Exosomes as Biomarker of Cancer

Sumrin, Aleena; Moazzam, Shumaila; Khan, Aleena Ahmad; Ramzan, Irsa; Batool, Zunaira; Kaleem, Sana; Ali, Moazzam; Bashir, Hamid; Bilal, Muhammad

doi:10.1590/1678-4324-2018160730

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Human and Animal Health • Braz. arch. biol. technol. 61 • 2018 • https://doi.org/10.1590/1678-4324-2018160730 copy

Exosomes as Biomarker of Cancer

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Rapid advances in medicine and biotechnology resulted in the development of non-invasive diagnostic and prognostic biomarkers enabling convenient and accurate detection. Exosomes has recently emerged as non-invasive biomarker for a number of diseases including cancer. Exosomes are the small endosome originated membranous vesicles secreted in a number of biological fluids such as serum, saliva, urine, ascites, cerebrospinal fluid, etc. Exosomes contain microRNA proteins and mRNA which can be used as disease specific biomarkers. Here we reviewed recent advancement in the field of exosomes as diagnostic biomarker for cancer along with a brief overview of their biogenesis, function and isolation.

Key words:
Exosome; Biomarker; Cancer biomarker

Diseases	Exosomal Proteins	Level/Expression	Potencial Use	Methodology	Source	Ref.
Melanoma and other malignant cancers	CD63 and Caveolin 1 enriched exosomes.	Elevated	Diagnosis	In-house sandwich ELISA	Plasma	²⁷27 Logozzi M, De Milito A, Lugini L, Borghi M, Calabro L, Spada M, et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One. 2009;4(4):17.
Melanoma and other malignant cancers	β1 integrin, α6 integrin, basigin, CD 73.	Elevated surface expression	Prognosis	Mass spectrometry, Western blot, Flow cytometry	Plasma	²⁸28 Blackwell RH, Franzen CA, Flanigan RC, Kuo PC, Gupta GN. The untapped potential of urine shed bladder cancer exosomes: biomarkers, signaling, and therapeutics. Bladder. 2014;1(1):e7.
Non-small cell lung carcinoma (NSCLC)	CD9, CD81	Elevated signal	Diagnosis	Extracellular Vesicle Array (EV Array)	Plasma	²⁹29 Jakobsen KR, Paulsen BS, Baek R, Varming K, Sorensen BS, Jorgensen MM. Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma. J Extracell Vesicles. 2015;4(26659).
	CD 63	Co-variation in signal as compared to control	Diagnosis	Extracellular Vesicle Array (EV Array)	Plasma
	FAM3C	Over expression	Prognosis	LTQ-FT mass spectrometry	NSCLC cell lines	³⁰30 Wang L-Z, Soo RA, Thuya WL, Wang TT, Guo T, Lau JA, et al., editors. Exosomal protein FAM3C as a potential novel biomarker for non-small cell lung cancer. ASCO Annual Meeting Proceedings; 2014.
Prostate Cancer (PCa)	FASN, XPO1 and PDCD6IP proteins	Elevated expression	Diagnosis	LCFTMS/ Western blot/ Immuno-histochemistry	Immortalized primary prostate epithelial cells	³¹31 Duijvesz D, Burnum-Johnson KE, Gritsenko MA, Hoogland AM, Vredenbregt-van den Berg MS, Willemsen R, et al. Proteomic profiling of exosomes leads to the identification of novel biomarkers for prostate cancer. PLoS One. 2013;8(12).
Prostate Cancer (PCa)	ENO-1	Decreased expression
Ovarian Cancer	Epithelial cell adhesion molecule (EpCAM) and CD24	Over expression	Diagnosis	Magnetic activated cell sorting procedure (MACS)	Plasma/ Ovarian tumor derived exosomes	³²32 Beach A, Zhang HG, Ratajczak MZ, Kakar SS. Exosomes: an overview of biogenesis, composition and role in ovarian cancer. J Ovarian Res. 2014;7(14):1757-2215. ³³33 An T, Qin S, Xu Y, Tang Y, Huang Y, Situ B, et al. Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis. J Extracell Vesicles. 2015;4(27522).
