Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell

Table 1 Putative cell surface markers of gastric tumor-initiating cell

Putative marker	Tumor sphere formation (in vitro)	Tumor formation during serial engraftment (in vivo)	Limiting dilution assay	Chemo-resistance	Others	Ref.
CD44	+	+	Not conducted	+	(1) Capacity of cell differentiation (2) Giving rise to both CD44+ and CD44- GC cells (3) Independent prognostic factor of GC patients	Takaishi et al[29] Yoon et al[119]
CD44/CD24	+	+	+	Not conducted	Capacity of cell differentiation	Zhang et al[32]
CD44/CD54	+	+	+	Not conducted	(1) Capacity of cell differentiation (2) Detectable from peripheral blood	Chen 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+ cell	Han et al[31]
CD44v810/EpCAM	+	+	+	+	CD44v8-10 but not CD44 standard increase the frequency of tumor initiation	Lau et al[30]
CD90	+	+	+	+	Restoration of cellular hierarchy from single CD90+ cell	Jiang et al[35]
CD133	+	+	Not conducted	+	Independent prognostic factor of GC patients	Zhang et al[128]
Lgr5	+	+	Not conducted	Not conducted	/	Wang et al[40]
ALDH	+	+	+	+	/	Nishikawa et al[42]
ALDH1/REG4						Katsuno et al[45]
Oct4/Sox2/Nanog	+	+	Not conducted	+	Independent prognostic factor of GC patients	Liu et al[129]

ALDH: Aldehyde dehydrogenase; GC: Gastric cancer.

Table 2 Gastric tumor-initiating cell-targeted therapeutic strategies/agents

Therapeutic target	Therapeutic agent	Investigation status	Underlying mechanism	Treatment	Result of treatment	Ref.
ATOH1	Lentiviral vector-based	Preclinical investigation	Overexpression of ATOH1 mediates its transcriptional activity to downstream genes and induces the differentiation of GATICs	Lentiviral vector-based overexpression of ATOH1	(1) Induction of CD44+/Lgr5+ GATICs differentiation (2) Reduced tumorigenicity of GATICs both in vitro and in vivo	Han et al[115]
PGK1	Lentiviral vector-based	Preclinical investigation	Knockdown of PGK1 alters the glycolytic metabolism of GATICs not only induces GATIC differentiation but also improve their chemosensitivity	Lentiviral vector-based knockdown of PGK1	(1) Induction of CD44+ GATICs differentiation (2) Inhibited tumor growth and metastasis in vivo	Zieker et al[116]
CD44v	Sulfasalazine	Phase I dose-escalation clinical study in EPOC1205	Targeting CD44v by inhibiting xCT which mainly interacts with CD44v and maintains high level of GSH	12 g/d, 4x/d with 2 wk as one cycle, oral administration	Reduced level of CD44v positive GATICs in some patients	Shitara et al[130]
EpCam	Catumaxomab	Phase II/III clinical trial of advanced gastric carcinoma_NCT00836654	Direct targeting CD3 and EpCam	Paracentesis +/- Catumaxomab	Clinical benefit (prolonged PFS and less symptoms of ascites) in GC patients with secondary malignant ascites	Heiss et al[131]
EpCam	Catumaxomab	Phase II clinical trial of advanced gastric carcinoma_NCT01784900	Direct targeting CD3 and EpCam	Surgical resection followed by Catumaxomab	Intra-/postoperative administration of catumaxomab within multimodal treatment is feasible and tolerable	Goéré et al[132]
c-MET	Rilotumumab	Phase III clinical trial of locally advanced or metastatic gastric and GEJ carcinoma_NCT01697072	Competitively targeting hepatocyte growth factor (HGF), ligand of c-MET receptor	ECX +/- Rilotumumab	Stopped early due to increased death risk	Doshi et al[133]
c-MET	Onartuzumab	Phase III clinical trial of metastatic HER2(-) and c-MET(+) Gastroesophageal Cancer_NCT01662869	Direct targeting c-MET as a MET antagonist	FOLFOX6 +/- Rilotumumab	Insignificant prolong of PFS (6.9 mo vs 5.7 mo) and OS (11.0 mo vs 9.7 mo)	Shah et al[134]
c-MET	Tivantinib	Phase I/II clinical trial of advanced and metastatic adenocarcinoma of distal esophagus, GEJ and stomach_NCT01611857	Inhibition of c-Met receptor tyrosine kinase	FOLFOX6 combined with Tivantinib	PFS: 6.1 mo and OS: 9.6 mo	Pant et al[135]
SHH signaling pathway	Cyclopamine	Preclinical investigation	Targeting 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 sphere	Song et al[80]
SHH signaling pathway	Vismodegib	Phase II clinical trial of advanced gastric and GEJ carcinoma_NCT00982592	Targeting Smoothened (SMO) and its downstream GLI family members	FOLFOX +/- Vismodegib	(1) No significant improvement of anti-tumor activity (2) Potentially reverse the chemotherapy resistance of patients with high CD44-expressing tumor cells	Cohen et al[136]
Wnt/β-catenin signaling pathway	Salinomycin	Preclinical investigation	Blocking 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 CDDP	Mao et al[87]
Wnt/β-catenin signaling pathway	ICG-001	Preclinical investigation	Inhibiting 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/cisplatin	Liu et al[122]
STAT3 signaling pathway	Napabucasin	Phase Ib/II dose-escalation and extension study of advanced gastric and GEJ carcinoma_NCT01325441	Direct targeting Stat3, β-catenin and NANOG	Paclitaxel +/- 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 trial	Shah et al[137]

GATIC: Gastric tumor-initiating cell; SHH: Sonic hedgehog; GEJ: Gastroesophageal junction; GC: Gastric cancer; ALDH: Aldehyde dehydrogenase.