Abstract
In recent years, genitourinary system tumors are common in people of all ages, seriously affecting the quality of life of patients, the pathogenesis and treatment of these diseases are constantly being updated and improved. Exosomes, with a lipid bilayer that enable delivery of their contents into body fluids or other cells. Exosomes can regulate the tumor microenvironment, and play an important role in tumor development. In turn, cellular and non-cellular components of tumor microenvironment also affect the occurrence, progression, invasion and metastasis of tumor. Non-coding RNAs have been shown to be able to be ingested and released by exosomes, and are seen as a potential tool in cancer diagnosis and treatment. Here, we summarize the effect of non-coding RNAs of exosome contents on the tumor microenvironment of genitourinary system tumor, expound the significance of non-coding RNAs of exosome in the occurrence, development, diagnosis and treatment of cancers.
Introduction
Exosomes were discovered as bilayers in sheep reticulocytes, actively secreted by the cells, and named by the discoverers as exosomes. 1 Exosomes were not recognized at the early stage of their discovery. They were thought to beāJunkā produced by cells. In recent years, with the development of medical technology and the increase of relevant research, the role of exosomes in drug targeted delivery and as disease biomarkers were be explored. It has great potential in diagnosis, prognosis and treatment of respiratory system, urinary system, reproductive system and digestive system diseases. 2
Non-coding RNA refers to RNA that does not code for proteins. These include microRNA (miRNA), small interfering RNA (siRNA), circular RNA (circRNA), and Long non-coding RNA (lncRNA). 3 At present, non-coding RNA (ncRNA) is one of the hotspots in medical research. Among the various types of RNA, ncRNA is in an important position. Approximately 98% of the human genome is made up of non-coding DNA. 4 Although it is not involved in the production of proteins, it plays an important role in the life activities of cells and the occurrence and development of diseases. 5 It has been proved that ncRNA can be seen in the progression of renal cancer, gastric cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, bladder cancer, cervical cancer, breast cancer and so on. 6
Recent studies have proposed the hypothesis of ācompetitive endogenous RNAā, which means that RNAs can interact with each other and competitively bind miRNA response elements to regulate the expression level of miRNAs. 7 The role of NcRNAs cannot be viewed in isolation and they often interact to regulate cellular programs. MiRNAs not only target mRNAs from many other different genes, but also functionally interact with other kinds of ncRNAs (such as circRNAs and lncRNAs) to regulate their stability. In contrast, lncRNAs and circRNAs can regulate miRNA abundance through certain mechanisms. 8 For example, in breast cancer, H19, an LncRNA, inhibits miR-152 expression and upregulates DNA methyltransferase-1 (DNMT1) expression, leading to enhanced proliferation and invasion of breast cancer cells. LncRNA-RoR targets the 3ā²-untranslated region of miR-145, leading to overexpression of ARF6 mRNA, which in turn inhibits E-cadherin localization, promoting invasion and metastasis of triple-negative breast cancer cells. 9 In addition, ncRNAs can bind to functional proteins, perform corresponding biological functions: miR-103 secreted by hepatocellular carcinoma cells may be delivered to endothelial cells via exosomes, and then diminish the integrity of endothelial junctions by directly inhibiting the expression of vascular endothelial cadherin, P120-catenin and zonula occludens. MiR-103 promotes tumor cell migration by inhibiting the expression of P120-catenin in hepatoma cells. MiR-103 may also promote expression in hepatoma cells to promote tumor cell migration. 10 In summary, NcRNAs being packaged into exosomes to influence the pathophysiological processes of tumors. NcRNAs are transported via exosomes and involved in relevant pathways and intercellular communication. Currently, there are few reports on the role of exosomes and ncRNAs in genitourinary tumors, although exosomal ncRNAs are a new frontier in cancer research, only a few ncRNAs have established functional roles or clinical applications.
The tumor microenvironment (TME) is a very complex and integrated system. In addition to tumor cells, adipocytes, fibroblasts, tumor vessels, lymphocytes, dendritic cells and cancer-associated fibroblasts are also present in the tumor microenvironment. 11 Each of these cell types has unique immune capabilities that determine whether a tumor will survive and affect neighboring cells. 12 TME is involved in the development of cancer and response to treatment. Recent studies have identified an important role for exosomes in TME. 13 Exosomes can regulate tumor and host cell function by docking with receptor cells and delivering the contents they carry (Figure 1), and promote tumor progression through delivery in the tumor microenvironment. Exosomes derived from tumor cells also have transfer miRNA and proangiogenic effects. 14
Effect of exosomes on tumor microenvironment.