	TGF-beta1, MAGE3/6, L1CAM, ADAM10, EMMPRIN, Claudin-4	Over expression	Diagnosis/ Prognosis	Fluorescent microscopy and cytofluorographic analysis.	Ascites/Blood	³⁴34 Liang B, Peng P, Chen S, Li L, Zhang M, Cao D, et al. Characterization and proteomic analysis of ovarian cancer-derived exosomes. J Proteomics. 2013;80:171-82.
	TSG101 and Alix	Over expression	Prognosis	Protein profiling	Ovarian cancer cell lines
Hepatitus C induced HCC	CD81	Over expression	Diagnosis	Immunoblotting and densitometry.	Exosomal serum fraction	²⁰20 Lin J, Li J, Huang B, Liu J, Chen X, Chen X-M, et al. Exosomes: novel biomarkers for clinical diagnosis. The Scientific World Journal. 2015;2015.
Bladder cancer	MUC1, β1 integrin, α6 integrin, CD44, CD10, CD 73	Increased surface expression	Diagnosis/ Prognosis	Mass spectrometry/ Western blot/ Flow cytometry	HT1376 bladder cancer cells	²⁸28 Blackwell RH, Franzen CA, Flanigan RC, Kuo PC, Gupta GN. The untapped potential of urine shed bladder cancer exosomes: biomarkers, signaling, and therapeutics. Bladder. 2014;1(1):e7.
Bladder cancer	HBA, HBB and TACSTD2	Upregulated expression	Prognosis	Mass spectrometry	Urine
Breast cancer	Survivin (Inhibitor of apoptosis), MUC 1, β1 integrin, CD73	Elevated level	Diagnosis/ Prognosis	SDS PAGE, Protein staining, Western Blot	Serum exosomes/ Saliva	³⁵35 Yu Dd, Wu Y, Shen Hy, Lv Mm, Chen Wx, Zhang Xh, et al. Exosomes in development, metastasis and drug resistance of breast cancer. Cancer science. 2015;106(8):959-64.
Breast cancer	Breast cancer resistance protein (BCRP)	Elevated level	Prognostic biomarker	Immuno fluorescence	Plasma	³⁶36 Chen Y, Wang L, Zhu Y, Chen Z, Qi X, Jin L, et al. Breast cancer resistance protein (BCRP)-containing circulating microvesicles contribute to chemoresistance in breast cancer. Oncology letters. 2015 Dec;10(6):3742-8. PubMed PMID: 26788201. Pubmed Central PMCID: 4665209.
Pancreatic cancer	CD44v6, Tspan 8, EpCAM, CD104	Elevated level	Diagnosis/ Prognosis	Flow cytometry	Serum exosomes	³⁷37 Madhavan B, Yue S, Galli U, Rana S, Gross W, Muller M, et al. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. International journal of cancer. 2015 Jun 1;136(11):2616-27. PubMed PMID: 25388097. Epub 2014/11/13. eng.
Pancreatic cancer	Glypician 1 (Proteoglycan) circulating exosomes (GPC1+crExos)	Upregulated surface expression	Diagnosis	Mass spectrometry/ Flow cytometry	Serum/ Mice with pancreatic tumors	³⁸38 Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015 Jul 9;523(7559):177-82. PubMed PMID: 26106858. Pubmed Central PMCID: 4825698. Epub 2015/06/25. eng.
Colorectal cancer	CD81, CD63, CD9	Elevated	Diagnosis/ Prognosis	SDS PAGE, Protein staining, Western Blot	Colorectal cancer cell lines./Ascites	³⁹39 Chiba M, Kimura M, Asari S. Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncology reports. 2012;28(5):1551-8.
Colorectal cancer	Claudin 3	High level of detection	Diagnosis	Nano-LC-MS/MS analysis and 1-Dimensional SDS-PAGE	CRC-ascites	³³33 An T, Qin S, Xu Y, Tang Y, Huang Y, Situ B, et al. Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis. J Extracell Vesicles. 2015;4(27522).
Gastric cancer	MAGE-1 and Her-2/neu+, CRC6	High expression	Prediction/ Prognosis Little diagnostic Value	Protein profiling	Platelet Depleted Plasma	⁴⁰40 Kalnina Z, Meistere I, Kikuste I, Tolmanis I, Zayakin P, Line A. Emerging blood-based biomarkers for detection of gastric cancer. World journal of gastroenterology. 2015;21(41):11636.
Gastric cancer	CxCR4	Down regulated expression	Prediction/ Prognosis Little diagnostic Value	Protein profiling	Platelet Depleted Plasma

