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. 2023 Aug 26;32:09636897231195240. doi: 10.1177/09636897231195240

The Role and Applications of Exosomes in Gynecological Cancer: A Review

Kai-Hung Wang 1, Dah-Ching Ding 2,3,✉
PMCID: PMC10467393  PMID: 37632354

Abstract

Exosomes are phospholipid bilayer vesicles that are released by all types of cells, containing proteins, lipids, and nucleic acids such as DNAs and RNAs. Exosomes can be transferred between cells and play a variety of physiological and pathological regulatory functions. Noncoding RNAs, including micro RNAs, long noncoding RNAs, and circular RNAs, are the most studied biomolecules from exosomes and more and more studies found that noncoding RNAs play an important role in the diagnosis, prognosis, and treatment of diseases, including various types of cancer. Gynecological malignancies such as ovarian, endometrial, and cervical cancer seriously threaten women’s life. Therefore, this article reviews the roles and applications of exosomes in gynecological malignancies, including the promotion or inhibition of tumor progression and regulation of tumor microenvironments, and as potential therapeutic targets for treating gynecological cancers.

Keywords: exosome, miRNA, noncoding RNAs, gynecological cancer, endometrial cancer, ovarian cancer, cervical cancer

Introduction

Ovarian cancer (OC), endometrial cancer (EC), and cervical cancer (CC) are the three most common gynecological malignancies 1 . Ovarian cancer is the fifth most frequent cause of death in women and the leading cause of death in females diagnosed with gynecological cancers, with about 313,959 new cases and 207,252 deaths worldwide in 2020 2 . The morbidity and mortality of EC are increasing globally, with about 417,367 new cases and 97,370 deaths worldwide in 2020 3 . Cervical cancer was the fourth most common cancer and the fourth leading cause of women dying from cancer, with about 604,100 new cases and 341,831 deaths worldwide in 2020 3 . Thus, treatments for gynecological cancer are needed urgently and extracellular vesicles (EVs), especially exosomes, are receiving more attention for treating gynecological cancers 4 .

Exosomes are one type of EC, ranging in diameter from 30 to 150 nm, making them the smallest nano-size EVs. Nearly all cells produce exosomes, and the cargo of exosomes can be transferred to the neighbor cells, contributing to cell–cell communication and playing important roles in biological processes, including cancer development 5 . Among the cargo of exosomes, miRNAs were broadly studied and showed great potential for diagnosis and prognosis markers as well as therapeutic targets and nanocarrier for treatments. Therefore, we review the research progress of exosomes in gynecological malignancies.

Exosomes

Exosomes were first identified in platelets in 1967 6 . Exosomes are small vesicles with lipid bilayer membrane structure and are produced by most cells, including immune cells, stem cells, and cancer cells. Exosomes could be detected in body fluid, including plasma, serum, urine, semen, saliva, bronchial fluid, cerebral spinal fluid (CSF), breast milk, amniotic fluid, synovial fluid, tears, lymph, bile, and gastric acid 7 . Exosomes range in size from 30 to 150 nm and contain a variety of biomolecules such as proteins, lipids, and nucleic acids (eg, RNA, DNA) 8 . Exosomal vesicles form by inward budding and envelop the biomolecules, as mentioned above, into intracavity vesicles (ILVs) contained in the endosome and mature into multivesicular bodies (MVBs)8,9.

The CD63 along with CD9 and CD81 are considered markers for exosomes, and the functions are closely related to exosome production 10 . Exosomes participate in cell–cell communication, cell maintenance, and tumor progression and can be easily sampled by liquid biopsy 11 . Among those biomolecules, miRNAs, either promoting or inhibiting cancer, is the most studied. One miRNA can target several genes, regulating a series of biological functions and serve as a biomarker for diagnosis, prognosis, therapeutic target, and nanocarrier for cancer treatment, including gynecological cancer 12 .

Noncoding RNAs

Noncoding RNAs mainly include small RNA, such as micro RNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and others 13 . miRNAs were first discovered in Caenorhabditis elegans14,15, negatively regulating complementary target genes (mRNAs). miRNAs are transcribed by RNA polymerase II as primary miRNAs (pri-miRNAs) 16 and processed to single hairpins termed precursor miRNAs (pre-miRNAs) by RNase III enzyme Drosha, DiGeorge critical region 8 (DGCR8), and others 17 , after exporting pre-miRNAs to cytoplasm and processing to double-strand RNA (dsRNA) by Dicer 18 . These mature miRNAs are 20 to 25 nucleotides in length and bind the Argonaute (AGO) protein, forming the RNA-induced silencing complex (RISC) and mediating gene silencing 19 .

Conversely, lncRNAs are commonly defined on the threshold of 200 nucleotides (nt) of the RNA length, regulating chromatin remodeling, transcriptional controlling, and post-transcriptional processing 20 . The cellular localization of lncRNAs decides their functions. Cytoplasmic lncRNAs regulate mRNA stability, translation, and protein phosphorylation 21 and nuclear lncRNAs modulate gene expressions 22 . Genomic localization and context of lncRNAs include intergenic lncRNAs, intronic lncRNAs, sense lncRNAs, and antisense lncRNAs 23 . Unlike mRNA and miRNAs, lncRNAs are poorly evolutionarily conserved among species 24 . LncRNAs may also regulate miRNA biogenesis 19 .

CircRNAs are the covalently linked transcripts formed by the back-splicing of mRNA 25 . Most circRNAs are expressed from known protein-coding genes 26 , including exonic circRNAs, exon–intron circRNAs (EIcircRNAs), circular intronic RNAs (ciRNAs), and mitochondria-encoded circRNAs (mecciRNAs). Except intron-containing circRNAs, most circRNAs are exported to the cytoplasm 27 . Many circRNAs exert important biological functions by acting as microRNA or protein inhibitors (sponges), enhancer of protein function, scaffold and recruitment for protein, and templates for translation 25 .

