Molecular mechanism of therapeutic approaches for human gastric cancer stem cells

Table 1 Potential gastric cancer stem cells cell-surface markers by using flow cytometric analysis

Cell-surface markers	Function	Physiological significance					Involved signaling pathways	Therapeutic targets or inhibitor	Prognostic marker of GC	Ref.
		Tumorigenicity/GCSC generation	Spheroid formation	Chemo-resistance	Radio-resistance	EMT/metastasis
CD44	Hyaluronic acid receptor	●	●	●	ND	●	Wnt/β-catenin pathway	CD44	●	[21-24]
CD44H	Hyaluronic acid receptor	●	●	●	ND	ND	Wnt/β-catenin pathway	CD44	●	[25]
CD44v	Hyaluronic acid receptor	●	●	ND	ND	●	Glutathione metabolism	Glutathione metabolismsulfasalazine (SSZ)	●	[25-28]
CD44+CD24	Cell adhesion molecule	●	●	●	ND	ND	Notch pathway	CD44+CD24	●	[24,29]
CD44+CD54	Cell adhesion molecule	●	●	●	ND	ND	Wnt/β-catenin pathway	CD44+CD54	ND	[22,24,30]
CD44+EpCAM	Cell adhesion molecule/epithelial cell adhesion molecule	●	●	●	ND	ND	Wnt/β-catenin pathway	ND	ND	[24,31]
CD71-	Transferrin receptor	●	ND	ND	ND	●	uptake of transferrin/iron	CD71	●	[32]
CD90	Immunoglobulin superfamily/Thy-1 cell-surface antigen	●	●	ND	ND	●	Notch pathway	CD90trastuzumab	ND	[24,33]
CD133	Pentaspan transmembrane glycoprotein	●	●	ND	ND	ND	MAPK/ERK pathway	CD133	●	[24]
Lgr5	Leucine-rich repeat-containing G-protein coupled receptor 5	●	ND	●	ND	●	Notch-mTOR pathway	Notch-mTOR pathwayMiR-132Anti-Lgr5	●	[34-38]
ALDH1	Aldehyde dehydrogenase 1	●	●	●	●	●	Wnt/β-catenin pathway	TGF-	●	[39]
CD44+CD166+ALDH	Activated leukocyte cell adhesion molecule (ALCAM)	●	●	●	ND	●	Wnt/β-catenin pathway	CD44CD166TGF-	●	[24,40,41]
CXCR4	C-X-C chemokine receptor type 4	●	●	●	ND	●	CXCR4/SDF-1pathway	CXCR4	●	[42]
ABCB1/MDR1ABCG2	ABC transporters	●	●	●	ND	●	JAK/STAT pathwayHH/PTCH1 pathway	ABCB1/MDR1ABCG2	●	[23,33,43-45]
SP	Side population	●	●	●	ND	●	Wnt/β-catenin pathway	ND	●	[21,23,44,46-48]
Lrig1	Regulatory factor of cell cycle	●	●	●	ND	●	ErbB pathway	Lrig1	●	[49]
2-, 5-, 3- and 5- integrins	Cell adhesion molecule	●	●	ND	ND	●	p38/ERK pathway	Integrins	ND	[23]

●: Determined; ND: Not determined. CD44: Cluster of differentiation 44; CD44v: CD44 splice variant; Lgr5: Leucine-rich repeat-containing G-protein coupled receptor 5; ALDH1: Aldehyde dehydrogenase 1; CXCR4: C-X-C chemokine receptor type 4; GCSCs: Gastric cancer stem cells; GC: Gastric cancer; EpCAM: Epithelial cell adhesion molecule; Lgr5: Leucine-rich repeat-containing G-protein coupled receptor 5; ABCB1: ATP-binding cassette subfamily B member 1; ABCG2: ATP-binding cassette subfamily G member 2; MDR1: Multidrug resistance protein 1; SP: side population; Lrig1: Leucine rich repeats and immunoglobulin like domains protein 1; SDF-1: Stromal cell-derived factor-1; SSZ: Sulfasalazine; TGF-β: Transforming growth factor-β; HH: Hedgehog; PTCH1: Patched homolog 1; MAPK: Mitogen-activated protein kinase; ERK: Extracellular-signal-regulated kinase; JAK :Janus kinase; STAT3: Signal transducer and activator of transcription 3; mTOR: Mechanistic target of rapamycin; EMT: Epithelial–mesenchymal transition; EGFR: Epidermal growth factor receptor; miRNA: MicroRNA.

