Intervention on toll-like receptors in pancreatic cancer

Table 1 Toll-like receptors found in human pancreatic adenocarcinoma cell lines

Cell line	Source	Phenotype	Expressed TLR	Ref.
AsPC-1	Metastasis: ascites	Du	TLR3, TLR4, TLR9	[23,57,58]
BxPC-3	Primary tumor	Du	TLR2-4	[40,50,57]
CFPAC	Metastasis: liver	Du	TLR4	[57]
Colo357	Metastasis: lymph node	Un	TLR3, TLR7	[48]
GER	Primary tumor	An	TLR9	[72]
MIA PaCa-2	Primary tumor	An	TLR2-4, TLR7, TLR9	[23,40]
MDAPanc-28	Primary tumor	Du/Ac	TLR2-4, TLR7, TLR9	[23]
Panc-1	Primary tumor	Du/An	TLR2-4, TLR7, TLR9	[23,40,50,58,79]
Panc-89	Metastasis: lymph node	Du	TLR3 , TLR7	[48]
PancTu-1	Primary tumor	Du	TLR3, TLR7	[48]
Pt45P1	Primary tumor	Du	TLR3, TLR7	[48]
SU.8686	Metastasis: liver	Du	TLR2	[41]
SW-1990	Metastasis: spleen	Du	TLR2-4, TLR7, TLR9	[23]
T3M4	Metastasis: lymph node	Du	TLR9	[77]

TLR: Toll-like receptor; Du: Ductal; Ac: Acinar; An: Anaplastic; Un: Undefined.

Table 2 Toll-like receptors expressed in pancreatic ductal adenocarcinoma and their reported implications

	Pathophysiological significance	Ref.
TLR2	Cell growth	[33,40,43]
	Immunosuppression	[33,41,43]
	Mean survival	[33,35]
	Progression and metastasis	[43]
TLR3	Carcinogenesis	[47]
	Cell growth and migration	[50]
	Immune responses	[48]
TLR4	Angiogenesis	[63]
	Carcinogenesis	[49]
	Cell growth	[49,57,61]
	Epithelial-to-mesenchymal transition	[61]
	Leukocyte recruitment and genomic instability	[57]
	Mean survival	[62]
	Progression and metastasis	[49,58,61]
	Stromal expansion	[49,61]
TLR7	Carcinogenesis, stromal expansion, progression and metastasis	[67]
	Immune responses	[48]
TLR9	Cell growth	[77,79]
	Mean survival	[77]
	Metastasis	[72,77,79]

TLR: Toll-like receptor.

Table 3 Toll-like receptors and their intervention in pancreatic ductal adenocarcinoma

	Substance/compound	Intervention	Effects	Ref.
TLR2	MALP-2 (G)	Activation	Induce lymphocyte invasion and tumor necrosis	[33]
			Inhibit tumor growth	[33]
			Prolongs mean survival	[35]
			Reverse tumor-associated immunosuppression	[33]
	Polysaccharide-K (G)	Activation	Inhibit tumor growth and induce apoptosis in tumor cells	[40]
	Dmt-Tic-Cy5	Activation	Acts as vaccine adjuvant in pancreatic cancer	[41]
			Target imaging and therapy	[41,42]
	PAUF	Mixed	Facilitates tumor growth	[43]
			Promotes tumor immune-resistance	[43]
TLR3	Polycytidylic acid	Activation	Accelerates carcinogenesis	[49]
			Induces T cell invasion and tumor lysis	[48]
	Phenylmethimazole	Inhibition	Inhibits tumor growth and migration	[50]
TLR4	Lipopolysaccharide	Activation	Accelerates carcinogenesis	[49]
			Induce desmoplastic stroma	[49]
			Induce increased H2O2 extracellular production	[57]
			Increased invasiveness	[58,61]
			Induce M2-polarization in tumor-associated macrophages	[61]
TLR7	Imiquimod	Activation	Induce T cell invasion and tumor lysis	[48]
	IRS661	Inhibition	Prevent tumor progression and stromal expansion	[67]
			Regulates cell cycle in cancer cells	[67]
TLR9	CpG-ODN 1816/26 (G’)	Activation	Delays tumor development, reduce invasiveness	[72]
			Prolongs mean survival	[72]
	IMO (C)	Activation	Prolongs mean survival, inhibit tumor growth and migration	[77]
			Reestablish cetuximab sensibility in cancer cells	[77]
	CpG-ODN 2216	Activation	Inhibits tumor growth and migration	[79]

TLR: Toll-like receptor; MALP-2: Macrophage activating lipopeptide-2; PAUF: Pancreatic adenocarcinoma upregulated factor; IRS661: Immunoregulatory sequence 661; CpG-ODN: CpG oligodeoxynucleotide; IMO: Immunomodulatory nucleotides. (G): Synergism when combined with gemcitabine; (G’): Effect mainly when combined with gemcitabine; (C): Effect merely when combined with cetuximab.