The growth, metastasis, proliferation and invasion of tumor cannot be separated from intercellular communication. This communication cannot achieve, without biomolecules carried by exosomes in the tumor microenvironment, and these exosome contents can also cause profound phenotypic changes of TME. 15 Exosomes provide a platform for the development of clinical tumor biomarkers. Exosomes, new biomarkers to improve the detection of indistinguishable disease with a minimally invasive approach. 16 Thus, the potential for the use of exosomes to assess disease progression, intervene in the course of disease is enormous. This review focuses on the role of exosomal non-coding RNA in the tumor microenvironment of genitourinary system tumors.
Structure and Biological Properties of Exosomes
Extracellular vesicles are mainly divided into exosomes, microvesicles and apoptotic bodies. 17 The isolation methods of exosomes commonly including ultrafiltration, ultracentrifugation, density gradient centrifugation, poly-ethylene glycol-based precipitation, immunoaffinity capture, microfluidics,18,19 and other emerging approaches for exosome isolation such as microvortex chip, acoustofluidic platform and microfluidic nanowire array. 20 Exosomes are about 30ā150 nm in diameter and are vesicular structures with lipid bilayer membranes. They are widely present in various body fluids: blood, urine, saliva, breast milk, amniotic fluid, ascites, cerebrospinal fluid and bile. 21 Exosomes can carry a variety of biological molecules such as DNA, RNA, proteins and metabolites. 22 For example, exosomes derived from chronic granulocytic leukaemia cells contain a cytokine named TGFĪ²1, which binds to the TGFĪ²1 receptor on leukaemia cells. TGFĪ²1 promoting tumor growth by activating ERK, AKT and anti-apoptotic pathways in the cells. 23 Under hypoxic conditions, exosomal miR-23a levels are upregulated, directly inhibiting its target prolyl hydroxylases 1 and 2 (PHD1 and 2), leading to the accumulation of hypoxia-inducible factor-1Ī± (HIF-1Ī±) in endothelial cells. Thus, exosomes from hypoxic lung cancer cells are able to promote angiogenesis. In addition, exosomal miR-23a inhibits the zonula occludens-1, increasing vascular permeability and cancer cell migration. 24 Thus, it appears that this specific structure and properties allow it to be involved in mediating signaling pathways and intercellular communication, participate in the immune and development of tumor processes. 25
The Role of Exosomes in Tumours Through the Tumour Microenvironment
Exosomes secreted by cancer cells and their surrounding stromal cells can target receptor cells to communicate with each other, leading to metabolic changes in TME and altering tumor angiogenesis, metastasis and drug resistance. 26 Firstly, about blood vessels: exosomes carry a relevant gene that increases the level of vascular endothelial growth factor (VEGF) in cells, thus promoting angiogenesis. 27 Exosome contents act directly on endothelial cells and increase vascular permeability. 10 The up-regulation of some genes results in the secretion of exosomes, which leads to the formation of tubes and tumor growth of HUVEC cells, and finally leads to tumor angiogenesis. 28 Mesenchymal-derived exosomes activate endothelial cells through Akt phosphorylation and promote the formation of the metastatic vascular microenvironment. 29 Secondly, exosomes can be involved in cancer growth and metastasis: exosomes can promote apoptosis and chemosensitivity, inhibit cancer cell migration and invasion. 30 Exosomes can transfer the oncogenes in serum exosomes into cancer cells to enhance the ability of cell proliferation and migration. 31 Exosomes secreted by fibroblasts promote the extension activity and motility of cancer cells, thus driving the invasion behavior of cancer cells. 32 Third, exosomes are involved in the epithelial-mesenchymal transition (EMT) of tumors: Tumor-associated fibroblasts (CAF) can directly transfer exosomes to colorectal cancer cells, significantly increase miR-92a-3p levels, activate the Wnt/Ī²-catenin pathway, and enhance cell stemness and epithelial-mesenchymal transition in colorectal cancer to promote metastasis and chemotherapy resistance. 33 Exosome-mediated transfer of miR-193a-3p, Mir-210-3p and miR-5100 can promote the invasion of lung cancer cells by activating EMT induced by STAT3 signal. 34 Fourth, exosomes have dual roles in immune regulation, as well as anti-tumor and tumor promoting effects 35 : Tumor-derived exosomes can induce myeloid-derived inhibitory cell expansion and inhibit T cell function and dendritic cell differentiation. 36 Dendritic cell (DC) -derived or tumor-derived exosomes induce tumor-specific T cell responses and specific antitumor immunity. 37 Finally, exosomes can also alter the sensitivity of tumor cells to drugs: stroma-derived exosomal miR-21 can confer chemoresistance and invasive phenotype to ovarian cancer cells by targeting APAF 1 and confer taxol resistance through metastasis from surrounding stromal cells. 38 Cancer-associated fibroblasts (CAF) are resistant to cisplatin and it can confer cisplatin resistance to head and neck cancer by targeting CDKN1B and ING5 through exosomal delivery of functional miR-196a from CAF to tumor cells. 39
