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Page 4 of 8                           Uchihara et al. J Cancer Metastasis Treat 2018;4:9  I  http://dx.doi.org/10.20517/2394-4722.2017.81


               Table 1. Gastric cancer stem cell markers
                Marker              General function         Significance    Therapeutic targets  References
                CD44         Cell adhesion molecule, hyaluronic acid  Tumorigenicity, spheroid   Glutathione metabolism  [16,28,58]
                             receptor                  formation, chemoresistance  (CD44v)
                CD24/CD44    Cell adhesion molecule    Tumorigenicity                       [17]
                CD54/CD44    Cell adhesion molecule    Tumorigenicity, hierarchical         [18]
                                                       organization
                Lgr5         Wnt target gene, restriction to the crypt  Tumorigenicity  Notch-mTOR signal  [21,23,24,46,59-62]
                             base                                          miR-132
                Lrig1        Regulatory factor of cell cycle  Tumorigenicity  Not shown     [32]
                Mist1        Transcriptional regulator  Tumorigenicity     Not shown        [33]
                EpCAM/CD44   Cell adhesion molecule    Tumorigenicity, phenotypical   Not shown  [19]
                                                       heterogeneity, chemoresistance
                ALDH1        Detoxifying enzyme        Tumorigenicity, phenotypical   Not shown  [27,28]
                                                       heterogeneity
                CD90         Immunoglobulin superfamily  Tumorigenicity, trastuzumab   CD90  [29,30]
                                                                  +
                                                       reduce the CD90  population
                CD71         Transferrin receptor      Tumorigenicity,     Not shown        [31]
                                                       chemoresistance, tumor cell
                                                       invasion
                CD133        Pentaspan transmembrane glycoprotein Poorly differentiated gastric   CD133  [25,26,56,63]
                                                       cancer, independent prognostic
                                                       factor

               One study showed that CAFs significantly increased the number of spheroid colonies, the expression
               level of CSC markers and the fraction of side population cells in scirrhous GC cell lines. The influence
               of CAFs was significantly inhibited by TGF-b inhibitors, but not by fibroblast growth factor receptor or
               cMet inhibitors. These findings suggest that CAFs might promote CSC properties in scirrhous GC through
                             [44]
               TGF-b signaling . IL-17B induced the expression of the self-renewal-related genes Nanog, Sox2, and Oct4
               in mesenchymal stem cells and promoted tumor progression. After treatment with exogenous IL-17B, the
               supernatant from cultured mesenchymal stem cells promoted the proliferation and migration of GC cells.
               This suggests that IL-17B might promote the production of soluble factors by mesenchymal stem cells, which
               leads to GC progression .
                                   [45]
               A recent compelling study demonstrated that nerves help to regulate both normal and neoplastic stem
               cell dynamics in the gastrointestinal stem cell niche. The authors of that study utilized a series of Dclk1-
               CreERT mouse models to show that acetylcholine from nerves and from Dclk1+ tuft cells, which acted as
               intermediary niche cells to coordinate neural input to help regulate subsequent stem cell activity, induced
                                                                                                       [46]
               nerve growth factor in gastric epithelial cells; this in turn promoted neuron expansion and tumorigenesis .

               CURRENT TREATMENT OF GC AND THE POTENTIAL FOR TARGETING GCSCS
               Surgical resection is currently the only curative modality to eliminate GC. Endoscopic screening has become
               widespread, however, GCs are frequently diagnosed at an advanced stage, when the clinical outcomeis still
               poor. Even after curative surgery, patients with advanced GC still experience recurrence, which implies that
               undetectable GC cells exist in the blood at the time of surgery. Based on this possibility, definitive evidence
               has been found that multimodal treatments consisting of surgery with neoadjuvant chemotherapy, adjuvant
               chemotherapy, or chemoradiation would improve the poor outcomes compared with surgery alone.


               In recent years, several molecular-targeted agents have been investigated in various combinations with
               conventional treatment as a first-line chemotherapy against advanced GC. The Trastuzumab for Gastric
               Cancer (ToGA) trial revealed that trastuzumab, a recombinant monoclonal antibody against HER2 (also
               known as ERBB2), combined with fluoropyrimidine plus cisplatin provided a significant survival advantage
               compared with fluoropyrimidine plus cisplatin alone in patients with HER2-positive advanced GC [29,47,48] .
               The ramucirumab for patients with previously treated advanced gastric or gastro-esophageal junction
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