cohort and to examine the role of the antigens targeted by
the autoantibodies, as they may play a role in neoplastic pathogenesis or progression.
Conclusion
Exploiting the immune response to tumors provides a
unique opportunity for developing new tools for the serological
detection of cancer as well as a lead for therapy. A test based on
the demonstration of autoantibodies to tumor antigens in sera
of patients could be of great importance for the early detection
of cancer because of the prolonged time course of carcinogenesis
and because a detectable level of antibodies against carcinogen
stimulus could form well before the tumor phenotype arises.
Like other cancers, prostate cancer develops as the result of the
derailment of heterogeneous and multiple regulatory processes;
therefore, it is not a single biomarker that needs to be elucidated.
Multiplexed biomarker patterns have a significantly higher positive predictive value than single markers in discriminating diseased patients from noncancer controls.
The autoantibody signature test holds great promise, but
the limited sample number from the initial report requires much
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more research to confirm the test’s reliability and to adapt the
technique for mass screening. In addition, doctors will also need
to learn if early diagnosis improves the outlook for men with
prostate cancer, thus helping to produce antibodies for disease
treatment. Therefore, bridging the gap between basic science
and clinical practice represents the main goal in the near future
to enable physicians to tailor risk-adjusted screening and treatment strategies for current prostate cancer patients. LM
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