The Role of Exosomal Non-Coding RNA in the Tumour Microenvironment
Cervical Cancer
Cervical cancer is the leading cause of cancer deaths in women worldwide, cervical cancer ranks fourth for both incidence and mortality among the top 10 cancer types for estimated cases and deaths in men and women worldwide. 40 Cervical cancer is associated with persistent HPV infection, and if the virus is not cleared by the immune system, it can increase the risk of cancer in the body. 41 Currently, the accuracy of cervical cancer screening tests remains low, the use of exosomes as a diagnostic biomarker for non-invasive screening holds promise as a new screening modality. 42
More studies have shown that dysregulation of miRNA in exosomes plays a crucial role in the development and progression of cervical cancer; exosomal miR-423-3p secreted by cervical cancer cells can inhibit macrophage M2 polarization, thereby inhibiting the progression of cervical cancer cells. 43 Exosomal miR-221-3p secreted by cervical squamous cell carcinoma is transferred to human lymphatic endothelial cells, promoting lymphangiogenesis through downregulation of angiostatin-1(Vash1), and then promotes lymphatic metastasis. 44 Cervical cancer cell-derived exosomes containing miR-221-3p enhance proliferation, invasion, migration, and angiogenesis of endothelium in cervical cancer by reducing mitogen-activated protein kinase 10(MAPK10). 45 MiR-1468-5p secreted by cervical cancer cells promotes lymphatic PD-L1 upregulation as well as lymphangiogenesis and impairs T-cell immunity. Subsequently, exosomal miR-1468-5p activates the JAK2/STAT3 pathway in cancer-associated lymphatic endothelial cells by directly targeting the transcription factor HMBOX1 in the SOCS1 promoter, activating an immunosuppressive program that allows cancer cells to evade anti-cancer immunity. 46 MiR-1323 is transferred by exosomes secreted by cancer-associated fibroblasts (CAF), miR-1323 targets polyadenylate-binding protein (PABPN1), which controls insulin-like growth factor 2-mRNA binding protein 2 (IGF2BP2) regulates glycogen synthase kinase 3Ī² (GSK-3Ī²) and affects the Wnt/Ī²-linked protein signaling pathway. Down-regulation of miR-1323 in exosomes could inhibit cell proliferation, migration and invasion, and increase the radiosensitivity of cervical cancer cells. 47 Secretion of exosomal miR-142-5p from cervical squamous carcinoma cells translocates into lymphatic endothelial cells, downregulates the expression of AT-rich interactive domain-containing protein 2(ARID2), inhibits DNA methyltransferase 1(DNMT1) promoter methylation and enhances gamma-interferon transcription, leading to increased indoleamine 2, 3-dioxygenase (IDO) activity to mediate CD8 T-cell depletion. 48 Upregulated exosomal miR-221/222 in cervical cancer cells promotes cervical carcinogenesis by suppressing the expression of Methyl CpG Binding Domain Protein 2(MBD2) and methyl-CpG binding protein 2(MECP2). 49 Exosomes secreted by cervical cancer cells can carry miR-663b to vascular endothelial cells and promote angiogenesis and tumor growth in cervical cancer by inhibiting the expression of vincamine. 50 Cervical cancer cell-derived exosomal miR-663b is endocytosed by adjacent or distant cervical cancer cells after transforming growth factor-Ī²1 exposure and inhibits expression of beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3), thereby accelerating the epithelial-mesenchymal transition process and ultimately promoting local and distant metastasis. 51 It has been found that HIV-infected patients are more likely to develop cervical cancer, and that the exosome miR-155-5p, derived from HIV-infected T cells, promotes the proliferation, migration and invasion of cervical cancer cells. miR-155-5p is secreted by HIV-infected T cells that directly target ARID155 for degradation, leading to activation of the NF-ĪŗB signaling pathway. MiR-155-5p promotes cervical cancer progression by secretion of pro-inflammatory cytokines (including IL-6 and IL-8) to promote cervical cancer progression. 52
In addition, long non-coding RNA (lncRNA) is also an important regulator of cervical cancer progression. lncRNA LINC01305, which acts on KH-type splicing regulatory proteins, can be released via cervical cancer exosomes and promote the progression of cervical cancer. 53 Cervical cancer exosomal lncRNA uroepithelial carcinoma associated 1 (UCA1) affects miR-122-5p expression, targets and promotes transcriptional SOX2 expression, and enhances cervical cancer cell invasion and proliferation. 54 Exosomal lncRNA HNF1A-AS1 secreted by cervical cancer cells promotes proliferation and cisplatin resistance and inhibits apoptosis of cervical cancer cells through downregulation of miR-34b and upregulation of TUFT1. 55 Upregulation of STAT370 by exosomal lncRNA MALAT1 through adsorption of miR-3-370p and upregulation of STAT370 expression in cervical cancer tissues increases cervical cancer cell resistance to cisplatin by activating the PI3K/AKT pathway. 56