Instituto de Tecnologia do Paraná - Tecpar Rua Prof. Algacyr Munhoz Mader, 3775 - CIC, 81350-010 Curitiba PR Brazil, Tel.: +55 41 3316-3052/3054, Fax: +55 41 3346-2872 - Curitiba - PR - Brazil
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[1] ^*Author for correspondence: aleena.camb@pu.edu.pk

Pathology	Biomarker	Level	Source	Study type	Potential	Ref.
Prostate Cancer (PC)	miR-375 and miR-141	Up-regulation	Serum	Cohort Study	Diagnosis and Stage Determination	⁵⁴54 Bryant R, Pawlowski T, Catto J, Marsden G, Vessella R, Rhees B, et al. Changes in circulating microRNA levels associated with prostate cancer. British journal of cancer. 2012;106(4):768-74.
	miR-107 and miR-574-3p	Up-regulation	Urine	Cohort Study	Diagnosis and Stage Determination
	miR-34a	Down-regulation	Cell line conditioned medium (CM)	Cell Line Models	Predictive Biomarker for Response to Docetaxel in PCa Progression	⁶⁹69 Corcoran C, Rani S, O'Driscoll L. miR-34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression. The Prostate. 2014;74(13):1320-34.
	miR-1290 and miR-375	Higher	Plasma	Cohort Study	Prognostic Biomarker in Castration-Resistant PCa	⁷⁰70 Huang X, Yuan T, Liang M, Du M, Xia S, Dittmar R, et al. Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. European urology. 2015;67(1):33-41.
	hsa-41 miR375, hsa-miR21 and hsa-miR574	Higher	Serum	Non Cohort Study	Discriminating Biomarker	⁷¹71 Li M, Rai AJ, DeCastro GJ, Zeringer E, Barta T, Magdaleno S, et al. An optimized procedure for exosome isolation and analysis using serum samples: Application to cancer biomarker discovery. Methods. 2015;87:26-30.
	miR-141	Up-regulation	Serum	Cohort Study	Diagnosis	⁷²72 Li Z, Ma Y-Y, Wang J, Zeng X-F, Li R, Kang W, et al. Exosomal microRNA-141 is upregulated in the serum of prostate cancer patients. OncoTargets and therapy. 2016;9:139.
	miR-574-3p, miR-141-5p and miR-21-5p	Up-regulation	Urine	Non Cohort Study and Cell Line Model	Diagnosis	⁷³73 Samsonov R, Shtam T, Burdakov V, Glotov A, Tsyrlina E, Berstein L, et al. Lectin-induced agglutination method of urinary exosomes isolation followed by mi-RNA analysis: Application for prostate cancer diagnostic. The Prostate. 2016;76(1):68-79.
Ovarian Cancer	miR-21, miR-214, miR-200a, miR-200b, miR-200c, miR-203, miR-205 and miR-141	Elevated	Serum	Non Cohort Study	Diagnosis	⁵²52 Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecologic oncology. 2008;110(1):13-21.
	Let-7	High expression in SKOV-3	Cell Culture Media	Cell Line Models (SKOV-3 and OVCAR-3)	Diagnosis	⁷⁴74 Kobayashi M, Salomon C, Tapia J, Illanes SE, Mitchell MD, Rice GE. Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let-7 miRNA and miR-200. Journal of translational medicine. 2014;12:4. PubMed PMID: 24393345. Pubmed Central PMCID: 3896684. Epub 2014/01/08. eng.
	miR-200	Expressed only in OVCAR-3	Cell Culture Media	Cell Line Models (SKOV-3 and OVCAR-3)	Diagnosis
	miR-21	Over Expression	-	Non Study Cohort	Diagnosis	⁷⁵75 Cappellesso R, Tinazzi A, Giurici T, Simonato F, Guzzardo V, Ventura L, et al. Programmed cell death 4 and microRNA 21 inverse expression is maintained in cells and exosomes from ovarian serous carcinoma effusions. Cancer cytopathology. 2014;122(9):685-93.
	miR-30a-5p	Up-regulation	Urine	Non Study Cohort and Cell Line Model	Diagnostic and Therapeutic target of Ovarian Serous Carcinoma	⁷⁶76 Zhou J, Gong G, Tan H, Dai F, Zhu X, Chen Y, et al. Urinary microRNA-30a-5p is a potential biomarker for ovarian serous adenocarcinoma. Oncology reports. 2015;33(6):2915-23.
	miR-373, miR-200a, miR-200b and miR- 200c	Elevated	Serum	Cohort Study	Diagnosis and Prognosis	⁵⁵55 Meng X, Muller V, Milde-Langosch K, Trillsch F, Pantel K, Schwarzenbach H. Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Oncotarget. 2016.
