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Uchihara et al. J Cancer Metastasis Treat 2018;4:9  I  http://dx.doi.org/10.20517/2394-4722.2017.81                            Page 5 of 8







































               Figure 1. GCSCs in the microenvironment and the activated pathway in GCSCs. GCSCs: Gastric cancer stem cells; CAF: cancer-associated
               fibroblasts; TGF: transforming growth factor; IL: interleukin

               adenocarcinoma (RAINBOW) trial showed that the combination of ramucirumab and paclitaxel significantly
               improved overall survival compared with placebo plus paclitaxel and that this combination could be regarded
               as a new standard second-line chemotherapy for patients with advanced GC [49,50] .

               Immune checkpoint blockade is new topic in cancer therapy. The immune checkpoint pathways, which
               basically maintain self-tolerance and limit collateral tissue damage during anti-microbial immune
                                                                         [51]
               responses, can be co-opted by cancer to evade immune destruction . Nivolumab is a human monoclonal
               IgG4 antibody that blocks the human programmed cell death-1 (PD-1) receptor. Preliminary data from
               a double-blinded, randomized, phase III trial (ONO-4538/BMS-936558) demonstrated the efficacy of
               nivolumab as salvage treatment as a third- or later line of treatment in 493 patients with advanced gastric
               or gastroesophageal junction cancer compared with placebo (NCT02267343). Finally, a clinical study
               demonstrated that nivolumab was effective as the salvage treatment for pretreated advanced GC with
                                                                        [52]
               significantly improved clinical outcomes compared with the placebo .

               To develop a treatment strategy to target GCSCs, we must select critical molecules that regulate the biological
               characteristics of CSCs [Figure 1]. Several molecules have been investigated as possible targets including
               those associated with specific signaling pathways, cell surface markers, and microenvironmental factors. We
               previously used K19-Wnt1/C2mE mice, a transgenic GC mouse model, to demonstrate that the CD44 variant
               isoform (CD44v), one of the cell surface markers of GCSCs, contributed to the defense against reactive
               oxygen species by stabilizing the glutamate-cystine transporter subunit xCT and promoting the synthesis of
               the primary intracellular antioxidant glutathione [53,54] . Moreover, we found that CD44v expression was up-
               regulated in these gastric tumor cells. We also showed that the inhibition of the cystine transport system
               xc(-) with sulfasalazine, an inhibitor of xCT-dependent cystine transport, suppressed the progression of
                                                [55]
               gastric tumors in these transgenic mice . Our findings suggest that targeted therapy against the CD44v-xCT
               system may provide a strategy for the targeting of CD44v positive GCSCs. CD133 was a potential therapeutic
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