Progress on pivotal role and application of exosome in lung cancer carcinogenesis, diagnosis, therapy and prognosis

Li, Ming-Yue; Liu, Li-Zhong; Dong, Ming

doi:10.1186/s12943-021-01312-y

Molecular Cancer

Table 1 Exosomes and exosomal molecules involved in lung cancer carcinogenesis, diagnosis, prognosis and therapy

From: Progress on pivotal role and application of exosome in lung cancer carcinogenesis, diagnosis, therapy and prognosis

Exosome promotes lung cancer cell proliferation and growth
2003Exosome/Molecule	Parental cell	Recipient cell	Target(s) /mechanisms	Functions		Reference
A549-derived exosomes	NSCLC cell A549	Mesenchymal stem cells	NFκB-TLR signaling pathway	Promote MSCs getting tumor supportive characteristics		[104]
COX-2	lung cancer cells H460,11-18	Monocytic cell THP-1	PGE2 and VEGF	Affect the microenvironments		[105]
EGFR, GRB2 and SRC	NSCLC cells A549, HCC827	HBE3(bronchial epithelial cells)		Actively regulate recipient cells proliferation		[106]
miR-660-5p	NSCLC cells H1299, H460, A549, H358; 16HBE (bronchial epithelial cells)		KLF9	Promote NSCLC progression		[107]
circSATB2	H1299 cells transfected with circSATB2-OE or circSATB2-sh	H460, A549, BEAS-2B	FSCN1	Promote NSCLC cells proliferation and metastasis, induce proliferation in normal human bronchial epithelial cells.		[108]
Exosome promotes EMT and metastasis
Exosome/Molecule	Parental cell	Recipient cell	Target(s) /mechanisms	Functions		Reference
Mutant p53s, podocalyxin	H1299 (p53R273H /R175H)	H1299 (p53−/− )	Integrin trafficking	Drive integrin trafficking and cell migration		[112]
TGF-β and IL-10	SCLC cell H1688, NSCLC cell H2228	HMEC-1		Regulate the cellular migration of tumor cells		[114]
miR-23a	NSCLC cell A549		miR-23a significantly enriched by TGF-β1	Be involved in the EMT		[115]
AREG	NSCLC cells CRL-2868, A549	Murine macrophage cells Raw 264.7	EGFR pathway	Trigger a vicious cycle in osteolytic bone metastasis		[116]
circSATB2	H1299 cells transfected with circSATB2-OE or circSATB2-sh	H460, A549, BEAS-2B	FSCN1	Induce cell proliferation, and promote NSCLC cells metastasis		[108]
Exosome promotes angiogenesis
Exosome/Molecule	Parental cell	Recipient cell	Target(s) /mechanisms	Functions		Reference
miR-23a	Lung adenocarcinoma cell CL1-5	HUVEC (Umbilical vein endothelial cells)	PHD1, PHD2 and ZO-1	Induce angiogenesis and increase permeability in HUVEC.		[118]
miR-21	Cigarette smoke extract (CSE)-transformed HBE cells	HBE, HUVEC	STAT3 activation, VEGF	Increase VEGF levels in recipient cells to promote angiogenesis and malignant transformation.		[119]
miR-210	Tagged A549L cells	HUVEC	PI3K/AKT/HIF-1/miR-210/EphA3 signaling	Promote tube formation activity in HUVECs and increase angiogenesis in A549L-derived tumor xenografts.		[120]
miR-192	NSCLC cell A549 and metastatic subpopulations of A549 M1/M3 /M4	HUVEC	IL-8, ICAM and CXCL1	Induce angiogenesis and associate with high metastatic activity of bone due to a repressed miR-192 regulation on IL-8, ICAM and CXCL1.		[121]
Exosome modulates antitumor immune responses
Exosome/Molecule	Parental cell	Recipient cell	Target(s) /mechanisms	Functions		Reference
EGFR	30 NSCLC patients’ lung biopsies for exosomes extraction and then pool together	Dendritic cells (DC) CD3+ CD4+ CD25− Th0 cells CD8+ T cells	Induce DCs into tolerogenic DCs to facilitate formation of Tregs and inhibit CD8+ T cells anti-tumor function	Help immune escape of lung cancer cells and promote lung cancer growth.		[123, 124]