In summary, noncoding RNAs exert important biological functions and have been implicated in various diseases, including cancer. Elevated evidence showed that noncoding RNAs were presented in exosomes and regulated the cells in tumor microenvironments (TMEs), such as tumor cells, mesenchymal stem cells (MSCs), and immune cells. Thus, we review the sources of exosomes and the functions in received cells in the TME of gynecological cancers.

Exosomes in OC

Human epididymis protein 4 (HE4) and carbohydrate antigen-125 (CA-125) are the main application markers in diagnosing OC with lacking sensitivity and specificity. Among the OC subtypes, high-grade serous carcinoma (HGSC, type II) is the most prevalent and lethal, representing more than 70% of OC. Type I tumor includes low-grade serous, endometrioid, clear cell, and mucinous carcinomas, carrying a good prognosis except for clear cell carcinoma. About 60% of OC are diagnosed at a later stage (stage III or IV), associated with poor prognosis28,29. Therefore, improving diagnosis and prognosis biomarkers and therapeutic targets is crucial for OC. Exosomes derived from OC or other cells from TME may have great potential to become new biomarkers and therapeutic targets 30 .

The Roles of Exosomes for Diagnosis and Prognosis of OC

miR-21, miR-141, miR-200a, miR-200c, miR-200b, miR-203, miR-205, and miR-214 were significantly increased in cancer cells, exosomes, and serum of OC patients (Table 1) 31 . miR-21, miR-100, miR-200b, and miR-320 were significantly enriched, whereas miR-16, miR-93, miR-126, and miR-223 were decreased in exosomes from the plasma of OC patients 32 . Exosomal miR-1260a, miR-7977, and miR-192-5p were significantly decreased in OC patients compared with healthy controls 33 . miRNA-1290 was significantly overexpressed in serum exosomes and tissues compared to the benign ovarian neoplasm 34 . Exosomal miR-21-5p, miR-29a-3p, and miR-30d-5p were overexpressed in ovarian clear cell carcinoma cells 35 . Ascites-derived miR-200a, miR-200b, miR-200c, and miR-1290 were overexpressed, and the high expression level of miR-200b was related to poor overall survival 36 . Serum exosomal miR-484 levels were significantly lower in OC patients, and the combination of miR-484 with CA-125 showed an elevated area under the curve (AUC) of 0.912 in identifying OC patients from controls 37 . The expression level of miR-205 in plasma exosomes was significantly higher in OC patients than in benign and control groups. The level of miR-205 was related to OC staging and lymph node metastasis 38 . Among seven upregulated plasma-derived exosomal miRNAs, miR-4732-5p showed great potential to be a biomarker for diagnosing OC 39 . Conversely, plasma exosomal miR-320d, miR-4479, and miR-6763-5p were significantly downregulated in OC patients and associated with lymph node metastasis 40 .

Table 1.

Exosomes and Their Components as Biomarkers for Ovarian Cancer.

Biomarker Trend Type Source Recipient cells Functions Application Ref
miR-21, miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, miR-214 Increase miRNA Cancer cells/serum — Biomarker Early detection in serum 31
miR-21, miR-100, miR-200b, miR-320 Increase miRNA Cancer cells/plasma Cancer cells Biomarker Early detection in plasma 32
miR-16, miR-93, miR-126, miR-223 Decrease miRNA Cancer cells/plasma Cancer cells Biomarker Early detection in plasma 32
miR-192-5p, miR-1260a, miR-7977 Decrease miRNA Plasma — Biomarker Early detection 33
miR-1290 Increase miRNA Cancer cells/serum — Biomarker Early detection 34
miR-21-5p, miR-29a-3p, miR-30d-5p Increase miRNA Clear cell carcinoma — Biomarker Early detection 35
miR-200a, miR-200b, miR-200c, miR-1290 Increase miRNA Ascites — Biomarker Early detection/prognosis 36
miR-484 Decrease miRNA Serum — Biomarker Early detection in serum 37
miR-205 Increase miRNA Plasma — Biomarker Prognosis 38
miR-4732-5p Increase miRNA Plasma — Biomarker Early detection in plasma 39
miR-320d, miR-4479, miR-6763-5p Decrease miRNA Plasma Biomarker Early detection in plasma 40
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The Therapeutic Application of Exosomes in OC

Exosomal miR21 from cancer-associated adipocytes (CAAs) and cancer-associated fibroblasts (CAFs) suppresses OC apoptosis and confers chemoresistance by targeting APAF1 (Table 2) 41 . Exosomal miR-21-5p enhanced migration, invasion, and tumor formation by targeting CDK6 and enhanced chemoresistance through PDHA142,43. Exosomal miR-429, regulated by NF-κB, enhanced the chemoresistance of OC cells by targeting CASR 44 . Ascites-derived exosomal miR-6780b-5p promoted epithelial–mesenchymal transition (EMT) and tumor metastasis in OC cells and correlated to poor patient survival 45 . miR-130a was highly expressed in the exosome from drug-resistant OC cells and promoted angiogenesis 46 . miR-205 was overexpressed in OC tissues, and a high level of miR-205 in serum exosomes was associated with OC metastasis. Besides, exosomal miR-205 promoted angiogenesis by regulating the PTEN-AKT pathway 47 . miR-141-3p-containing exosome derived from OC cells promoted angiogenesis by activating the JAK/STAT3 and NF-κB signaling pathways 48 . The expression of miR-543 was significantly decreased in exosomes derived from OC cell lines, tissues, and patient serum, and overexpression of miR-543 resulted in the suppression of OC cell proliferation and tumor growth by targeting IGF2 49 .

Table 2.

Exosomes and Their Components as Therapeutic Targets for Ovarian Cancer.

