Copyright ©The Author(s) 2018.
World J Gastroenterol. Jun 28, 2018; 24(24): 2567-2581
Published online Jun 28, 2018. doi: 10.3748/wjg.v24.i24.2567
Table 1 Putative cell surface markers of gastric tumor-initiating cell
Putative markerTumor sphere formation (in vitro)Tumor formation during serial engraftment (in vivo)Limiting dilution assayChemo-resistanceOthersRef.
CD44++Not conducted+(1) Capacity of cell differentiation (2) Giving rise to both CD44+ and CD44- GC cells (3) Independent prognostic factor of GC patientsTakaishi et al[29] Yoon et al[119]
CD44/CD24+++Not conductedCapacity of cell differentiationZhang et al[32]
CD44/CD54+++Not conducted(1) Capacity of cell differentiation (2) Detectable from peripheral bloodChen et al[33]
CD44/CD26++Not conducted+/Nishikawa et al[127]
CD44/EpCam++++(1) Capacity of cell differentiation (2) Restoration of histological heterogeneity from single CD44/EpCam+ cellHan et al[31]
CD44v810/EpCAM++++CD44v8-10 but not CD44 standard increase the frequency of tumor initiationLau et al[30]
CD90++++Restoration of cellular hierarchy from single CD90+ cellJiang et al[35]
CD133++Not conducted+Independent prognostic factor of GC patientsZhang et al[128]
Lgr5++Not conductedNot conducted/Wang et al[40]
ALDH++++/Nishikawa et al[42]
ALDH1/REG4Katsuno et al[45]
Oct4/Sox2/Nanog++Not conducted+Independent prognostic factor of GC patientsLiu et al[129]
Table 2 Gastric tumor-initiating cell-targeted therapeutic strategies/agents
Therapeutic targetTherapeutic agentInvestigation statusUnderlying mechanismTreatmentResult of treatmentRef.
ATOH1Lentiviral vector-basedPreclinical investigationOverexpression of ATOH1 mediates its transcriptional activity to downstream genes and induces the differentiation of GATICsLentiviral vector-based overexpression of ATOH1(1) Induction of CD44+/Lgr5+ GATICs differentiation (2) Reduced tumorigenicity of GATICs both in vitro and in vivoHan et al[115]
PGK1Lentiviral vector-basedPreclinical investigationKnockdown of PGK1 alters the glycolytic metabolism of GATICs not only induces GATIC differentiation but also improve their chemosensitivityLentiviral vector-based knockdown of PGK1(1) Induction of CD44+ GATICs differentiation (2) Inhibited tumor growth and metastasis in vivoZieker et al[116]
CD44vSulfasalazinePhase I dose-escalation clinical study in EPOC1205Targeting CD44v by inhibiting xCT which mainly interacts with CD44v and maintains high level of GSH12 g/d, 4x/d with 2 wk as one cycle, oral administrationReduced level of CD44v positive GATICs in some patientsShitara et al[130]
EpCamCatumaxomabPhase II/III clinical trial of advanced gastric carcinoma_NCT00836654Direct targeting CD3 and EpCamParacentesis +/- CatumaxomabClinical benefit (prolonged PFS and less symptoms of ascites) in GC patients with secondary malignant ascitesHeiss et al[131]
EpCamCatumaxomabPhase II clinical trial of advanced gastric carcinoma_NCT01784900Direct targeting CD3 and EpCamSurgical resection followed by CatumaxomabIntra-/postoperative administration of catumaxomab within multimodal treatment is feasible and tolerableGoéré et al[132]
c-METRilotumumabPhase III clinical trial of locally advanced or metastatic gastric and GEJ carcinoma_NCT01697072Competitively targeting hepatocyte growth factor (HGF), ligand of c-MET receptorECX +/- RilotumumabStopped early due to increased death riskDoshi et al[133]
c-METOnartuzumabPhase III clinical trial of metastatic HER2(-) and c-MET(+) Gastroesophageal Cancer_NCT01662869Direct targeting c-MET as a MET antagonistFOLFOX6 +/- RilotumumabInsignificant prolong of PFS (6.9 mo vs 5.7 mo) and OS (11.0 mo vs 9.7 mo)Shah et al[134]
c-METTivantinibPhase I/II clinical trial of advanced and metastatic adenocarcinoma of distal esophagus, GEJ and stomach_NCT01611857Inhibition of c-Met receptor tyrosine kinaseFOLFOX6 combined with TivantinibPFS: 6.1 mo and OS: 9.6 moPant et al[135]
SHH signaling pathwayCyclopaminePreclinical investigationTargeting overexpressed Ptch/Gli1 (key effectors in SHH pathway)Direct addition of cyclopamine (5 μmol/L in vitro and 10 μmol/L in vivo)(1) Reduced self-renewing capacity of GATIC-enriched tumor sphere (2) Enhanced efficacy of Oxaliplatin/Mitomycin inhibiting proliferation of tumor sphereSong et al[80]
SHH signaling pathwayVismodegibPhase II clinical trial of advanced gastric and GEJ carcinoma_NCT00982592Targeting Smoothened (SMO) and its downstream GLI family membersFOLFOX +/- Vismodegib(1) No significant improvement of anti-tumor activity (2) Potentially reverse the chemotherapy resistance of patients with high CD44-expressing tumor cellsCohen et al[136]
Wnt/β-catenin signaling pathwaySalinomycinPreclinical investigationBlocking and degrading LRP6 (Wnt co-receptor)Direct addition of Salinomycin (ranging from 1 μmol/L to 100 μmol/L in vitro)Effectively kill ALDH-high GATICs which are resistant to 5-FU and CDDPMao et al[87]
Wnt/β-catenin signaling pathwayICG-001Preclinical investigationInhibiting CBP (co-activator of Wnt/β-catenin pathway)Direct addition of ICG-001 (50 mg/kg/d, in vivo)(1) Suppressed GC cell growth and metastasis both in vitro and in vivo (2) Reduced self-renewal capacity and enhanced efficacy of 5-Fu/cisplatinLiu et al[122]
STAT3 signaling pathwayNapabucasinPhase Ib/II dose-escalation and extension study of advanced gastric and GEJ carcinoma_NCT01325441Direct targeting Stat3, β-catenin and NANOGPaclitaxel +/- Napabucasin(1) Well-tolerated by GC patients even receiving high doses of chemotherapy (2) Observed anti-tumor activity but still needs to be further confirmed in the on-going BRIGHTER phase III clinical trialShah et al[137]