Hsp72	Lung adenocarcinoma cells H23	MDSCs (myeloid-derived suppressor cells)	Hsp72/TLR2 induced Stat3 activation	Suppress T cell activation		[124, 125]
miR-21 miR-29a	Human A549, SK-MES and murine LLC cells, Dotap liposomal formulations of interest miRNAs (mimicking the exosomes)	Macrophages and spleen cells from WT and TLR7^−/− B6 mice TLR7-/TLR8- human HEK-293 cells WT and TLR7^{− /−} B6 mice	Activate TLR7 and TLR8 on immune cells	Activate NFκB and prometastatic inflammatory response, ultimately leading to tumor growth and metastasis		[126]
Exosomal contents as potential diagnostic biomarkers in lung cancer
Exosomal contents	Type of lung cancer studied	Number of patients/cells studied	Biopsy material	Method for exosome extraction	Potential roles in clinical practice	Reference
miR-17-3p miR-21 miR-106a miR-146 miR-155 miR-191 miR-192 miR-203 miR-205 miR-210 miR-212 miR-214	Adenocarcinoma	36 (27patients + 9 healthy controls)	Plasma	Exclusion chromatography and magnetic activated cell sorting using anti-epithelial cell adhesion molecule	Might be useful as a screening test for lung adenocarcinoma.	[128]
miR-378a miR-379 miR-139-5p miR-200b-5p	Adenocarcinomas + carcinomas	105 (50 lung adenocarcinomas +30 granulomas +25 healthy smokers)	Plasma	ExoQuick	As potential diagnostic biomarkers of lung adenocarcinoma.	[129]
miR-320d miR-320c miR-320b	Patients with advanced EGFR/ALK WT NSCLC who received PD-1/PD-L1 inhibitors	37 (30 patients+ 7 healthy individuals)	Plasma	Ultracentrifugation	As potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs.	[130]
miR-181-5p miR-30a-3p miR-30e-3p miR-361-5p miR-10b-5p miR-15b-5p miR-320b	Early-stage NSCLC patients	88 for miRNA-seq (46 stage I NSCLCs + 42 healthy controls) 60 symptomatic patients for RT-PCR	Plasma	Ultracentrifugation and Immunoaffinity magnetic beads	AD-specific miR-181-5p/-30a-3p, /-30e-3p/-361-5p SCC-specific miR-10b-5p/-15b-5p/-320b as effective biomarkers for early NSCLC diagnosis.	[131]
miR-146a-5p miR-486-5p	Early NSCLC at stages I/II	128 (48 NSCLC patients at stages I/II + 32 patients with lung benign lesion + 48 healthy controls	Serum	Exosome extraction kit (Umibio Shanghai)	Serum exosomal miRNAs other than serum miRNAs be preferable biomarkers for NSCLC at early stages.	[132]
GAS5	NSCLC	104 (64 NSCLC + 40 healthy subjects)	Serum	Exosome Isolation Kit (from serum; Thermo, Carlsbad, CA)	Lower expression of Exo-GAS5 may be a marker for early-stage NSCLC.	[133]
miR-17-5p CEA CYFRA21-1 SCCA	NSCLC	190 training set (100 NSCLC patients + 90 healthy controls) 119 validation set (72 NSCLC patients + 47 healthy controls).	Serum	ExoQuick™	Have clinical value in diagnosis of NSCLC.	[134]
circSATB2	NSCLC	178 (83 NSCLC patients + 95 non-cancerous donors)	Serum	Ultracentrifugation	Be potential biomarker for diagnosis of lung cancer and cancer metastasis.	[108]
EGFR mutations	NSCLC	84 patients enrolled in TIGER-X (NCT01526928)	Plasma	ExoLution^TM Plus Extraction technology (Exosome Diagnostics, Inc.)	Combining exoRNA and ctDNA increases the sensitivity for EGFR mutation detection.	[135]
exoDNA	A broader panel of cancer cell lines, including lung, melanoma, breast, prostate and pancreatic cancers.	lung, melanoma, breast, prostate and pancreatic cancer cell lines + two normal stromal fibroblast lines	Cell culture medium	Differential ultracentrifugation	Highlight the value of exoDNA in TDEs as biomarkers in the early detection of cancer and metastasis.	[136]
