Biliary tract cancer stem cells - translational options and challenges

Table 1 Surface and functional cancer stem cell markers in biliary tract cancer and their clinical consequences

Marker	Tissue	M	R	S	TS	Comment	Ref
Surface stem cell markers
CD24	CC, IHC	↑	↑	↓			[68-70]
CD44	CC, EHC, IHC, peri-hilar CC, HCC-CC	↑		↓		↓differentiation, ↑recurrence	[28,71-75]
CD133	CC			↓	↑		[28,63,71]
CXCR4	GBC, IHC	↑		↓	↑	↑vascular invasion	[52,76]
EpCAM	IHC			↓			[28,77]
Functional stem cell markers
ALDH1	EHC, IHC, perihilar CC		↑	↓			[58,78]
BMI1	EHC, HCC-CC, IHC, perihilar CC					↑in tumor specimens	[71,79,80]
NANOG	EHC, IHC, perihilar CC
NESTIN	EHC, IHC, perihilar CC
OCT3/4	GBC, CC	↑		↓	↑	↑tumor size	[63,81]
SALL4	IHC	↑		↓		↑vascular and nerve invasion	[82]
SOX2	EHC, IHC, perihilar CC	↑		↓	↑		[71,74]

CC: Cholangiocarcinoma; EHC: Extrahepatic cholangiocarcinoma; GBC: Gallbladder cancer; HCC-CC: Combined hepatocellular-cholangiocarcinoma; IHC: Intrahepatic cholangiocarcinoma; M: Metastasis; R: Therapeutic resistance; S: Survival; TS: Tumor stage.

Table 2 Overly active pathways associated with cancer stem cell-like phenotype in biliary tract cancer specimens

Pathway	Component	Tissue	Outcome	Ref.
Hh	GLI1	GBC	↑ lymph node metastasis	[92,100]
	SHH	CC, GBC	↑ grade (by trend)	[92,100,101]
	SMO	GBC		[92]
JAK / STAT	STAT3	CC, IHC	↑ tumor size, ↑ metastasis, ↑ vascular invasion, ↓ survival, poor histological differentiation	[102,103]
mTOR	mTOR	BTC	↓ survival	[104]
	pmTOR1	GBC	↓ survival	[105]
NOTCH	NOTCH 1	EHC	poor histological differentiation, ↓ survival, ↑ tumor grade, ↑ Cyclin E	[86,87]
	NOTCH 2	EHC	↓ survival	[86]
	NOTCH 3	EHC	↓ survival, ↑ tumor grade, ↑ Cyclin E	[86,87]
	NOTCH 4	EHC		[86]
	HES-1	EHC	↓ survival	[86]
Wnt	β-catenin	CC	↑ metastasis	[91]2

¹Phosphorylated mTor;

²In this study, no non-tumor control samples were used as control. CC: Cholangiocarcinoma; EHC: Extrahepatic cholangiocarcinoma; GBC: Gallbladder cancer; IHC: Intrahepatic cholangiocarcinoma.