Emerging evidence of the molecular landscape specific for hematogenous metastasis from gastric cancer

Table 1 Molecules reported to be associated with hematogenous metastasis from gastric cancer

Molecule	Full name	Biological function	Specimens	Detection methods	In vivo	Associating molecules and cells	Ref.
EMT and invasion into the circulation
VIM	Vimentin	Type III intermediate filament	GC tissue	IHC	-	HER2	[16]
GPR155	G protein-coupled receptor 155	Seven-pass transmembrane receptor	GC tissue, GC cell line	qPCR, IHC	-	TWIST1, WNT5B, p-ERK1/2, p-STAT1	[19]
Survival in the circulation
HIF-1α	Hypoxia inducible factor-1 alpha	Transcription factor in response to hypoxia	GC tissue	IHC	-	-	[25]
EGFL7	Epidermal growth factor-like domain-containing protein 7	Epidermal growth factor for vasculogenesis	GC tissue, GC cell line	qPCR, WB, IHC	Yes	AKT, SNAI1	[30]
Premetastatic niche
CXCL1	C-X-C motif chemokine ligand 1	Inflammatory chemokine binding CXCR2	CRC cell line, liver (M)1, lung (M)1, cecum (M)1	ELISA, FCM	Yes	CXCR2, VEGF-A, MDSCs	[36]
TIMP1	Tissue inhibitor of metallopeptidase 1	Inhibitor of MMPs	Plasma, CRC tissue, CRC cell line, liver (M)1	qPCR, ELISA	Yes	SDF-1, Neutrophil	[43]
			Plasma, PDAC tissue, PDAC cell line (M), liver (M)	qPCR, ELISA, IHC	Yes	PI3K, CD63, SDF-1, HSC, Neutrophil	[44]
Exosome	-	Cell-derived membrane vesicle	CRC tissue, serum, CRC cell line	qPCR, WB	Yes	miR-203	[51]
			PDAC cell line, liver (M)1, lung (M)1, spleen (M)1, kidney (M)1, brain (M)1, bone marrow (M)1	WB, IHC, IF, FCM, Proteomics	Yes	Proteins2	[52]
Migration, invasion and proliferation at the target organs
NFKB1/p105	Nuclear factor kappa B subunit 1	Transcription factor	GC tissue	FCM	-	-	[55]
			GC tissue	FCM	-	Ki-67	[57]
MAP1LC3	Microtubule associated protein 1 light chain 3	Subunit of MAP1 and associated with autophagy	GC tissue	IHC	-	-	[63]
BECN1	Beclin1	Autophagy regulator and component of PI3K complex	GC tissue	IHC	-	-	[63]
SQSTM1/p62	sequestosome 1	Activator of NF-kB signaling	GC tissue	IHC	-	-	[63]
MFSD4	Major facilitator superfamily domain containing 4	Multi-pass transmembrane protein	GC tissue, GC cell line	qPCR	-	BMP2, NUDT13, OCLN	[64]
PAK1	p21 (RAC1) activated kinase 1	serine/threonine p21-activating kinase	GC tissue, GC cell line	qPCR, WB, IHC, IF	Yes	ATF2, miR-132, CD44, FN1	[66]
Angiogenesis
VEGF-D	Vascular endothelial growth factor-D	Growth factor for angiogenesis	GC tissue	IHC	-	-	[70]
TYMP	Thymidine phosphorylase	Angiogenic factor	GC tissue	IHC	-	-	[72]
			GC tissue	IHC	-	-	[73]
Biomarkers predicting hematogenous metastasis from GC
IL-6	Interleukin-6	Inflammatory cytokines	Serum	ELISA, CLEIA	-	HGF	[78]
Glut1	Glucose transporter-1	Glucose transporter	GC tissue	IHC	-	-	[79]
HER2	Human epidermal growth factor receptor 2	Epidermal growth factor receptor	GC tissue	IHC, FISH	-	-	[80]
			GC tissue	IHC, FISH	-	-	[81]
NCPAP3	NTase domain containing non-canonical poly(A) polymerase 3	mRNA stabilizing factor	GC tissue, GC cell line	qPCR	-	-	[82]
NPM1	Nucleophosmin 1	Nucleolar protein	GC tissue	IHC	-	-	[83]
CXCR4	C-X-C motif chemokine receptor 4	Inflammatory chemokine receptor binding CXCL12	GC tissue	IHC	-	CXCL12	[84]
CXCL12	C-X-C motif chemokine ligand 12	Inflammatory chemokine binding CXCR4	GC tissue	IHC	-	CXCR4	[84]
D-Dimer	-	Fibrin degradation product	Plasma	LEIA	-	-	[85]
Fibrinogen	-	Coagulation factor	Plasma	Clauss clotting method	-	-	[86]
CD44v6	CD44 variant 6	Adhesion molecule	GC tissue	qPCR, IHC	-	-	[87]

¹(M): Specimen obtained from mouse;

²70 proteins were listed in the original article. IHC: Immunohistochemistry; qPCR: Quantitative reverse transcription polymerase chain reaction; TWIST1: Twist family bHLH transcription factor 1; WNT5B: Wingless-type MMTV integration site family, member 5B; p-: Phosphorylated; ERK1/2: Extracellular signal-regulated kinase 1 and 2; STAT1: Signal transducer and activator of transcription 1; WB: Western blotting; AKT: AKT serine/threonine kinase; SNAI1: Snail family transcriptional repressor 1; CRC: Colorectal cancer; ELISA: Enzyme-linked immunosorbent assay; FCM: Flow cytometry; MDSCs: Myeloid-derived suppressor cells; MMPs: Matrix metalloproteinases; SDF-1: Stromal cell-derived factor 1; PDAC: Pancreatic ductal adenocarcinoma; PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; HSC: Hepatic stellate cell; miR: MicroRNA; IF: Immunofluorescence; Ki-67: Marker of proliferation Ki-67; MAP1: Microtubule-associated proteins 1; BMP2: Bone morphogenetic protein 2; NUDT13: Nudix hydrolase 13; OCLN: Occluding; ATF-2: Activating transcription factor 2; FN1: Fibronectin 1; CLEIA: Chemiluminescent enzyme immuno assay; HGF: Hepatocyte growth factor; FISH: Fluorescence in situ hybridization; GC: Gastric cancer.