Breast Cancer	miR-21 and miR-146ª	Over expression	Plasma	Non Cohort Study	Diagnosis	⁶²62 Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, et al. Circulating exosomal microRNAs as biomarkers of colon cancer. PloS one. 2014;9(4):e92921.
Breast Cancer	miR-106a	Up-regulated	Plasma	Non Cohort Study	Biomarker for metastatic Breast Cancer	⁷⁷77 Zhao Q, Deng S, Wang G, Liu C, Meng L, Qiao S, et al. A direct quantification method for measuring plasma MicroRNAs identified potential biomarkers for detecting metastatic breast cancer. Oncotarget. 2016.
Colorectal Cancer (CRC)	let-7a, miR-1246, miR-1229, miR-23a, miR-223, miR-21, and miR-150	Higher	Serum	Non Cohort Study	Diagnosis	⁶²62 Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, et al. Circulating exosomal microRNAs as biomarkers of colon cancer. PloS one. 2014;9(4):e92921.
	miR-19a	Over expression	Serum	Non Cohort Study	Prognostic Biomarker	⁷⁸78 Matsumura T, Sugimachi K, Iinuma H, Takahashi Y, Kurashige J, Sawada G, et al. Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. British journal of cancer. 2015;113(2):275-81.
	miR-372	Up-regulation	Serum	Non Cohort Study	Diagnosis and Prognosis	⁵⁶56 Yu J, Jin L, Li W, Jiang L, Hu Y, Zhi Q, et al. Serum miR-372 is a diagnostic and prognostic biomarker in patients with early colorectal cancer. Anti-cancer agents in medicinal chemistry. 2015.
Lung Cancer	miR-125a-5p, miR-145 and miR-146a*	Over expression	Serum	Non Cohort Study	Diagnosis	⁷⁹79 Wang R-J, Zheng Y-H, Wang P, Zhang J-Z. Serum miR-125a-5p, miR-145 and miR-146a as diagnostic biomarkers in non-small cell lung cancer. International journal of clinical and experimental pathology. 2015;8(1):765.
	miR-29a-3p and miR-150-5p	Down-regulation	Plasma	Cohort Study	Predict response To Radiation Therapy	⁸⁰80 Dinh T-KT, Fendler W, Chalubinska-Fendler J, Acharya SS, O'Leary C, Deraska PV, et al. Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer. Radiation Oncology. 2016;11(1):1.
	miR-21 and miR-155	Up-regulation	Serum and Conditioned media	Non Study Cohort (Cell lines and recurrent nude mouse xenograft)	Diagnosis	⁸¹81 Munagala R, Aqil F, Gupta RC. Exosomal miRNAs as biomarkers of recurrent lung cancer. Tumor Biology. 2016:1-12.
Gastric Cancer (GC)	miR-214, miR-221 and miR-222	Up-regulation	Serum	Non Cohort Study	Diagnosis and Prognosis	⁸²82 Wang M, Zhao C, Shi H, Zhang B, Zhang L, Zhang X, et al. Deregulated microRNAs in gastric cancer tissue-derived mesenchymal stem cells: novel biomarkers and a mechanism for gastric cancer. British journal of cancer. 2014;110(5):1199-210.
Gastric Cancer (GC)	miR-21 and miR-1225-5p	Higher	Malignant ascites and Peritoneal lavage fluid	Non Cohort Study	Diagnosis and Prognosis of Peritoneum Dissection of Gastric Cancer	⁶⁰60 Tokuhisa M, Ichikawa Y, Kosaka N, Ochiya T, Yashiro M, Hirakawa K, et al. Exosomal miRNAs from peritoneum lavage fluid as potential prognostic biomarkers of peritoneal metastasis in gastric cancer. PloS one. 2015;10(7):e0130472.
Cervical Cancer (CC)	miR-21 and miR-146a	Up-regulation	Cervicovaginal lavage Fluid	Non Cohort Study	Non-invasive CC screening	⁵⁸58 Liu J, Sun H, Wang X, Yu Q, Li S, Yu X, et al. Increased exosomal microRNA-21 and microRNA-146a levels in the cervicovaginal lavage specimens of patients with cervical cancer. International journal of molecular sciences. 2014;15(1):758-73.
Retinoblastoma	miR-320, miR-let-7e, and miR-21	Down-regulation	Plasma	Non Cohort Study	Diagnosis	⁵⁹59 Liu SS, Wang YS, Sun YF, Miao LX, Wang J, Li YS, et al. Plasma microRNA-320, microRNA-let-7e and microRNA-21 as novel potential biomarkers for the detection of retinoblastoma. Biomedical reports. 2014;2(3):424-8.