LRG1	NSCLC	18 (8 NSCLC patients + 10 healthy controls)	Urine	Ultracentrifugation	Be a biomarker for diagnosis of NSCLC.	[137]
EGFR	Lung cancer patients	9 lung cancer patients + 9 normal controls	Plasma	A targeted ELISA with an anti-CD81 antibody	Be a possible biomarker for characterization of lung cancer.	[138]
CD91	Lung cancer patients	259 (165 lung cancer patients + 29 interstitial pneumonia patients + 64 normal controls)	Serum	Anti-CD9 MSIA tips	May be a lung adenocarcinoma biomarker.	[85]
CD151 CD171 tetraspanin 8	Lung cancer patients	581 (431 lung cancer patients + 150 controls)	Plasma	extracellular vesicle array contained 49 antibodies for capturing exosomes	Be promising diagnostic biomarkers in lung cancer	[140]
EGFR GRB2 SRC	NSCLC cell lines	NSCLC cells A549, HCC827 + Bronchial epithelial cells HBE3, HBE4	Cell culture medium	Ultracentrifugation	May be as biomarkers for NSCLC patients.	[106]
Tim-3 Galectin-9	NSCLC	159 (103 NSCLC patients including 60 early stages and 43 advanced stages disease samples + 56 healthy subjects)	Plasma	Exosome Precipitation Solution (3D Medicines biotechnology, Shanghai, China)	A decreased Tim-3 and Galectin-9 levels are biomarkers for response to first generation ALK-TKIs.	[141]
TP53 EGFR PKD1 ALK	Lung adenocarcinoma patients	20 stage IV lung adenocarcinoma patients	Plasma Pleural effusion	Ultracentrifugation	As the top 4 mutated genes in plasma-derived exoDNA and pleural effusion-derived exoDNA, may be used in clinical genetic testing.	[143]
exosomal lipids	NSCLC	120 (91 NSCLC subjects (44 early/47 late stage) + 39 normal controls)	Plasma	Ultracentrifugation	Exosomal lipid features as metabolomics-based biomarkers distinguish early stage lung cancer from healthy individuals.	[144]
Exosomal contents as potential prognostic biomarkers in lung cancer
Exosomal Biomarkers	Type of lung cancer studied	Number of patients/cells studied	Biopsy material	Method for exosome extraction	Roles in clinical practice	Reference
NY-ESO-1 EGFR PLAP EpCam Alix	NSCLC	276 NSCLC patients	Plasma	EV Array slides with biotinylated antibodies (anti-human-CD9, -CD63 and -CD81)	Act as strong prognostic biomarker in NSCLC.	[147]
miR-10b-5p miR-23b-3p miR-21-5p	Adenocarcinoma	20 (10 adenocarcinoma patients + 10 healthy controls)	Plasma	ExoQuick™	Be promising prognostic biomarkers of NSCLC.	[148]
miR-146a-5p	NSCLC	100 advanced NSCLC patients who received standard cisplatin-based chemotherapy	Serum	ExoQuick™	Downregulated miR-146a-5p indicates higher recurrence rates and predicts the cisplatin effect.	[149]
miR-125b-5p	Patients with advanced EGFR/ALK WT NSCLC who received PD-1/PD-L1 inhibitors	37 (30 patients+ 7 healthy individuals)	Plasma	Ultracentrifugation	Downregulated miR-125b-5p indicates well respond to immunotherapy in patients.	[130]
miR-29a-3p miR-150-5p	NSCLC Human NSCLC cell lines NCI-H460, A549, NCI-H1299 and embryonic lung fibroblasts MRC5, IMR90	5 patients with Stage IIIA NSCLC under radical thoracic RT for miRNA profiling 21 NSCLC patients receiving radical thoracic RT for validation cohort 5 lung cell lines	Plasma Cell culture medium	Solvent-exchange exosome isolation kit (Exiqon)	Decreased miR-29a-3p and miR-150-5p in exosomes are biomarkers to predict unexpected responses to radiation therapy, such as toxicity.	[150]