Biomarker Trend Type Source Recipient cells Function Mechanisms Application Ref
miR-21 Increase miRNA CAAs, CAFs Cancer cells Enhance chemoresistance APAF1 Therapeutic target 41
miR-21-5p Increase miRNA Cancer cells/plasma Cancer cells Enhance migration, invasion, tumor formation CDK6 Early detection in plasma/therapeutic target 42
miR-21-5p Increase miRNA Cancer cells Cancer cells Enhance chemoresistance PDHA1 Therapeutic target 43
miR-429 Increase miRNA Cancer cells Cancer cells Enhance chemoresistance CASR Therapeutic target 44
miR-6780b-5p Increase miRNA Ascites Cancer cells Enhance EMT and metastasis — Therapeutic target 45
miR-130a Increase miRNA Cancer cells Endothelial cells Enhance angiogenesis — Therapeutic target 46
miR-205 Increase miRNA Cancer cells/ serum Endothelial cells Biomarker/enhance angiogenesis PTEN-AKT Early detection in serum/ Therapeutic target 47
miR-141-3p Increase miRNA Cancer cells Endothelial cells Enhance angiogenesis JAK/STAT3 and NF-κB Therapeutic target 48
miR-543 Decrease miRNA Cancer cells Cancer cells Inhibit proliferation, tumor growth IGF2 Therapeutic target 49
CircRNA Foxo3 Increase CircRNA Cancer cells Cancer cells Enhance proliferation, migration, invasion miR-422a/PLP2 Therapeutic target 50
circ-PIP5K1A Increase CircRNA Cancer cells Cancer cells Enhance proliferation, migration, invasion, chemoresistance miR-942-5p/nuclear factor I B (NFIB) Therapeutic target 51
circ_0007841 Increase CircRNA Cancer cells Cancer cells Enhance proliferation, migration, invasion, chemoresistance miR532-5p/NFIB Therapeutic target 52
CircRNA051239 Increase CircRNA Cancer cells/plasma Cancer cells Enhance proliferation, migration, invasion — Therapeutic target 53
Cdr1as Decrease CircRNA Cancer cells/serum Cancer cells Suppress chemoresistance miR-1270/SCAI Therapeutic target 54
CircFoxp1 Increase CircRNA Cancer cells/serum Cancer cells Enhance chemoresistance miR-22, miR-150-3p/CEBPG, FMNL3 Therapeutic target 55
circNFIX Increase LncRNA Cancer cells Endothelial cells Enhance angiogenesis miR-518a-3p/TRIM44 Therapeutic target 56
circIFNGR2 Increase LncRNA CAFs Cancer cells Inhibit proliferation, EMT, metastasis, tumor growth miR-378/ST5 Therapeutic target 57
MALAT1 Increase LncRNA Cancer cells/serum Cancer cells Enhance angiogenesis, tumor growth MALAT1 Therapeutic target 58
lncRNA ATB Increase LncRNA Cancer cells Cancer cells/endothelial cells Enhance angiogenesis, tumor growth miR-204-3p/TGFβR2 Therapeutic target 59
lncRNA SOX2-OT Increase LncRNA Cancer cells Cancer cells Enhance proliferation, migration, invasion, tumor growth miR-181b-5p/SCD1 Therapeutic target 60
miR-155-5p Decrease miRNA Cancer cells Macrophages Inhibit tumor growth PD-L1 Therapeutic target 61
miR-29a-3p Increase miRNA TAMs Cancer cells Enhance proliferation and immune escape FOXO3-AKT/GSK3β Therapeutic target 62
miR-200b Increase miRNA Serum Macrophages Enhance M2 polarization, proliferation, invasion KLF6 Therapeutic target 63
miR-221-3p Increase miRNA TAMs derived from ascites Cancer cells Enhance migration, EMT, chemoresistance ADAMTS6/TGF-β1/EGFR-AKT Therapeutic target 64
miR-330-3p Increase miRNA Plasma cell Cancer cells Enhance tumor growth, metastasis JAM2 Therapeutic target 65
miR-7 Increase miRNA TWEAK-stimulated macrophages Cancer cells Inhibit tumor growth, metastasis EGFR/AKT/ERK1/2 Therapeutic target/nanocarrier 66
miR-92b-3p Decrease miRNA Peptide-engineered exosomes Cancer cells Inhibit tumor growth, angiogenesis SOX4 Therapeutic target/nanocarrier 67
miR-484 Decrease miRNA Peptide-engineered exosomes Cancer cells/endothelial cells Inhibit tumor growth, angiogenesis, chemoresistance — Therapeutic target/ nanocarrier 68
miR-497 — miRNA Peptide-engineered exosomes Cancer cells Inhibit tumor growth, chemoresistance PI3K/AKT/mTOR Therapeutic target/nanocarrier 69
miR-21-3p, miR-125b-5p, miR-181d-5p Increase miRNA Hypoxic cancer cells Cancer cells/ macrophages Enhance proliferation, migration, tumor growth, M2 polarization, — Therapeutic target/ 70
miR-146a Decrease miRNA hUCMSC Cancer cells Inhibit chemoresistance LAMC2 and PI3K/Akt Therapeutic target/ nanocarrier 71
miR-18a-5p Decrease miRNA hMSC Cancer cells Inhibit proliferation, migration, invasion, chemoresistance, tumor growth — Therapeutic target/nanocarrier 72
piR-25783 Increase piRNA Cancer cells Omental fibroblasts/cancer cells Enhance proliferation, migration, invasion, metastasis to omentum TGF-β/SMAD2/SMAD3 Therapeutic target 73
miR-141 Increase miRNA Cancer cells Omental fibroblasts Activated CAFs, promoted metastasis YAP1/GROα/CXCRs Therapeutic target 74
miR-29c-3p Decrease miRNA Omental CAFs cancer cells Inhibit invasion, metastasis MMP2 Therapeutic target 75
— — exosome NK cells cancer cells Increase cytotoxicity, chemosensitivity, activate immunosuppressive microenvironment — Therapeutic target 76
— — exosome HGSC cells NK cells Downregulate NKG2d, inhibit cytotoxicity — Therapeutic target 77
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CAAs: cancer-associated adipocytes; EMT: epithelial–mesenchymal transition; CAFs: cancer-associated fibroblasts; TAMs: tumor-associated macrophages; hUCMSCs: human umbilical cord mesenchymal stem cells; hMSCs: human mesenchymal stem cells; NK cells: natural killer cells.

