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Huang et al. J Cancer Metastasis Treat 2019;5:34 I http://dx.doi.org/10.20517/2394-4722.2018.94 Page 13 of 18

Beyond enumeration alone, CTCs could provide crucial information of tumor malignancy via molecular
characterization, leading to better treatment monitoring and molecular-/cancer cell-targeted therapies. The
genotypic changes in CTCs provided the best suitable targeted therapy and enabled assessment treatment
regimen efficacy over time. Epidermal growth factor receptor (EGFR) on the CTC surface has been verified
as extremely significant in the process of tumor growth and progression. EGFR inhibitors (HER2 inhibitors,
tyrosine kinase inhibitors, TKI and monoclonal antibodies) have been licensed for treatment of cancers
caused by EGFR up-regulation, such as NSCL, breast, renal cell, squamous cell, colon and pancreatic cancers.
However, in some cases, EGFR-targeted inhibitors are not effective due to the emergence of drug-resistance
mutations. Mutation screening analysis of EGFR in CTCs may provide an explanation for drug-resistance
mechanism and also reveal possibilities for diagnostic and therapeutic interventions . Inhibitors of other
[60]
therapeutic molecular targets including mTOR, such as temsirolimus, and phosphoinositide 3-kinase
(PI3K), such as ZSTK474, LY294002, have shown to have anti-proliferation in clinical trials [86,87] . Most cell
populations of the immune system play an important role in survival and seeding, or even enhancing the
growth of tumorigenic subpopulations of CTCs. The molecular characterization of CTCs might assist in
unveiling intercellular interaction mechanisms and providing potential therapeutic targets. For instance,
the extracellular surface interacting protein, PD-L1, is one such target that is currently generating much
interest . In consideration of costs and toxicity of anti-PD-L1 therapy, predictive biomarkers able to
[84]
distinguish responders from non-responders are in urgent demand. Real-time CTC analysis provides
significant information on drug resistance . In addition, CTCs are now regarded as a new cellular therapeutic
[88]
target. Photodynamic therapy was used to selectively kill GFP-expressing CTCs by energy transfer between
expressed GFP and pre-accumulated rose bengal (RB) in cells, demonstrating that clearance of CTCs could
reduce metastasis and extend survival .
[89]

CONCLUSION AND OUTLOOK
The potential clinical value of CTCs has been established. Advances in CTC isolation and molecular
characterization offer the possibility for early detection and diagnosis, improve the satisfaction of therapies,
as well as expand our knowledge about underlying mechanisms of cancer dissemination and progression.

Although the tremendous technical advances in CTC isolation and detection make it possible to analyze
extremely rare CTCs, there are still many hurdles. First, a criterion to standardize different kinds of detection
assays is urgently needed in clinical applications. Secondly, while the emergence of new predictive biomarkers
leads to clearer recognition about tumor metastases and disease progression, novel targets for prognosis and
treatment need to be further validated and standardized. The next frontier of CTCs detection lies in thorough
characterization, which might rely on developing single-cell multi-omic technologies, including genomics,
proteomics, transcriptomics etc.. Finally, research findings provide arguments in favor of the hypothesis
that only a subpopulation (metastasis-initiating cells, MICs) of CTCs in patient blood is responsible for
initiating carcinoma metastasis. A majority of cancer cells may never develop into metastatic phase, but
instead maintain a dormant state or die from the anoikis, immune attacks and physical shear stress in the
vasculature. However, our understanding about the requirements for CTCs being activated from latency
into overt metastases is far from complete. Apart from CTCs, other noninvasive “liquid biopsies” might
provide more supplementary information, including some cell-free components such as circulating tumor
DNA (ctDNA) , microRNAs (miRNA), exosomes, as well as long-coding RNA (lncRNA) [91-94] . Recently, due
[90]
to the success in immunotherapy of cancers, immune checkpoint blocker programmed death-ligand 1 (PD-
L1), whose expression in CTCs correlate with tumor status , has gained interest as a potential independent
[95]
prognostic marker for PFS and OS , extending the spectrum of noninvasive liquid biopsies . And, CTC
[97]
[96]
detection may also have the potential to monitor the efficacy of anti-PD-L1 therapy . Comprehensive and
[98]
systemic liquid biopsy analyses may contribute to thorough understanding of metastatic malignancy and
better management of cancer patients.