Osophageal squamous cell carcinoma (ESCC)	miR-1246	Up-regulation	Serum	Non Cohort Study	Diagnosis and Prognosis	⁸³83 Takeshita N, Hoshino I, Mori M, Akutsu Y, Hanari N, Yoneyama Y, et al. Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma. British journal of cancer. 2013;108(3):644-52.
Hepatocellular Carcinoma (HCC)	miR-18a, miR-221, miR-222, and miR-224	Up-regulation	Serum	Non Cohort Study	Diagnosis	⁸⁴84 Sohn W, Kim J, Kang SH, Yang SR, Cho J-Y, Cho HC, et al. Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma. Experimental & molecular medicine. 2015;47(9):e184.
Hepatocellular Carcinoma (HCC)	miR-101, miR-106b, miR-122, and miR-195	Down- Regulation	Serum	Non Cohort Study	Diagnosis
Pancreatic Cancer	miR-17-5p and miR-21	Higher	Serum	Non Cohort Study	Diagnosis	⁶¹61 Que R, Ding G, Chen J, Cao L. Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma. World journal of surgical oncology. 2013;11(1):1.
Laryngeal Squamous Cell Carcinoma	miR-21and HOTAIR (lncRNA)	Higher	Serum	Non Cohort Study	Diagnosis and Prognosis	⁶³63 Wang J, Zhou Y, Lu J, Sun Y, Xiao H, Liu M, et al. Combined detection of serum exosomal miR-21 and HOTAIR as diagnostic and prognostic biomarkers for laryngeal squamous cell carcinoma. Medical Oncology. 2014;31(9):1-8.
Papillary Thyroid Cancer (PTC)	miR-146b and miR-222	Over expression	-	Cell Line Model	Biomarker of PTC recurrence	⁸⁵85 Lee JC, Zhao J-T, Gundara J, Serpell J, Bach LA, Sidhu S. Papillary thyroid cancer-derived exosomes contain miRNA-146b and miRNA-222. Journal of Surgical Research. 2015;196(1):39-48.
Melanoma	miR-125b	Down-regulation	Serum	Non Cohort Study	Prognosis	⁸⁶86 Alegre E, Sanmamed MF, Rodriguez C, Carranza O, Martin-Algarra S, Gonzalez A. Study of circulating microRNA-125b levels in serum exosomes in advanced melanoma. Archives of Pathology and Laboratory Medicine. 2014;138(6):828-32.
Glioblastoma	miR-320 and miR-574-3p	-	Serum	Cohort Study	Diagnosis	⁴²42 Manterola L, Guruceaga E, Pérez-Larraya JG, González-Huarriz M, Jauregui P, Tejada S, et al. A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro-oncology.2014:not218.
Glioblastoma	RNU6-1 (snRNA)	Up-regulation	Serum	Cohort Study	Diagnosis