CircRNA Foxo3 was significantly upregulated in OC cells and enhanced proliferation, migration, and invasion by targeting miR-422a/PLP2 axis 50 . Circ-PIP5K1A was highly expressed in chemoresistant OC cells. Knockdown of Circ-PIP5K1A constrained the proliferation, migration, and invasion as well as increased apoptosis and chemosensitivity in OC cells by targeting miR-942-5p/NFIB 51 . This phenomenon was also found in circ_0007841/miR532-5p/NFIB 52 . CircRNA051239 expression was increased in tissues and plasma exosomes from OC patients and could promote proliferation, migration, and invasion of OC cells in vitro 53 . Cdr1as suppressed cisplatin resistance of OC cells via miR-1270/SCAI axis 54 . Exosomal circFoxp1 was significantly increased in OC patients and positively regulated the expression of CEBPG and FMNL3 through miR-22 and miR-150-3p, resulting in cisplatin resistance of OC cells 55 . The expression of circNFIX was significantly increased in OC cells and tissues, promoting angiogenesis via miR-518a-3p/TRIM44 and downstream JAK/STAT1 signaling 56 . Interestingly, CAF-derived exosomal circIFNGR2 inhibited OC cell proliferation, EMT, metastasis, and tumor growth via targeting miR-378/ST5 axis 57 .

Long noncoding RNA (lncRNA) MALAT1 was increased in both metastatic OC cells and their secreted exosomes, which could promote angiogenesis and tumor growth. Serum exosomal MALAT1 levels were associated with poor prognosis in OC patients 58 . Exosomal lncRNA ATB promoted angiogenesis and tumorigenesis of OC cells via regulating miR-204-3p/TGFβR2 axis 59 . Exosomal lncRNA SOX2-OT enhanced proliferation, migration, invasion, and tumor growth of OC cells by miR-181b-5p/SCD1 (sterol CoA desaturase 1) signaling 60 .

Reactive oxygen species (ROS) greatly downregulated exosomal miR-155-5p from OC cells, while neutralization of ROS by N-acetyl-L-cysteine (NAC) reversed it. NAC-derived tumor exosomes were also taken up by macrophages and further inhibited tumor growth and macrophage infiltration and promoted cytotoxic T-cell (CD8+) activation in vitro by targeting PD-L1 61 . Tumor-associated macrophages (TAMs) derived exosomal miR-29a-3p promoted proliferation and immune escape of OC cells through the FOXO3-AKT/GSK3β axis and enhanced expression of PD-L1 62 . Exosomal miR-200b promoted macrophage M2 polarization while inhibiting M1 polarization through inhibiting KLF6 and further facilitated OC cell proliferation and invasion 63 . CD163+ TAMs from ascites promoted migration, EMT, and chemoresistance via miR-221-3p downregulated ADAMTS6 and the downstream TGF-β1/EGFR-AKT signaling 64 . Plasma cell–derived miR-330-3p significantly increased tumor growth and metastasis of OC cells by targeting JAM2 65 .

The tumor necrosis factor (TNF)–like weak inducer of apoptosis (TWEAK)–stimulated macrophages inhibited metastasis of OC cells via exosomal shuttling of microRNA, miR-7, and inhibiting the EGFR/AKT/ERK1/2 pathway 66 . The expression of exosomal miR-92b-3p of OC cells was low. The exosomal miR-92b-3p functions as a suppressor of tumor-associated angiogenesis via targeting SOX4. Tumor volume and angiogenesis were inhibited by the Arg-Gly-Asp peptide-engineered exosomes (RGD-SKOV3-92b/exo) from RGD-labeled SKOV3-92b cells, a stable miR-92b-3p overexpression SKOV3 cells 67 . Another study showed that targeted delivery of miR-484 via RGD-modified exosomes improved vascular normalization, sensitized OC cells to chemotherapy, and prolonged the survival time of tumor-bearing mice 68 . Furthermore, the hybrid nanoparticles, formed by membrane fusion of engineered miR497-overexpressing exosomes and liposomes modified by the target peptide RGD, in combination with the chemotherapeutic drug triptolide (TP), were effectively enriched in the tumor areas and exerted significant anticancer activity. This combination therapy decreased the PI3K/AKT/mTOR signaling pathway, boosted reactive oxygen species (ROS) generation, and upregulated the polarization of macrophages from M2 to M1 macrophages 69 . Similarly, miR-21-3p, miR-125b-5p, and miR-181d-5p from hypoxic exosomes derived from OC increased the M2 macrophage population and promoted proliferation, migration, and tumor growth of OC 70 .

Exosomal miR-146a released by hUCMSCs contributed to hUCMSC-derived exosome-mediated chemosensitivity of OC cells mediated by LAMC2 via the PI3K/Akt signaling pathway 71 . hMSC-exosomes, containing high miR-18a-5p expression, suppressed OC cell proliferation, migration, invasion, chemoresistance, and tumor growth 72 . OC cell–secreted exosomal piR-25783 activated the TGF-β/SMAD2/SMAD3 pathway in omental fibroblasts and promoted the fibroblast-to-myofibroblast transition (FMT), resulting in the elevation of proliferative, migratory, and invasive properties as well as tumor implantation and growth in the omentum 73 . Exosomal miR-141 was highly secreted by OC cells and reprogrammed stromal fibroblasts into proinflammatory CAFs, facilitating metastatic colonization through activating YAP1/GROα/CXCRs signaling 74 . miR-29c-3p was downregulated in omental CAFs-exosomes, and miR-29c-3p directly targeted MMP2 to suppress OC cell invasion and metastasis 75 .

Exosomes from NK cells, which were derived from cord blood mononuclear cells (CBMC), displayed cytotoxicity against OC cells. The NK exosomes loaded with cisplatin could sensitize drug-resistant OC cells and activate NK cells from the immunosuppressive TME. However, the detailed mechanisms are unclear 76 . Conversely, HGSC exosomes from patients’ sera downregulated NKG2D-mediated cytotoxicity in NK cells, and NKG2D expression on NK cells was upregulated after surgery, improving the NKG2D-mediated cytotoxic response 77 . The studies of exosomes serving as therapeutic targets on OC accumulate fast, and the results showed that exosomes and their components have great potential for treating OC.