Table 2 Potential gastric cancer stem cells intracellular markers

Intracellular markers	Function	Physiological significance					Involved signaling pathways	Therapeutic targets	Prognostic marker of GC	Ref.
		Tumorigenicity/GCSC generation	Spheroid formation	Chemo-resistance	Radio-resistance	EMT/metastasis
DOCK6	Dock-C subfamily guanine nucleotide exchanger	●	●	●	●	●	Wnt/β-catenin pathway	DOCK6	●	[50]
Mist1	Transcriptional factor	●	●	●	ND	●	Wnt/β-catenin pathway	Mist1	●	[51]
MSI-1	RNA-binding protein	●	●	●	ND	●	EGFR pathway	MSI-1	●	[48]
NANOG	Transcription factor	●	●	●	ND	●	Wnt/β-catenin pathwayJAK-STAT pathway	NANOG	●	[23,52]
Oct3/4	Octamer-binding transcription factor 3/4	●	●	●	ND	●	Wnt/β-catenin pathwayJAK-STAT pathway	Oct3/4	●	[23,53]
SOX2	Sex determining region Y-box 2	●	●	●	ND	●	Wnt/β-catenin pathwayJAK-STAT pathway	SOX2MiR-134all-trans retinoic acid	●	[52-57]

●: Determined; ND: Not determined; DOCK6: Dedicator of cytokinesis 6; Mist1: Muscle, intestine and stomach expression 1; MSI-1: Musashi RNA binding protein 1; GCSCs: Gastric cancer stem cells; GC: Gastric cancer; EMT: Epithelial–mesenchymal transition; NANOG: nanog homeobox; Oct3/4: Octamer-binding transcription factor 3/4; SOX2: Sex determining region Y-box 2; MAPK: Mitogen-activated protein kinase; ERK: Extracellular-signal-regulated kinase; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3; EGFR: Epidermal growth factor receptor; miRNA: MicroRNA.

Table 3 Regulators of gastric cancer stem cells-related pathway stimuli in gastric cancer stem cells stemless properties and gastric cancer stem cells-targeted therapy

GCSCs pathway	Involved pathway proteins	Therapeutic inhibitor or drug	Ref.
Hedgehog (HH)	PTCH1, SMO, GLI	Vismodegib5E1RobotnikininGANT58GANT61HPI1-4GenisteinResveratrolCyclopamineMir-218SaridegibBMS-833923ErismodegibPF-0449913LY2940680	[27,28,83,84]
Notch/STAT3	Notch ligands (DLL), Notch receptors, JAK, ERK, STAT3	NapabucasinDemclzumab (anti-DLL4)TarextumabBBI-608	[28,76,85,86]
NANOG	NANOG, STAT3, Kinases	NapabucasinBBI-608BB1-503	[28,73,75,85]
Wnt/β-catenin	Wnt, β-catenin, LRP/FZD	Napabucasin BBI-608Vantictumab (anti-FZD)LGK974Foxy-5	[28,77,78,85,86]

GCSCs: Gastric cancer stem cells; HH: Hedgehog; NANOG: Nanog homeobox; STAT3: Signal transducer and activator of transcription 3; GLI: Glioma-associated oncogene; SMO: Smoothened; PTCH1: Patched homolog 1; ERK: Extracellular-signal-regulated kinase; JAK: Janus kinase; Wnt: Wingless/int1; LRP: Lipoprotein receptor-related proteins/low density lipoprotein receptor-related proteins; FZD: Frizzled receptors; DLL: Notch ligands.