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

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.