Exosomes in EC

The current clinical screening of EC is based on vaginal ultrasound and biopsy of endometrial tissues lacking specificity 78 . There are two main types of ECs. About 80% belong to type I ECs, which mostly are well differentiated with endometrioid histology and show a high level of estrogen receptor (ER). Type II ECs are poorly differentiated with serous or clear cell histology and show an 80%~90% recurrence rate within 3 years, representing a poor prognosis 79 . Besides, ECs can be low-grade tumors (grades 1 and 2) carrying a better prognosis or high-grade carcinomas (grades 3) carrying an intermediate prognosis 80 . Thus, developing powerful biomarkers and therapeutic targets is urgent, and the source from exosomes had great potential.

The Roles of Exosomes for Diagnosis and Prognosis of EC

miR-15a-5p was consistently upregulated in plasma-derived exosomes from EC patients. Furthermore, higher exosomal miR-15a-5p expression was associated with larger tumors, p53 expression, and muscular infiltration depth (Table 3) 81 . Another study proved that the expression of miR-142-3p, miR-146a-5p, and miR-151a-5p was significantly overexpressed in the plasma of EC patients 82 . In the serum of EC patients, miR-143-3p, miR-195-5p, miR-20b-5p, miR-204-5p, miR-423-3p, and miR-484 were significantly overexpressed 83 . Besides, urine-derived exosomes from EC patients showed that miR-200c-3p was significantly increased 84 . Increased expression of plasma exosomal miR-93 was associated with smoking, grade of tumor, FIGO stage, distance organ metastases, and overall survival (OS). In contrast, decreased expression of miR-205 was associated with smoking, lymph node involvement, FIGO stage, and OS of EC patients 85 . FOXL2 was significantly lower in EC tissues and associated with worse OS. Conversely, miR-133a was highly expressed in EC cells and exosomes derived from EC cells and could be taken up by normal endometrial cells 86 . circ_0109046 and circ_0002577 were highly expressed in the serum of stage III EC patients, while the functions of these two circRNAs are still unclear 87 .

Table 3.

Exosomes and Their Components as Biomarkers for Endometrial Cancer.

Biomarker Trend Type Source Recipient cells Functions Application Ref
miR-15a-5p Increase miRNA Plasma — Biomarker Early detection in plasma 81
miR-142-3p, miR-146a-5p, miR-151a-5p Increase miRNA Plasma — Biomarker Early detection in plasma 82
miR-143-3p, miR-195-5p, miR-20b-5p, miR-204-5p, miR-423-3p, miR-484 Increase miRNA Serum — Biomarker Early detection in serum 83
miR-200c-3p Increase miRNA Urine — Biomarker Early detection in urine 84
miR-93 Increase miRNA Plasma — Biomarker Early detection in plasma 85
miR-205 Decrease miRNA Plasma — Biomarker Early detection in plasma 85
miR-133a Increase miRNA Cancer cells Cancer cells, normal endometrial cells Biomarker Early detection 86
circ_0109046, circ_0002577 Increase circRNA Serum — Biomarker Diagnosis in serum 87
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The Therapeutic Application of Exosomes in EC

Plasma exosomal miR-26a-5p from EC patients with lymph node metastasis (LNM) showed significantly reduced and correlated with the FIGO stage (Table 4). miR-26a-5p inhibited EC cell proliferation, migration, and invasion in vitro and tumor growth and lymph node metastasis in vivo. miR-26a-5p-silenced exosomes strongly enhanced human lymphatic endothelial cells (HLECs) lymphangiogenesis and migration ability by targeting LEF1, and miR-26a-5p-overexpressed exosomes reduced tumor growth and metastasis 88 . Under hypoxia conditions, miRNA-21-containing exosomes derived from EC cells promoted M2-like macrophage polarization that may contribute to an immune microenvironment favoring EC progression 89 .

Table 4.

Exosomes and Their Components as Therapeutic Targets for Endometrial Cancer.

Biomarker Trend Type Source Recipient cells Functions Mechanisms Application Ref
miR-26a-5p Decrease miRNA Plasma Cancer cells/HLECs Inhibit proliferation, migration, invasion, tumor growth, lymph node metastasis LEF1 Therapeutic target/nanocarrier 88
miR-21 Increase miRNA Hypoxic cancer cells Macrophages Enhance M2 polarization - 89
miR-148b Decrease miRNA CAFs Cancer cells Inhibit invasion, metastasis DNMT1 Therapeutic target/ nanocarrier 90
miR-320a Decrease miRNA CAFs Cancer cells Inhibit proliferation, migration, invasion HIF1α/VEGFA Therapeutic target/ 91
miR-499a-5p Decrease miRNA MSCs Cancer cells/endothelial cells Inhibit migration, invasion, tumor growth, angiogenesis VAV3 Therapeutic target/nanocarrier 92
miR-503-3p - miRNA hUMSCs Cancer cells Migration, invasion, tumor growth MEST Therapeutic target/ nanocarrier 93
miR302a - miRNA hUMSCs Cancer cells Proliferation, migration, invasion Cyclin D1/AKT Therapeutic target/nanocarrier 94
miR-192-5p Decrease miRNA TAMs Cancer cells Enhance apoptosis, inhibit EMT IRAK1/NF-κB Therapeutic target/ nanocarrier 95
lncRNA DLEU1 Increase lncRNA Cancer cells Cancer cells Enhance proliferation, migration, invasion, tumor growth miR-381-3p/E2F3 Therapeutic target 96
lncRNA NEAT1 Increase lncRNA Cancer cells Cancer cells Enhance tumor growth miR-26a/b-5p/STAT3/YKL-40 Therapeutic target 97
circ_0001610 Increase circRNA M2 macrophages Cancer cells Enhance radiosensitivity, tumor growth miR-139-5p/cyclin B1 Therapeutic target 98
miR-765 Decrease miRNA CD45RO-CD8+ T cells Cancer cells Inhibit EMT, invasion, tumor growth, metastasis ERβ//PLP2/Notch Therapeutic target/nanocarrier 99
tRF-20-S998LO9D Decrease tsRNA Cancer cells/serum Cancer cells Inhibit proliferation, migration, invasion, increase apoptosis SESN2 Therapeutic target 100
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HLECs: human lymphatic endothelial cells; EMT: epithelial–mesenchymal transition.