Bio Fluid	Disease	Biomarker (Protein/RNA)	Ref.
Saliva	Breast cancer		⁹¹91 Lau CS, Wong DT. Breast cancer exosome-like microvesicles and salivary gland cells interplay alters salivary gland cell-derived exosome-like microvesicles in vitro. PLoS ONE. 2012;7(3):e33037.
	Pancreatic cancer	mRNA	⁸⁷87 Palanisamy V, Sharma S, Deshpande A, Zhou H, Gimzewski J, Wong DT. Nanostructural and transcriptomic analyses of human saliva derived exosomes. PLoS ONE. 2010;5(1):e8577. ^, ⁹²92 Lau C, Kim Y, Chia D, Spielmann N, Eibl G, Elashoff D, et al. Role of pancreatic cancer-derived exosomes in salivary biomarker development. Journal of Biological Chemistry. 2013;288(37):26888-97.
	Sjogren’s syndrome	miRNA	⁹⁰90 Michael A, Bajracharya SD, Yuen PS, Zhou H, Star RA, Illei GG, et al. Exosomes from human saliva as a source of microRNA biomarkers. Oral diseases. 2010;16(1):34-8.
	Head and neck cancer	mRNA, miRNA	⁹³93 Principe S, Hui ABY, Bruce J, Sinha A, Liu FF, Kislinger T. Tumor-derived exosomes and microvesicles in head and neck cancer: Implications for tumor biology and biomarker discovery. Proteomics. 2013;13(10-11):1608-23.
Ascities	Ovarian cancer	Protein (CD24, EpCAM)	⁹⁴94 Runz S, Keller S, Rupp C, Stoeck A, Issa Y, Koensgen D, et al. Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM. Gynecologic oncology. 2007;107(3):563-71.
	Ovarian cancer	Protein (MMP2, MMP9, uPA)	⁹⁶96 Graves LE, Ariztia EV, Navari JR, Matzel HJ, Stack MS, Fishman DA. Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. Cancer Research. 2004;64(19):7045-9.
	Gastric cancer	miRNA	⁶⁰60 Tokuhisa M, Ichikawa Y, Kosaka N, Ochiya T, Yashiro M, Hirakawa K, et al. Exosomal miRNAs from peritoneum lavage fluid as potential prognostic biomarkers of peritoneal metastasis in gastric cancer. PloS one. 2015;10(7):e0130472.
	Colorectal cancer	Protein (claudin-3)	⁹⁷97 Choi DS, Park JO, Jang SC, Yoon YJ, Jung JW, Choi DY, et al. Proteomic analysis of microvesicles derived from human colorectal cancer ascites. Proteomics. 2011;11(13):2745-51.
CSF	Glioblastoma	miRNA (miR-21)	⁹⁵95 Akers JC, Ramakrishnan V, Kim R, Phillips S, Kaimal V, Mao Y, et al. miRNA contents of cerebrospinal fluid extracellular vesicles in glioblastoma patients. Journal of Neuro-oncology. 2015;123(2):205-16.
Milk /ductal fluid	Breast cancer	miRNA (miR-16, 1246, 451 and miR-720)	⁹⁸98 Pigati L, Yaddanapudi SC, Iyengar R, Kim D-J, Hearn SA, Danforth D, et al. Selective release of microRNA species from normal and malignant mammary epithelial cells. PLoS ONE. 2010;5(10):e13515.
Bile	Cholangiocarcinoma	miRNA	⁹⁹99 Li L, Masica D, Ishida M, Tomuleasa C, Umegaki S, Kalloo AN, et al. Human bile contains MicroRNAladen extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology. 2014;60(3):896-907.