Clinical significance of exosomes as potential biomarkers in cancer

Table 2 Studies included for meta-analysis of exosomal biomarkers in cancer prognosis

Ref.	Period	Country	Sample Size	Cancer Type	Stage	Sample	Isolation method of exosome	Marker	Detection method	Cut-off value	Survival analysis	HR (95%CI)
Peng et al[65]	2008-2014	China	108	Colorectal	All	Serum	Total exosome isolation kit	miR-548c-5p	qRT-PCR	NR	OS	3.40 (1.02‐11.27)
Sun et al[35]	2012-2017	China	92	Colorectal	All	Plasma	UC	CPNE3	ELISA	≥ 0.143 pg/μg exosome	OS	3.0 (1.0-8.9)
										≥ 0.143 pg/μg exosome	DFS	2.5 (1.1-5.5)
Tsukamoto et al[66]	2002-2012	Japan	326	Colorectal	II-IV	Plasma	UC	miR-21	qRT-PCR	> median	OS	2.28 (1.81-5.74)
											DFS	2.34 (1.87- 4.60)
Liu et al[37]	2007-2010	China	148	Colorectal	All	Serum	ExoQuick	CRNDE-h	qRT-PCR	> 0.02	OS	2.000 (1.269-3.154)
Liu et al[67]	2006-2011	United States	84	Colorectal	II-III	Serum	ExoQuick	miR-4772-3p	qRT-PCR	≥ 27.88	OS	6.19 (1.50-25.5)
										≥ 27.88	RFS	5.48 (2.49-12.1)
Liu et al[24]	2013-2014	China	158	Colorectal	All	Plasma	UC	lncRNA GAS5	qRT-PCR	NR	OS	0.265 (0.082 -0.844)
											RFS	0.449 (0.194- 0.909)
								miR-221	qRT-PCR	NR	OS	2.141 (1.368-3.054)
											RFS	1.600 (1.162-2.007)
Gao et al[68]	2011-2014	China	108	Colorectal	All	Serum	ExoQuick	91H	qRT-PCR	≥ 0.85	RFS	7.14 (1.23-21.35)
Yan et al[69]	NR	NR	168	Colorectal	All	Serum	Total Exosome Isolation kit	miR-6803	qRT-PCR	NR	OS	2.93 (1.35-6.37)
											DFS	3.26 (1.56-6.81)
Li et al[70]	2013-2015	China	85	Colorectal	III	Plasma	ExoCapTM	GPC1	Flow cytometry	> mean	OS	1.89 (1.23-2.89)
Silva et al[71]	2003-2009	Spain	91	Colorectal	All	Plasma	UC	Exosome	Flow cytometry of EpCAM	High	OS	0.87 (0.57-1.32)
Matsumura et al[72]	1992-2007	Japan	209	Colorectal	All	Serum	UC	miR-19	qRT-PCR	> mean	O	2.49 (1.12-6.61)
											DFS	2.49 (1.12-6.61)
Yan et al[73]	2012-2015	China	142	Colorectal	All	Serum	Total Exosome Isolation kit	miR-6869-5p	qRT-PCR	< mean	OS	2.32 (1.08-4.99)
Santasusagna et al[25]	2009-2013	Spain	32	Colon	I-III	Plasma	UC	miR-141	qRT-PCR	High	OS	1.89 (0.93-3.83)
Zhao et al[40]	2011-2012	China	126	Gastric	All	Serum	NR	HOTTIP	qRT-PCR	> 1.72	OS	2.037 (1.085-3.823)
Liu et al[74]	2012-2017	China	76	Gastric	All	Serum	Total Exosome Isolation kit	miR-451	qRT-PCR	> median	5yr-OS	4.344 (2.853‐5.721)
Yang et al[42]	NR	China	80	Gastric	All	Serum	ExoQuick	miR-423-5p	qRT-PCR	> median	DFS	1.93 (1.25-2.99)
											OS	1.42 (0.92-2.20)
Kumata et al[75]	2006-2013	Japan	232	Gastric	All	Plasma	UC	miR23b	qRT-PCR	> 0.78	OS	0.57 (0.370.78)
											DFS	0.64 (0.410.91)
Zhou et al[76]	2010-2014	China	152	Pancreatic	All	Plasma	ExoQuick	miR-125b-5p	qRT-PCR	< median	OS	0.285 (0.108-0.75)
Li et al[77]	2012-2016	China	87	Pancreatic	All	Plasma	NR	circPDE8A	qRT-PCR	> median	OS	1.764 (1.064-2.925)
Goto et al[43]	2013-2015	Japan	32	Pancreatic	All	Serum	ExoQuick	miR-21	qRT-PCR	> median	OS	4.071 (1.832-11.996)
Takahasi et al[78]	2013-2017	Japan	50	Pancreatic	I-II	Plasma	UC	miR-451a	qRT-PCR	> 1.75	OS	3.20 (1.07-11.94)
											DFS	2.87 (1.23-7.23)
Xu et al[49]	2012-2016	China	60	Liver	All	Serum	Total Exosome Isolation kit	ENSG00000258332.1	qRT-PCR	> 1.845	OS	2.22 (1.34-3.68)
								LINC00635	qRT-PCR	> 2.100	OS	1.46 (0.88-2.43)