miR-148b was significantly decreased in CAFs and CAFs-derived exosomes, and exogenously transfected miR-148b CAFs-derived exosomes could suppress EC cell invasion and metastasis by targeting DNMT1 90 . miR-320a is poorly expressed in EC cells as well as CAFs. The direct transfer of CAF-secreted exosomal miR-320a to EC cells inhibited their proliferation, migration, and invasion by targeting HIF1α–VEGFA axis 91 . miR-499a-5p was also downregulated in EC cells, and MSC-derived exosomes loaded with miR-499a-5p could suppress migration, invasion, tumor growth, and angiogenesis of EC cells via targeting VAV3 92 . Furthermore, human umbilical cord blood mesenchymal stem cells (hUMSCs)–derived exosomal miR-503-3p 93 and miR302a 94 inhibited migration, invasion, and tumor growth of EC cells by suppressing MEST, and cyclin D1–AKT axis, respectively. Upregulation of miR-192-5p in TAM-derived exosomes could significantly promote the apoptosis of EC cells and inhibit EMT via IRAK1/NF-κB signaling 95 .

LncRNA DLEU1 was highly expressed in EC cells and tissues and promoted proliferation, migration, and invasion of EC cells in vitro and tumor growth in vivo by regulating miR-381-3p–E2F3 axis 96 . Exosomal lncRNA NEAT1 from CAFs facilitated EC cell growth via miR-26a/b-5p-mediated STAT3/YKL-40 axis 97 . Exosomal circ_0001610 derived from M2 tumor-associated macrophage reduced the radiosensitivity in vitro and in vivo by miR-139-5p–cyclin B1 axis 98 . miR-765 was significantly decreased in EC cells and tissues, and exosomes of CD45RO-CD8+ T cells suppressed EMT, invasion, and tumor growth, metastasis via the ERβ//PLP2/Notch axis 99 .

Downregulated transfer RNA-derived small RNAs (tRNA, tRF-20-S998LO9D) in both EC tissues and serum exosomes were found. Overexpression of tRF-20-S998LO9D inhibited proliferation, migration, and invasion and promoted apoptosis of EC cells via upregulating SESN2 100 . These results showed that exosomes and the components might serve as therapeutic targets. However, more studies are needed to elucidate the detailed mechanisms.

Exosomes in CC

Human papillomavirus (HPV), especially the high-risk types, has been defined as a carcinogen, and the persistence of high-risk HPV (hr-HPV) infection is a necessary etiological cause of CC 101 . In low-resource countries, the simple and inexpensive way is to start with visual cytologic tests (pap smear test), and in high-resource situations, it starts with pap smear test and HPV tests to screen CC patients 102 . DNA methylation and epigenetic modification have gained attention as alternative methods for molecular diagnosis and prognosis in cervical neoplasia screening 103 . Combination tests, including HPV tests and DNA methylation tests, show great potential for improving the early detection and management of CC. However, most of the studies were limited to a country or cohort, and further research is needed to validate these biomarkers in larger national-wide or multicountry cohorts. Hence, the biomarkers, especially miRNAs, from exosomes show great potential because miRNAs may control multiple genes in one biological process rather than a single gene.

The Roles of Exosomes for Diagnosis and Prognosis of CC

Plasma exosomal let-7d-3p and miR-30d-5p were significantly decreased in the cervical intraepithelial neoplasia II+ (CIN II+) group compared with the CIN I group of CC patients (Table 5) 104 . Plasma exosomal miR-146a-5p, miR-151a-3p, miR-2110, and miR-21-5p were upregulated in CC patients 105 while miR-125a-5p was downregulated 106 . Exosomal miR-21, miR-146a 107 , and lncRNA HOTAIR and MALAT1 108 levels were increased in the cervicovaginal lavage specimens of CC patients, while lncRNA MEG3 was decreased 108 . Besides, serum exosomal lncRNA DLX6-AS1 level was significantly increased in CC patients and positively associated with lymph node metastasis, FIGO stage, and shortened survival 109 . The expression of lncRNA-EXOC7 in serum and serum-derived exosomes in CC patients was elevated 110 .

Table 5.

Exosomes and Their Components as Biomarkers for Cervical Cancer.

Biomarker Trend Type Source Recipient cells Functions Application Ref
let-7d-3p, miR-30d-5p Decrease miRNA Plasma — Biomarker Early detection in plasma 104
miR-146a-5p, miR-151a-3p, miR-2110, miR-21-5p Increase miRNA Plasma — Biomarker Early detection in plasma 105
miR-125a-5p Decrease miRNA Plasma — Biomarker Early detection in plasma 106
miR-21, miR-146a Increase miRNA Cervicovaginal lavage — Biomarker Early detection in cervicovaginal lavage 107
HOTAIR, MALAT1 Increase lncRNA Cervicovaginal lavage — Biomarker Early detection in cervicovaginal lavage 108
MEG3 Decrease lncRNA Cervicovaginal lavage — Biomarker Early detection in cervicovaginal lavage 108
DLX6-AS1 Increase lncRNA Serum — Biomarker Prognosis in serum 109
lncRNA-EXOC7 Increase lncRNA Serum — Biomarker Prognosis in serum 110
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The Therapeutic Application of Exosomes in CC

Exosomal miR-223 promoted CC migration and tumor growth by upstream STAT3 and downstream TGFBR3 and HMGCS1 axis 111 . Exosomal miR-106a and 106b expressions were downregulated in cisplatin-resistant CC cells, and miR-106a/b overexpressing exosomes inhibited chemoresistance of CC cells by targeting SIRT1 (Table 6) 112 . TGF-β1 promoted the upregulation of exosomal miR-663b resulting in the enhancement of EMT and migration by targeting MGAT3 113 . Besides, exosomal miR-663b also promoted angiogenesis and tumor growth by targeting vinculin (VCL) 114 . miR-22 is frequently downregulated in various tumors, and miR-22 overexpressing exosomes deriving from HEK293 cells enhanced the radiosensitivity of CC cells by targeting MYCBP and hTERT 115 . miR-221-3p was highly expressed in CC tissues and cells. Exosomes derived from miR-221-3p mimic-transfected CC cells promoted invasion, migration, and angiogenesis of CC cells through downregulation of MAPK10 116 and lymphangiogenesis and lymphatic metastasis of HLECs by targeting VASH1 117 . miR-320a expression was decreased in CC tissues, and engineered miR-320a exosomes enhanced the chemoresistance and tumor growth by targeting MCL1 118 .

