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Page 2 of 11 Nakamura et al. J Cancer Metastasis Treat 2018;4:32 I http://dx.doi.org/10.20517/2394-4722.2017.78

Cancer metastasis and recurrence have been conventionally diagnosed by imaging test or serum tumor
marker; however, these modalities cannot provide a precise and timely assessment of the process of
metastasis and recurrence. This process has been interpreted as involving the circulating tumor cells (CTCs),
[2]
which are infiltrated into the bloodstream. The detection of CTCs was first described in 1869 , and the “seed
[3]
and soil” hypothesis was proposed in 1889 . This hypothesis suggested that the dissemination of metastatic
tumor cells was organ-specific and not simply anatomic. Because the isolation and detection of CTCs in the
blood was technically difficult, the critical role of CTCs has finally been demonstrated more than a century
[4]
later . At last, recent technology has contributed to the diagnosis and treatment of various cancers. The
utility of CTCs for early diagnosis, prediction of prognosis, monitoring of the response to anticancer drugs,
[5-8]
and early detection of recurrence has been demonstrated in several types of human cancer . Moreover, it
is expected that the research of CTCs elucidates the biological mechanisms of cancer metastasis and leads to
better understanding of tumor heterogeneity. However, the clinical significance of CTCs and its biology in
gastric cancer remain controversial. In this article, we review the latest progress of CTCs in gastric cancer.

CANCER METASTASIS AND CTCS
Cancer metastasis is composed of several complex and interrelated steps, including transformation, migration,
local invasion, intravasation into circulation, detachment, arrest at organs, extravasation, colonization, and
proliferation. All steps are absolutely integral to the establishment of metastasis. In these processes, CTCs
exhibit phenotypic diversity, such as epithelial mesenchymal transition (EMT) phenotype, and cancer stem cell
[9]
(CSC) phenotype , which facilitates metastasis.
[10]
EMT has been shown to play a critical role in metastatic spread by enhancing cancer cell mobility . During
EMT, epithelial cells change phenotype, such as reduction of cell-cell contacts, loss of polarity, development
of cell mobility and invasiveness, repression of epithelial markers, and acquisition of mesenchymal
phenotype. Epithelial markers [e.g., epithelial cells adhesion molecule (EpCAM), cytokeratin (CK), or
E-cadherin] downregulate, while mesenchymal markers (e.g., vimentin, or N-cadherin) upregulate through
[11]
EMT. Cancer cells undergoing EMT may intravasate as CTCs. Iwatsuki et al. suggested that vimentin-
positive tumor cells could survive in the peripheral circulation and the bone marrow and that vimentin-
positive cancer cells invading intratumoral vessels must have undergone mesenchymal transition in gastric
[12]
cancer. Furthermore, Wu et al. reported that mesenchymal CTCs detected by using EMT markers were
more commonly found in patients with metastatic sites of several types of human cancers.

In the EMT process, cancer cells can acquire stem cell-like properties, such as self-renewal, tumor initiation,
[13]
undifferentiated status, and treatment resistance . CD44 has been reported as a representative marker of
[14]
CSCs in gastric cancer . It has been demonstrated that CD44-positive CTCs were associated with cancer
[15]
progression and recurrence in gastric cancer . A recent study revealed that CD44-positive CTCs decreased
after surgery or chemotherapy; therefore, they may be a predictive marker of treatment response in gastric
[16]
cancer .

METHODOLOGY IN CTCS IDENTIFICATION
CTC identification typically undergoes two processes of “enrichment” and “detection”. The enrichment
process is needed to detect CTCs efficiently, because CTCs are extremely rare, ranging between 1 to 10 cells
[17]
per 10 mL in the peripheral blood . CTCs can be enriched based on their biological and physical properties.
[18]
Then, CTCs are detected using immunological, molecular, and functional assays [Table 1 and Figure 1] .
Enrichment techniques
Biological property-based techniques
The biological enrichment techniques are based on specific surface makers detected by antibodies. Epithelial