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Open Access Journal of Biomedical
Engineering and Biosciences
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DOI: 10.32474/OAJBEB.2018.01.000115
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ISSN: 2637-4579
Liquid Biopsy in the OMICS Era of Tumor Medicine
Yi Jiang and Denong Wang*
Tumor Glycomics Laboratory, SRI International Biosciences Division, USA
Received:
March 01, 2018; Published:
March 07, 2018
*Corresponding author: Denong Wang, Tumor Glycomics Laboratory, SRI International Biosciences Division, 333 Ravenswood
Avenue, Menlo Park, CA 94025, USA, Tel:
; Email:
Abstract
Liquid biopsy uses noninvasive blood test to assess tumor heterogeneity and evolution in real time. It looks for tumor
components in the blood circulation, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), to provide tumorspecific information. By detecting multiplex tumor biomarkers, including nucleic acids, proteins, carbohydrates, and other tumorderived substances, liquid biopsy helps with early tumor diagnosis, tumor evolution monitoring, and prognosis prediction. With the
development of high-throughput OMICS tools like carbohydrate microarray and high-speed fiber-optic array scanning technology
(FAST scan), it is now practical to identify glycan markers of CTCs and cancer stem cells(CSCs), especially those that are cell-surface
exposed and readily accessible for immune recognition and targeting. Potential of this class of biomarkers in tumor sub typing and
targeted immunotherapy is yet to be explored
Keywords: Blood group precursor; Cancer stem cells; Carbohydrate microarray; Circulating tumor cells; Circulating tumor DNA;
Glycan markers; Glycomics; Liquid biopsy
Introduction
For long time, traditional tissue biopsy has been considered
as “golden standard” for tumor diagnosis and assessment.
However, clinicians have never been satisfied, because high risk of
complications come with highly invasive biopsy procedure, and only
limited samples are available, which prevents us from analyzing
tumor heterogeneity and real-time monitoring of tumor evolution
[1,2]. Questions have been raised: “Can we find a noninvasive test
to provide adequate information of tumor?” As the development
of new technologies, liquid biopsy comes as a blood test for tumor
analysis. It is considered to have tremendous potential to influence
the next generation of precision tumor medicine [3]. Compare to
tissue biopsy, liquid biopsy provides a new noninvasive modality
to assess tumor heterogeneity and evolution in real time. It uses
peripheral blood test to look for tumor components, including
CTCs, ct DNA, tumor-derived exosome, and tumor-educated
blood platelets (TEPs), etc. [4]. CTCs are tumor cells detected in
peripheral blood that escape from primary tumors. A subset of CTCs
called cancer stem cells (CSCs), are undifferentiated tumor cells
with embryonic characteristics and epithelial-to-mesenchymal
transition trait. CTCs/CSCs have ability to give rise to new tumors
and play key roles in tumor metastasis [5,6]. CtDNA is tumorderived fragmented DNA in the bloodstream that could reflect the
tumor genome. While CTCs and ctDNA are most widely studied in
the clinical and research area, relevant molecular information may
also be obtained from analyzing RNAs in the form of exosomes and
TEPs [7].
Compare to conventional serum-based biomarkers, liquid
biopsy offers tumor-specific information from multiple molecular
levels. In the clinical situation, the lack of tumor-specific biomarkers
has always been a road block to make good use of current serumbased protein biomarkers, such as carcinoma antigen-125(CA-125),
carcinoembryonic antigen (CEA), and prostate-specific antigen
(PSA). They are found in serum of individuals without cancer, and
in substantial portion of patients with advanced cancers, they are
not elevated [1,3].
Although clinicians have combined these biomarkers with
image and pathological parameters, their utility is greatly limited
by low specificity. Liquid biopsy study, especially characterization
of CTCs/CSCs molecular features, offers the opportunity to obtain
tumor information at the levels of nucleic acids, proteins and
carbohydrates, etc.. Moreover, it will facilitate the identification of
biomarkers that are exclusively expressed on tumor cells, but not
on normal blood cells [7,8].
Citation: Yi Jiang, Denong W. Liquid Biopsy in the OMICS Era of Tumor Medicine. Op Acc J Bio Eng & Bio Sci 1(3)- 2018. OAJBEB.
MS.ID.000115. DOI: 10.32474/OAJBEB.2018.01.000115.
79
Op Acc J Bio Eng & Bio Sci
Liquid biopsy utilizes multiple biomarkers to help with
early tumor detection that leads to early treatment. Cohen et
al introduced the Cancer SEEK test [9], which was a blood test
that utilized combined assays for genetic alterations and protein
biomarkers, to identify eight common cancer types in relatively
early stage and also to localize the organ of origin of these cancers.
Also, for patients with risk factors of developing cancer, CTCs-based
liquid biopsy study can be used for early cancer screening[8],
like early diagnose lung cancer in chronic obstructive pulmonary
disease(COPD) patients [10] and detection of hepatocellular cancer
in patients with viral hepatitis and cirrhosis [11].
Liquid biopsy also provides information for prognosis, monitors
tumor evolution in real time. Clinical guidelines have reached
agreement that numeration of baseline CTCs provides significant
prognostic information for metastatic cancers of breast, colon and
prostate [8]. Real-time monitoring CTCs enumeration and specific
ctDNA mutations related to relapse and resistance of anti-cancer
treatment can also guide patient management [7,8].