Table 6.

Exosomes and Their Components as Therapeutic Targets for Cervical Cancer.

Biomarker Trend Type Source Recipient cells Functions Mechanisms Application Ref
miR-223 Increase miRNA Cancer cells Cancer cells Enhance migration, tumor growth TGFBR3/HMGCS1 Therapeutic target/nanocarrier 111
miR-106a, miR-106b Decrease miRNA Cancer cells Cancer cells Inhibit chemoresistance SIRT1 Therapeutic target/ nanocarrier 112
miR-663b Increase miRNA Cancer cells Cancer cells Enhance EMT, migration MGAT3 Therapeutic target 113
miR-663b Increase miRNA Cancer cells Cancer cells/endothelial cells Enhance tumor growth, angiogenesis VCL Therapeutic target 114
miR-22 Decrease miRNA Cancer cells Cancer cells Inhibit radiosensitivity MYCBP /hTERT Therapeutic target/nanocarrier 115
miR-221-3p Increase miRNA Cancer cells Cancer cells/endothelial cells Enhance migration, angiogenesis MAPK10 Therapeutic target/nanocarrier 116
miR-221-3p Increase miRNA Cancer cells HLECs Enhance lymphangiogenesis, lymphatic metastasis VASH1 Therapeutic target/ nanocarrier 117
miR-320a Increase miRNA Cancer cells Cancer cells Enhance chemoresistance, tumor growth MCL1 Therapeutic target/nanocarrier 118
miR-423-3p Increase miRNA Cancer cells Cancer cells/macrophages Enhance M2 polarization, chemoresistance, tumor growth — Therapeutic target 119
miR-1323 Increase miRNA CAFs Cancer cells Enhance proliferation, migration, invasion, inhibit radiosensitivity PABPN1/IGF2BP1/GSK-3β/Wnt/β-catenin Therapeutic target 120
miR-142-5p Increase miRNA Cancer cells HLECs Suppress and exhaust CD8+ T cells IDO/ARID2–DNMT1–IFN-γ Diagnosis/therapeutic target 121
miR-1468-5p Increase miRNA Cancer cells HLECs Enhance lymphangiogenesis HMBOX1/ JAK2/STAT3 Therapeutic target 122
miR-155-5p Increase miRNA HIV-1 infected T cells Cancer cells Enhance proliferation, migration, invasion ARID2/ERCC5/NF-κB Therapeutic target 123
lncRNA HNF1A-AS1 Increase lncRNA Cancer cells Cancer cells Enhance proliferation, tumor growth and Inhibit apoptosis miR-34b/TUFT1 Therapeutic target 124
lncRNA UCA1 Increase lncRNA Cancer cells CSCs Enhance proliferation, migration, invasion, tumor growth miR-122-5p/SOX2 Therapeutic target 125
lncRNA LINC01035 Increase lncRNA Cancer cells Cancer cells Enhance migration, invasion, tumor growth KHSRP Therapeutic target 126
lncRNA PDHB-AS Decrease lncRNA HKF/cancer cells Cancer cells Inhibited proliferation, invasion, EMT, and chemoresistance miR-582-5p/Wnt/β-catenin Therapeutic target 127
lncRNA MALAT1 Increase lncRNA Cancer cells Cancer cells Promoted proliferation, chemoresistance, inhibited apoptosis STAT3/PI3K/AKT Therapeutic target 128
lnc LRRC75A-AS1 Increase lncRNA M2 macrophages Cancer cells Promoted proliferation, migration, invasion, EMT, tumor growth, metastasis miR-429 /SIX1/STAT3/MMP-9 Therapeutic target 129
circ_0074269 Increase circRNA Cancer cells Cancer cells Increase proliferation, migration, chemoresistance, induce apoptosis miR-485-5p/TUFT1 Therapeutic target 130
Circ_0006646 Increase circRNA Cancer cells Cancer cells Increase proliferation, migration, invasion, tumor growth, metastasis miR-758-3p/RRM2 Therapeutic target 131
— — — Paclitaxel loading WJ-MSC’s exosomes Cancer cells Induce apoptosis, Suppress EMT signaling — Therapeutic target/nanocarrier 132
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HLECs: human lymphatic endothelial cells; HKF: human keloid fibroblasts; WJ-MSC: Wharton jelly-derived mesenchymal stem cells; EMT: epithelial–mesenchymal transition.

