Table 2.

Summary of EVs as diagnosis biomarkers in pancreatic cancer

Cargo	Sample	Methods for analysis of EVs	Findings	Diagnostic Performance	Refs.
GPC1	Serum	Flow analysis	The presence of GPC1+ exosomes distinguished healthy subjects and patients with a benign pancreatic disease from patients with early-stage pancreatic cancer	Sensitivity 100%; specificity 100%; AUC 1.0;	[124]
GPC1	Serum	Advanced multiplexed plasmonic assay	Sensitivity and specificity of diagnosis are improved significantly when a panel of five markers (EGFR, EPCAM, MUC1, GPC1 and WNT2) are used for PDAC detection	Sensitivity 86%; specificity 81%; diagnostic accuracy 84%	[125]
GPC1	Serum	Flow cytometry	Combining diagnostic tools, i.e. GPC1-positive EVs, CA19-9 and EUS-FNA improves all diagnostic performance parameters, and displays the best diagnosis accuracy as high as 84%	Sensitivity 64%; specificity 90%; Diagnosis accuracy 78%	[126]
GPC1	Plasma	Flow cytometry	GPC1 as a novel prognostic biomarker for patients with advanced pancreatic cancer following regional intra-arterial chemotherapy treatment	The level of GPC1+ EVs is associated with prognosis	[127]
EphA2	Plasma	nanoplasmon-enhanced scattering (nPES) assay	The nPES assay for ephrin type-A receptor 2 (EphA2)-EVs distinguishes pancreatic cancer patients from pancreatitis patients. EphA2-EVs are also predictive in cancer staging and in evaluating responses to neoadjuvant therapy	Sensitivity 94%;	[131]
ALPPL2	Cells	quantitative ALISA	Direct and ALPPL2 or CD9 anti-body-based sandwich ALISA were established, which could detect both free and EV-bound forms of ALPPL2	Not determined	[132]
O-glycan-binding lectins ABA or ACA	Serum	ExoCounter	EVs recognized by O-glycan-binding lectins ABA or ACA were identified as candidate markers by lectin microarray. The ABA-or ACA-positive EVs were significantly increased in the serum of pancreatic cancer patients	Sensitivity 7.8%; specificity 73.5%; AUC 0.838	[133]
Microbiome composition	blood samples	16S rRNA gene analysis	These microbiome markers, which altered microbial compositions, are candidate biomarkers for early diagnosis of pancreatic cancer with a high area under the receiver operating characteristic curve (0.966 and 1.000, at the phylum and genus level, respectively)	AUC 0.966;	[134]
EVs-derived RNAs	plasma samples	RT-qPCR	An RNA-ratio based plasma samples including eight EVs-derived RNAs, including FBXO7, MORF4L1, DDX17, TALDO1, AHNAK, TUBA1B, CD44, and SETD3	AUC 0.89	[135]
Zinc transporter protein ZIP4	Serum	proteomic analysis	The elevated serum levels of exosomal ZIP4 in patients with PDAC showed a diagnostic value of AUC 0.89	AUC 0.89	[136]
MIF	Plasma	ELISA	MIF was higher in exosomes from stage I PDAC patients who later developed liver metastasis and may be a prognostic marker for the development of PDAC liver metastasis	Not determined	[137]
CD63, Rab5	Serum	Western Blot	Alteration in the expression level in isolated exosomes of patients with pancreatic cancer was reported for proteins CD63 (3.17 fold) and Rab5 (1.73 fold)	Not determined	[138]
HULC	Serum	PCR	EVs-encapsulated HULC could be a potential circulating biomarker for early diagnosis PDAC	AUC 0.92	[139]