More and more innovative tools of technologies are bringing
novel insights into cancer evolution. For CTCs evaluation, the most
popular technology CellSearch [12,13] have involved magnetically
tagged antibodies against the epithelial cell surface marker EpCAM
for CTCs isolation. To achieve a highly pure CTCs population for
better isolation and characterization, “CTC-Chip” and further “CTCiChip” make use of integrated microfluidic technology [3]. Another
technology HD-CTC is able to identify CTCs in high definition
based on automated digital microscopy (ADM) [14]. For Analysis
of ct DNA, the challenge is not isolation but is to detect genetic
alterations in such a small fraction of total DNA in the circulation.
Digital polymerase chain reaction(PCR)-based technologies have
been used to evaluate point mutations of ct DNA [1]. While for
whole genome analyses, Personalized Analysis of Rearranged Ends
(PARE) and related approaches [15] use genome rearrangements
information for detection of tumor biomarkers in the circulation,
another genome-wide method called digital karyo typing [16]
detects copy-number alterations. Meanwhile, certain structural
alterations in gene regions can also be detected by targeted
sequencing [3].
Recognition of abnormal glycosylation in virtually every cancer
type has raised great interest in exploring the tumor glycome
for biomarker discovery [17-20]. A team of tumor glycomics
researchers integrated the use of carbohydrate microarrays and
FAST scan to explore cell-surface glycan markers of breast tumor
CTCs (bCTCs) and targeting antibodies [6,20-22]. First, using
carbohydrate microarrays, anti-tumor monoclonal antibodies
(mAbs) were scanned against a large panel of carbohydrate
antigens to identify those specific for tumor glycan markers.
Subsequently, using FAST-scan technology, the identified mAb
was applied to monitor CTC expression of corresponding glycan
markers in patients with advanced breast cancer (BCA). This
approach revealed the glyco-epitope gpC1 as a cell-surface marker
Copyrights@ Yi Jiang, et al.
of bCTCs and breast tumor CSCs (bCSCs). Interestingly, the gpC1
marker is a conserved antigenic determinant of human blood group
precursors, i.e., the internal domains or core structures of human
blood group substances. These structures are generally masked by
other sugar moieties, such as the -L-fucosyl end groups and other
sugar residues essential for blood group A, B, H, or Lewis (Le) active
side chains [6,23], but become over expressed or surface-exposed
by bCTCs and bCSCs that play vital role in tumor metastasis.
Of note, tumor-associated over expression of blood-grouprelated autoantigens is not limited to BCA [17,18]. Recently, Gao et
al reported the natural ligand of a prostate cancer (PCA)-specific
mAb F77 is in fact blood-group H [24,25]. Over expression of
gpF77 in PCA may reflect increased blood-group H expression
together with up-regulated expression of branching enzymes.
The mAb C1, which recognizes gpC1, differs from F77 in glycanbinding specificities and tumor-binding profiles and does not react
with blood group H nor the cell surface targets of PC3 [21,23].
These studies demonstrate epithelial tumor expression of blood
group substance-related autoantigens and suggest blood group
precursor-based “cryptic” molecules may be appropriate targets
for immunotherapy of epithelial tumors.
Liquid biopsy study, together with multiplex tumor biomarkers
explored by high-throughput Omics tools, is continuously
making progress in the “OMICS” era, where tumor heterogeneity
analysis, real-time tumor evolution monitoring, and personalized
tumor therapy become applicable in research and ultimately in
clinical situation. Meanwhile, there are still questions that could
potentially guide future research development. First, rare CTCs
and ct DNA in the circulation require more sensitive and reliable
detection platforms, especially for early tumor screening and
diagnosis. For tumors origin from central nervous system, where
physical blood-brain barrier prevents adequate CTCs or ct DNA
from entering the circulation [1], noninvasive liquid biopsy faces
more challenges in detecting and analyzing tumor information;
Secondly, the discordance of tumor biomarkers between primary
tumor and metastatic sites, and the heterogeneity of CTCs increase
the difficulty of selecting the correct anti-cancer treatment. Thus,
further investigation on tumor heterogeneity based on single-cell
assessment technologies may provide more information to improve
personalized medicine. Lastly, based on the findings of tumor
glycomics, natural blood group substance-related autoantigens that
expressed on epithelial tumors require further characterization
and evaluation. Ultimately, by molecular engineering and chemoenzymatic synthesis of the antigens, more progress in the field
of tumor vaccine development and targeted immunotherapy is
expected.
Acknowledgements
This work was supported in part by NIH grants U01CA128416,
R56AI118464, and R21AI124068 to DW. The content is solely the
responsibility of the authors and does not necessarily represent the
official views of the National Institutes of Health.
Citation: Yi Jiang, Denong W. Liquid Biopsy in the OMICS Era of Tumor Medicine. Op Acc J Bio Eng & Bio Sci 1(3)- 2018. OAJBEB.
MS.ID.000115. DOI: 10.32474/OAJBEB.2018.01.000115.
80
Op Acc J Bio Eng & Bio Sci
Copyrights@ Yi Jiang, et al.
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Citation: Yi Jiang, Denong W. Liquid Biopsy in the OMICS Era of Tumor Medicine. Op Acc J Bio Eng & Bio Sci 1(3)- 2018. OAJBEB.
MS.ID.000115. DOI: 10.32474/OAJBEB.2018.01.000115.
81