Exosomal miR-423–3p inhibited macrophage M2 polarization to suppress the tumor growth of CC cells 119 . miR-1323, which was transferred by CAFs-secreted exosomes, showed upregulation in CC cells, and downregulation of miR-1323 suppressed CC cell proliferation, migration, invasion, and increased cell radiosensitivity. By targeting poly(A)-binding protein nuclear 1 (PABPN1) and recruiting insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), miR-1323 regulated the downstream protein glycogen synthase kinase 3 beta (GSK-3β) and influenced Wnt/β-catenin signaling pathway 120 . miR-142-5p could be delivered from CSCC-secreted exosomes into HLECs and suppress and exhaust CD8+ T cells by induction of IDO expression via ARID2–DNMT1–IFN-γ signaling. Serum exosomal level of miR-142-5p also positively correlated with the progression of CC patients 121 . miR-1468-5p promoted lymphatic PD-L1 upregulation and lymphangiogenesis by targeting homeobox containing 1 (HMBOX1) and activating the JAK2/STAT3 signaling 122 . Exosomal miR-155-5p derived from HIV-1 infected T cells enhanced proliferation, migration, and invasion of CC cells by ARID2–ERCC5–NF-κB axis 123 . LncRNA-HNF1A-AS1 enhances proliferation and tumor growth by targeting miR-34b/TUFT1 axis 124 . LncRNA UCA1 was overexpressed in CC cells, and it promoted proliferation, migration, invasion, and tumor growth of cancer stem cells (CSCs) by miR-122-5p/SOX2 axis 125 . LncRNA LINC01305 was increased in CC tumor tissues, and it promoted migration, invasion, and tumor growth of CC through interaction with KHSRP 126 . lncRNA PDHB-AS was significantly downregulated in CC cells, and overexpression of PDHB-AS inhibited proliferation, invasion, EMT, and chemoresistance of CC cells. PDHB-AS targeted miR-582-5p and inactivated the Wnt/β-catenin pathway via regulating Wnt7b and DKK1. Human keloid fibroblasts (HKFs)–derived exosomal miR-4536-5p downregulates PDHB-AS in CC cells 127 . lncRNA MALAT1 was highly expressed in CC tissues, exosomes, and chemoresistant cells. lncRNA MALAT1 promoted proliferation and inhibited apoptosis of CC cells by targeting miR-370-3p. While miR-370-3p was inhibited by lncRNA MALAT1, STAT3 could be re-expressed and further bind the promoter of lncRNA MALAT1, resulting in a positive feedback regulation. On the contrary, lncRNA MALAT1 promoted the chemoresistance of CC cells through STAT3/PI3K/AKT pathway 128 . Lnc LRRC75A-AS1 was highly expressed in exosomes derived from M2 macrophages, inducing proliferation, migration, invasion, EMT, tumor growth, and metastasis of CC cells through downregulating miR-429 and SIX1/STAT3/MMP-9 signaling 129 .

Circ_0074269 was overexpressed in chemoresistant CC samples and cells. Silencing of circ_0074269 elevated chemosensitivity, repressed chemoresistant CC cell proliferation and migration, and induced apoptosis through regulating TUFT1 expression via sponging miR-485-5p 130 . Circ_0006646 expression was elevated in CC cells and exosomes of CC patients, and its knockdown suppressed CC cell proliferation, migration, invasion, tumor growth, and metastasis through regulating RRM2 expression via sponging miR-758-3p 131 . Paclitaxel loading into Wharton jelly-derived mesenchymal stem cells (WJ-MSCs) exosomes, serving as nanocarrier, induced apoptosis and suppressed EMT signaling of CC cells 132 . Since the HPV vaccines were developed, however, inexpensive tests have been needed in developing or less developed countries. Other than HPV tests, exosomes could be great targets to approach.

Limitation

There are some limitations of exosomal biomarkers and therapeutic targets. First, only a few studies showed the results of subtypes of OC and EC, both of them have type I and type II cancers. Different cancer cell types may have different tumor etiology and studies for identifying subtype-specific exosomal biomarkers are needed. Second, all the studies of therapeutic targets were still in the exploratory stage; the real clinical applications of exosomal therapeutic targets are needed to further elucidate, such as how to specifically target cancer cells or the TME and how the biomolecules exchange between cells. Since the TME is complex, all the studies only confirm the exosomes from one cell to another or reverse it. However, the effects of exosomes may also be from one cell to more cells, which is unknown and may cause side effects. Thus, studies or clinical trials are needed to elucidate the altogether effects of exosomal biomolecules from one cell to another or the other cells bidirectionally or multiple-directionally (eg, bidirectional: cancer cells ⇄ CAFs, cancer cells ⇄ immune cells, cancer cells ⇄ MSCs, or multiple-directional: cancer cells ⇄ CAFs ⇄ MSCs ⇄ immune cells) in the TME.

Conclusion and Perspectives

Discovery of new diagnostic and prognostic biomarkers, as well as therapeutic targets, for gynecological cancers are urgent. Exosomes play pivotal roles in the pathogenesis of gynecological cancers by orchestrating the communication between cancer cells and the TME, including CAFs, MSCs, and immune cells. Exosomes, especially miRNAs, may function as positive or negative regulators of cancer development through various signaling pathways and associate with the diagnosis and prognosis. It is easy to approach because exosomes can secret into body fluid serving as liquid biopsy. Thus, exosomes have great potential as diagnostic and prognostic biomarkers for gynecological cancers.

Exosomes-derived biomolecules also could serve as therapeutic targets for precision medicine. Each miRNA, regardless of upregulation (oncomiR) or downregulation (tumor suppressor), regulates various signaling pathways contributing to cancer development. One miRNA could target multiple genes and regulate at least one biological process which makes it more efficient when taking miRNAs as therapeutic targets. Furthermore, due to the nano-size of exosomes, it could be engineered by modifying the surface molecules to increase the tissue-targeting specificity as a nanocarrier to deliver drugs or functional biomolecules. In summary, exosomes could not only be biomarkers but also therapeutic targets as well as nanocarriers.

Footnotes

Author Contributions: D.-C.D. contributed to conceptualization, writing—review and editing, visualization, supervision, project administration, and funding acquisition. K.H.W. contributed to methodology, software, formal analysis, investigation, and writing—original draft preparation. Both authors contributed to validation, resources, and data curation, and have read and agreed to the published version of the manuscript.

Statement of Human and Animal Rights: This article does not contain any studies with human or animal subjects.

Statement of Informed Consent: There are no human subjects in this article and informed consent is not applicable.

Data Availability Statement: All data are presented in the manuscript.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Buddhist Tzu Chi Medical Foundation (TCRD-111-080, TCMF-EP 111-01, TCRD 111-057, and TCMF-ST 111-02).

ORCID iD: Dah-Ching Ding Inline graphic https://orcid.org/0000-0001-5105-068X

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