Shi et al[79]	2008-2011	China	126	Liver	All	Serum	Total Exosome Isolation kit	miR-638	qRT-PCR	NR	3yr-OS	3.52 (1.37-6.02)
											5yr-OS	2.80 (1.24-4.31)
Liu et al[26]	2012	China	128	Liver	All	Serum	ExoQuick	miR-125b	qRT-PCR	< median	RFS	0.14 (0.07-0.29)
											OS	0.36 (0.18-0.74)
Xue et al[80]	2015-2017	China	85	Liver	All	Serum	Total Exosome Isolation kit	miR-93	qRT-PCR	NR	OS	1.47 (0.96-2.25)
Liu et al[81]	2008-2013	China	32	Hepatoblastoma (children)	All	Serum	ExoQuick	miR-21	qRT-PCR	NR	EFS	1.434 (1.257-2.766)
Matsumoto et al[82]	2011-2012	Japan	66	Esophageal	All	Plasma	Total Exosome Isolation kit	exosome	AChE activity	< 600 x 108/mL	OS	2.177 (1.085-3.605)
Lu et al[83]	2007-2015	China	110	Nasopharyngeal	All	Plasma	UC	miR-9	qRT-PCR	NR	OS	1.5 (1.03-2.18)
Ye et al[84]	2011-2013	China	83	Nasopharyngeal	II-IV	Serum	UC	protein concentration	BCA assay	> 11 μg/mL	DFS	214.22 (139.27-329.49)
Huang et al[85]	NR	NR	23	Prostate	All	Plasma	ExoQuick	miR-1290	qRT-PCR	> mean	OS	1.79(1.30-2.48)
								miR-375	qRT-PCR	> mean	OS	2.69(1.52-4.77)
Tang et al[86]	NR	NR	35	Ovarian	All	Ascitic fluid	UC	E-cadherin	NR	> 10 μg/mL	OS	1.82 (0.53-3.58)
Vaksman et al[87]	1998-2003		86	Ovarian	III-IV	Effusion supernatant	ExoQuick	miR-21	qRT-PCR	> median	OS	1.70 (1.1-2.59)
Kanaoka et al[88]	2012-2017	Japan	285	Lung	I-III	Plasma	UC	miR-451a	qRT-PCR	> 1.45	OS	6.06 (2.61-15.94)
											DFS	2.55 (1.44-4.65)
Liu et al[89]	2012-2014	China	196	Lung	All	Plasma	ExoQuick	miR-23b-3p	qRT-PCR	High	OS	2.42 (1.45-4.04)
								miR-21-5p	qRT-PCR		OS	2.12(1.28-3.49)
								miR-10b-5p	qRT-PCR		OS	2.22 (1.18-4.16)
Liu et al[90]	2012-2014	China	208	Lung	All	Plasma	ExoQuick	Exosome	AChE activity		OS	1.72 (1.05-2.83)
Sandfeld-Paulsen et al[91]	2011-2014	Denmark	276	Lung	All	Plasma	/	CD171	ELISA	NR	OS	0.56 (0.41-0.79)
								Flotilin1	ELISA	NR	OS	0.63 (0.46-0.86)
								HER3	ELISA	NR	OS	0.63 (0.46-0.86)
								GRP78	ELISA	NR	OS	0.69 (0.51-0.91)
Manier et al[92]	2006-2008	France	156	Multiple myeloma	All	Plasma	ExoQuick	let-7b	qRT-PCR	< median	OS	2.83 (1.07-7.50)
								let-7b	qRT-PCR	< median	DFS	1.90 (1.22-2.94)
								let-7e	qRT-PCR	< median	DFS	2.01 (1.30-3.11)
								miR-106a	qRT-PCR	< median	DFS	2.34 (1.52-3.61)
								miR-106b	qRT-PCR	< median	DFS	3.54 (2.21-5.68)
								miR-155	qRT-PCR	< median	OS	2.41 (0.96-6.05)
								miR-155	qRT-PCR	< median	DFS	1.76 (1.15-2.69)
								miR-16	qRT-PCR	< median	DFS	2.21 (1.41-3.47)
								miR-17	qRT-PCR	< median	DFS	2.29 (1.48-3.55)
								miR-18a	qRT-PCR	< median	DFS	4.52 (1.57-12.98)
								miR-18a	qRT-PCR	< median	OS	2.76 (1.79-4.26)
								miR-20a	qRT-PCR	< median	DFS	2.31 (1.52-3.53)
Alegre et al[61]	NR	NR	53	Melanoma	NR	Serum	ExoQuick	MIA	ELISA	2.5 μg/L	OS	1.28 (0.65-2.51)
Lan et al[93]	2011-2012	China	60	Glioma	All	Serum	ExoQuick	miR-301a	qRT-PCR	>median	OS	4.4 (3.1-9.6)
Ge et al[64]	NR	China	35	Cholangiocarcinoma	All	Bile	UC	ENST00000588480.1	qRT-PCR	> median	OS	2.40 (1.24-4.66)
								ENST00000517758.1	qRT-PCR		OS	1.55 (0.80-3.01)
Fujii et al[94]	2005-2014	Japan	108	Renal cell	I-III	Serum	Total Exosome Isolation kit	miR-224	qRT-PCR	> median	OS	9.1 (1.8-166.1)

UC: Ultracentrifugation; OS: Overall survival; DFS: Disease-free survival; RFS: Recurrence free survival; EFC: Event-free survival; NR: Not reported.