Table 3.
A summary of EV-based diagnostic, prognostic, and predictive biomarkers in CCA.
| Type of Biomarker | Sample | Type of Cargoes | Expression in CCA Samples |
|---|---|---|---|
| Diagnostic | Bile | cel-miR-39 miR-126 miR-486-3p miR-222 miR-19a |
↑ concentration in CCA patient’s bile vs. (null expression) PSC, bile leak syndrome, bile obstruction [96] |
| Bile Bile Bile Serum |
miR-31 mir-484, miR-1274b miR-16 miR-618 miR-19a, miR-486-3p miR-191 Bile-EVs long-non-coding RNAs ENST00000517758 ENST00000588480.1 circulating serum EVs and A-fetoprotein levels AnnV+CD44v6+ PiRNAs piR-10506469 PiRNAs piRNAs nov-piR-2002537 nov-piR-14022777 nov-piR-17802142 nov-piR-4813367 nov-piR-12355115 nov-piR-15024555 nov-piR-9052713 nov-piR-4262304 nov-piR-3659538 nov-piR-5114107. nov-piR-4333713 nov-piR-10506469, piR-20548188 nov-piR-14090389 nov-piR-10506469, piR-20548188 miR-218-5p NC_000010.11_20947 miR-433-3p miR-9-3p miR-129-5p NC_000001.11_1920 miR-151a-5p, miR-4732-3p miR-191-5p miR-96-5p Fibrinogen FRIL CRP FRIL/CRP VWF/CRP/PIGR FIBG A1AG1 VNN1 GGT1 CRP IGHA1 CRP, VTDB FIBG A1AG1 mRNA transcripts PHGDH ATF4 PON1 miR-200b-3p miR-200c-3p RRAGD MAP6D1 INO80D |
↑ concentration in CCA patient’s bile vs (lower expression) PSC, bile leak syndrome, bile obstruction [96] ↑ over 10-fold increased levels in CCA and pancreatic cancer Higher diagnostic accuracy than CA19-9 Differentiation of malignant stenosis vs. cholelithiasis Threshold of 9.46 × 10 nanoparticles/L in the bile sample [84,97,98] ↑ in malignant stenosis vs. obstructive pathology [99] Synergistic effect of serum EVs and AFP differentiation of hepatobiliary malignancies vs. other types of cancers [101] Differentiation of biliary malignancies vs. HCC ↑ diagnostic value by combining AFP [101] ↑ concentration levels of 323 EV-piRNAs in GBC /694 piRNAs CCA vs. healthy [102] ↓ concentration levels of 191 EV-piRNAs in GBC/36 in CCA vs. healthy [102] Downregulated only in CCA [102] Upregulated in CCA (↑ pre-surgical levels) [102] ↓ post-surgical exosomal piRNA concentration levels in CCA [102] Downregulated EV-miRNAs in CCA/GBC vs. healthy [102] Upregulated EV-miRNAs in CCA/GBC vs. healthy (↑ stage II CCA) [103] ↓ post-surgical levels (7 days after) +/− CA-19-9 for diagnosis of local PSC-associated CCA vs. PSC ↑ in Pan-CCA vs. healthy Non-PSC vs. healthy [104] ↑ in CCA vs. (PSC, HCC, healthy) [67,105] ↑ in iCCA vs. HCC [67,105] ↑ in CCA vs. PSC patients [106] ↑ in CCA—early detection of CCA proportional to tumor-stage [71] Most auspicious urine EV biomarkers for CCA [106] |
|
|
Serum Plasma Plasma Plasma Plasma Serum Serum Serum Serum Serum Serum |
|||
| Predictive | Serum Bile |
PIGR/CRP/ FRIL/Fibrinogen MiR-183-5p |
Predictive biomarkers for CCA development in patients with PSC, before it is clinically evident [104] ↑ PD-L1-expression-immune suppression Immune tolerance of ICC [72] |
| Staging | Serum | FIBG SAMP FCN2 IC1 ITIH4 miR-96-5p miR-4732-3p miR-151a-5p miR-191-5p |
Overexpressed in I–II stage vs. PSC [67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105] Overexpressed in II stages vs. healthy [103] |
| Serum | miR-192-5p miR-182-5p miR-191-5p |
Overexpressed in III stage [103] | |
| Prognosis | Serum CCA Tissue Serum Tissue/bile |
PF4V/ACTN1/MYCT1 CFAI/COMP/GNAI2 BM1 MiR-200 family miR-200b-3p miR-200c-3p miR-182/183-5p |
Good prognosis-survival of CCA patients [104] Poor prognosis-survival of CCA patients [104] Independent poor prognostic biomarker [79] ↑ levels in CCA—↑ proportionally to tumor-stage [71] ↑ levels—poor prognosis [72,73] |
(FRIL) ferritin light chain protein and (CRP) C-reactive protein, (CA19-9) carbohydrate antigen 19-9, (PIGR) polymeric immunoglobulin receptor, (VWF) Von Willebrand factor, (ACTN1) alpha-actinin-1, (MYCT1) MYC target 1 proteins, (CFAI) complement factor I, (COMP), G protein subunit i2 (GNAI2) cartilage oligomeric matrix protein, (FIBG) fibrinogen gamma chain, (A1AG1) alpha-1-acid glycoprotein 1, (VNN1) pantetheinase, (GGT1) gamma-glutamyltranspeptidase 1, (VTDB) vitamin D-binding protein, (PHGDH) phosphoglycerate dehydrogenase, (ATF4) activating transcription factor 4 and (PON1) paraoxonase 1, (RRAGD) Ras-related GTP binding D, (MAP6D1) MAP6-domain-containing 1, (INO80D) INO80 complex subunit D, (SAMP) serum amyloid P-component, (FCN2) ficolin-2, (IC1) plasma protease C1 inhibitor, (ITIH4) inter-alpha-trypsin inhibitor heavy chain H4, (BMI1) B-cell-specific Moloney murine leukemia virus integration site 1, ↑ upregulated, ↓ downregulated.