miR-21 miR-155	Lung cancer cell NCI-H1299, The established subcutaneous primary and recurrent lung cancer xenografts in nude mouse	Lung cancer cell NCI-H1299 + normal lung cell BEAS-2B + 25 nude mice inoculated with NCI-H1299 cells	Cell culture medium tumor and serum	Ultracentrifugation	Be significantly upregulated in serum exosomes of recurrent tumor-bearing animals.	[151]
miR-21 miR-4257	NSCLC	201 NSCLC patients	Plasma	Ultracentrifugation	Be potential as predictive biomarkers for recurrence in NSCLC patients.	[152]
Exosomes in the targeted drug resistance of lung cancer
Exosome/Molecule	Parental cell	Recipient cell	Target(s) /mechanisms	Functions		Reference
Exosomes obtained from EGFR-mutant NSCLC cells PC9	PC9 cells treated with gefitinib (for Exo-GF) or cisplatin (for Exo-DDP)	PC9 cells treated with gefitinib or cisplatin	Upregulate LC3-II and Bcl-2 and downregulate p62 and Bax.	Exo-GF increases autophagic activity, leading to cells an increased cisplatin resistance.		[158]
EGFR withT790M mutation	84 patients enrolled in TIGER-X			Lead to gefitinib resistance. A 90% sensitivity for detection of EGFR T790M using exoRNA.		[135, 159]
Exosomes after A549 cells exposure to cisplatin (DDP)	A549 cells exposure to DDP	A549 cells	Increased miR-21, ERCC1/BRCA1/RRM1 mRNAs, and decreased miR-98/-133b/-138/-181a/-200c	Mediate DDP drug resistance via miRNAs and mRNAs exchange by exosomes.		[160]
miR-100-5P	A549/DDP cells (A549 resistance to cisplatin)	A549 cells	miR-100-5p-targeted mTOR	Increase cisplatin resistance of recipient cells.		[161]
miR-21	Lung cancer cells H827R (gefitinib-resistant HCC827)	NSCLC HCC827	miR-21-mediated Akt activation	Mediate the transfer of drug resistance.		[162]
ZEB1 mRNA	Mesenchymal cells HBEC	Bronchial epithelial cells HBECs		Transfer chemoresistance and mesenchymal phenotypes to recipient cells.		[163]
miR-1246	Irradiated A549 and H446 cells	A549 and H446 cells	DR5 gene	Act as a messenger between irradiated and non-irradiated cells and promote cell radioresistance.		[164]
miR-208a	NSCLC cells A549, H1299, H1975, H460 Bronchial epithelial cells BEAS-2B, HBE		Targeting p21 with a corresponding activation of AKT/mTOR pathway	Increases the proliferation and radioresistance of human lung cancer cells.		[165]
Exosomes as drug delivery vehicles in the targeted therapy of lung cancer
Exosome	Drug loaded	Type of lung cancer treated	Method for exosome extraction	Functions		Reference
exosomes from raw bovine milk	Anthos	A549, H1299 Nude mice bearing A549 xenografts	Ultracentrifugation	Enhance therapeutic response compared with the free Anthos against lung cancer tumor with no signs of gross or systemic toxicity.		[172]
exosomes released by macrophages RAW 264.7	paclitaxel	Murine Lewis lung carcinoma cells 3LL-M27, C57BL/6 mice intra-tail vein injected with 3LL-M27 cells	ExoQuick ™	Reduce the IC50 values of chemotherapeutics and induce antitumor activity.		[174]
milk-derived exosomes	Paclitaxel	Nude mice bearing A549 xenografts	Ultracentrifugation	Show significant tumor growth inhibition of human lung tumor xenografts in nude mice.		[175]
Milk-derived exosomes	Celastrol	NSCLC cells A549, H1299, C57BL/6 mice bearing lung cancer cell xenografts	Ultracentrifugation	Enhance Celastrol efficacy and reduce dose related toxicity.		[176]
Exosomes from H1299 and MRC9 cells ferrying Gold nanoparticles	Doxorubicin cisplatin	NSCLC cells H1299, A549	Ultracentrifugation	Deliver drugs to lung cancer cells and produce therapeutic response with preferential cytotoxicity towards cancer cells.		[177]

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