Serum autoantibodies as biomarkers for early cancer detection. paper

2015-01-13

azim58 - Serum autoantibodies as biomarkers for early cancer detection.
paper

Tan HT, Low J, Lim SG, Chung MC.
2009
Department of Biological Sciences, Faculty of Science, National
University of Singapore, Singapore.
FEBS journal
article is accessible
"C:\kurt\storage\CIM Research
Folder\DR\2013\1-26-13\some_serex_papers\Serum autoantibodies as
biomarkers for early cancer detection..pdf"

Notes

Serum autoantibodies as biomarkers for early cancer
detection
2009
Singapore

q
Cancer is the second leading cause of death worldwide
[1].

?what is the 1st cause of death?

* Heart disease: 597,689
* Cancer: 574,743
from cdc faststats page:
http://www.cdc.gov/nchs/fastats/lcod.htm

q
Since the first serological identifications of
tumor antigens from the sera of melanoma patients [7],
there has been an increase in the number of reports of
TAAs and autoantibodies in patients with cancer [8].

q
five different approaches
(SEREX, phage display, protein microarray, SERPA
and MAPPing)

q
five most common cancers (liver, lung,
breast, colorectal and stomach)
q
Robert W. Baldwin was the first to establish the presence
of an immune response to solid tumors [15].

q
In addition, proteins that
are aberrantly localized during malignant transformation
can also provoke a humoral response.

?I wonder how the immune system can differentiate the localizatin of
proteins?

q
self-antigens that are aberrantly
expressed (e.g. HER2/ neu, p53 and ras)

q
most autoantibodies found in the sera of
cancer patients target cellular proteins with modifications,
aberrant localization or expression that are associated
with processes involved in carcinogenesis such
as cell cycle progression, signal transduction, proliferation
and apoptosis [51].

q
Thus, the production of autoantibodies can be
detected before any other biomarkers or phenotypic
aberrations are observed, rendering such autoantibodies
indispensable as biomarkers for early cancer
detection [43,55].

q
The persistence and
stability of the autoantibodies give them an advantage
over other biomarkers, including the TAAs themselves,
which are transiently secreted and may be rapidly
degraded or cleared.

Typically, autoantibodies against a particular
TAA are found in only 10–30% of patients [56].

?difference between sensitivity and specificity again?
Sensitivity and specificity

q
Initial studies of TAAs have focused on a few antigens
at a time, using techniques such as 1D SDS/PAGE or
ELISA.

?define concomitantly?
two events that happen at the same time or in connection with another

Serological analysis of tumor antigens by recombinant
cDNA expression cloning (SEREX) was first developed
in 1995 [38].

More than 2300 of these
autoantigens are documented in a public access online
database known as the Cancer Immunome Database
(CID) http://ludwig-sun5.unil.ch/CancerImmunomeDB/

?Is the cancer immunome database the one I am already familiar with?
Yes this is the one I am familiar with

q
the combination of several antigens in the panel would
greatly increase the sensitivity [93].

limitations of serex
-linear epitopes
-good expression in bacteria
-antigens with the most transcripts and expression are often detected by
SEREX (TAAs of low abundance are missed by SEREX)
-SEREX is time-consuming and labour-intensive

cDNA phage display library

protein microarray
-less sample required

this protein microarray is most similar to what I am doing

commercial human protein microarray (Proto-Array from Invitrogen)
80,000 recombinant antigens

q
Purified or recombinant
proteins, synthetic peptides, or fractionated proteins
from tumor or cancer cell lysates are spotted
systematically onto microarrays and then incubated
with specific sera

reverse-capture microarray
basically antibodies capture proteins from tumor lysate. Then cancer sera
is used to probe these native conformation proteins

SERPA
serological proteome analysis

2D electropheresis (of tumor lysate)-> western blotting -> MS
-only linear epitopes can be detected

MAPPing
immunoaffinity chromatography->nonspecific TAAs

types of TAAs identified
q
The growing list of TAAs identified in cancers
include oncoproteins (e.g. HER-2 / Neu, ras and
c-MYC) [27,52,160–163], tumor suppressor proteins
(e.g. p53) [31], survival proteins (e.g. survivin)
[93,157,164,165], cell cycle regulatory proteins (e.g.
cyclin B1) [25], mitosis-associated proteins (e.g. centromere
protein F) [166], mRNA-binding proteins (e.g.
p62, IMP1, and Koc) [61,167–169], and differentiation
and CTAs (e.g. tyrosinase and NY-ESO-1) [39,83,170–
172]. The following section shall discuss studies of
autoantibodies in the five major cancers.

q
Historically, HCC has been more prevalent in developing
countries such as Asia.

q
In terms
of serum biomarkers, AFP is still the best available for
HCC diagnosis

HCC is hepatocellular carcinoma

q
Two of the more established HCC-associated
TAAs are p53 [31,186] and p62 [37,169].

q
persistent infection with HBV is one of
the most important risk factors for HCC

q
Independently
of other risk factors, cirrhosis is the single most significant
risk factor for the development of HCC [198].

?what exactly is cirrhosis?
A chronic disease of the liver marked by degeneration of cells,
inflammation, and fibrous thickening of tissue. It is typically a result
of alcoholism or hepatitis

q
DEAD (Asp-Glu-Ala-Asp) box polypeptide 3,

q
Lung cancer is responsible for the largest number of
cancer-related deaths worldwide [2,203].

After lung cancer, breast cancer is the second most
common cancer in the world, and is the most common cancer in women [2].

?what is DCIS again?
Ductal Carcinoma In Situ (form of non-invasive breast cancer

q
Recently, using the SERPA approach, Desmetz et al.
[220] reported autoantibodies against HSP60 in breast
cancer patients.

q
These studies demonstrated
that the identification of autoantibodies and
TAAs has the potential to elucidate novel molecular
mechanisms of tumorigenesis.

q
For
example, proteins involved in the rapamycin-sensitive
mammalian target of rapamycin (mTOR) phosphorylation
pathway, such as ribosomal protein S6, eukaryotic
elongation factor 2, eukaryotic elongation factor 2
kinase and heat shock protein 90 (HSP90) have been
identified as TAAs in patients with breast cancer.

Colorectal cancer (CRC) is the third most common
cancer worldwide and the second leading cause of cancer-
related deaths in developed countries [2].

q
most stomach cancers
are known to arise from a chronic inflammatory background.

q
Since the approval of the CD20 mAb (rituximab) by
the Food and Drug Administration (FDA) for CD20-
positive B-cell malignancies, several antibody-based
immunotherapies have been developed for cancers.

q
This is because HSPs play important roles in cancer
initiation and progression, and are often overexpressed
in cancers [255–257].

q
autoantibodies have also been reported
to be present in healthy individuals. For example, Li
et al. [262] showed that > 50% of the sera of healthy
subjects contain autoantibodies to a-enolase and heterogeneous
nuclear ribonucleoprotein L.

q
These and other studies have shown
that a panel of autoantibodies is better in discerning
cancer patients from healthy individuals than the use of
a single autoantibody.

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