Circular RNA (circRNA) plays an important role in tumourigenesis and circ_0074269 can be delivered via exosomes. The cervical cancer cell-derived exosome circRNA_PVT1 can induce epithelial-mesenchymal transition (EMT). circ_PVT1 affects EMT by binding miR-1286 and plays a role in the migration and metastasis of cervical cancer via the exosomal pathway. 57
Ovarian Cancer
Ovarian cancer is usually not easily detectable early in the course of the disease and is prone to recurrence after treatment. Exosomal microRNAs are considered to be important mediators in the regulation of ovarian carcinogenesis; for example, exosomal miR-92b-3p regulates ovarian cancer-related angiogenesis 58 ; exosomes of hypoxic epithelial ovarian cancer transport miR-940 to macrophages and induce M2 macrophage polarization, promoting the proliferation of cancer cells. 59 , 60 The plasma cell-secreted exosomal miR-330-3p can enter the nucleus of ovarian cancer cells and induce epithelial-mesenchymal transition, bind to the junctional adhesion molecule 2 (JAM2) promoter and control ovarian cancer metastasis. 61 Exosomal miR-1246 is largely expressed in exosomes of ovarian cancer cells and promotes tumor progression in the tumor microenvironment through M2 tumor-associated macrophage. 62
Epithelial ovarian cancer (EOC)-derived exosomal LncRNA MALAT1 transfer to recipient human umbilical vein endothelial cells, eventually promoting angiogenesis. 63
One study found that circWHSC1, which is highly expressed in ovarian cancer, can adsorb miR-145 and miR-1182, upregulate the expression of downstream targets of MUC1 and hTERT, and promote cancer cell proliferation and invasion, a process that can also be achieved through secretion into exosomes. This process provides favorable conditions for tumor metastasis, contributes to tumor spread in the peritoneal cavity and promotes the progression of ovarian cancer. 64
Endometrial Cancer
Endometrial cancer is an epithelial malignancy that occurs in the endometrium. Tumour-associated macrophages (TAMs) are important regulators of endometrial cancer development. TAMs can block endometrial cancer progression by transferring miR-192-5p-bearing exosomes, whose upregulation promotes apoptosis and impedes the epithelial mesenchymal transition of cancer cells, and by targeting the IRAK1/NF-ĪŗB signaling pathway; in addition, miR-192-5p overexpression in TAM-derived exosomes can significantly inhibit tumor growth. 65 Low plasma exosomal miR-26a-5p levels are associated with lymph node metastasis in patients with endometrial cancer. Exosomal miR-26a-5p secreted by cancer cells and taken up by lymphatic endothelial cells can induce lymphatic vessel formation by activating lymphatic enhancer factor-1 and may contribute to the early identification of lymph node metastasis in patients with endometrial cancer. 66 Cancer-associated fibroblasts (CAFs) promote endometrial cancer cell invasion. miR-148b can be transferred from CAFs to endometrial cancer cells via exosomes. miR-148b binds directly to its downstream target gene encoding DNA methyltransferase 1 (DNMT1), which enhances cancer cell metastasis by inducing epithelial mesenchymal transition (EMT), and thus this binding inhibits endometrial cancer metastasis. 67 In addition, exosomal miR-499 can inhibit endometrial cancer cell proliferation by directly targeting guanine nucleotide exchange factors, inhibiting tumor growth and angiogenesis in vivo. 68 CAF has been shown to release extracellular vesicle loaded with miR-320a and inhibit the activation of the HIF1Ī±/VEGFA signaling pathway to suppress endometrial carcinogenesis and progression. 69 Endometrial cancer KEL cells under hypoxic conditions promote the conversion of monocytes to M2 polarized macrophages by delivery of exosomal miRNA-21, which may be a potential mechanism for immune escape in the tumor microenvironment. 70 CD45ROCD8 T cell-derived exosomes release high levels of miR-765 and limit the tumor promoting effect of estrogen on endometrial cancer in the uterine corpus by regulating the miR-765/PLP2 axis. 71 Study demonstrates that women with polycystic ovary syndrome (PCOS) are at increased risk of developing endometrial cancer, possibly through the targeting of SMAD4 by miR-27a-5p in serum exosomes of PCOS patients to stimulate endometrial cancer cell migration and invasion. 72
In addition, exosomal lncRNA NEAT1 from CAFs can be transferred to endometrial cancer cells and promote their development via the miR-26a/b-5p-mediated STAT3/YKL-40 pathway. 73
TAM derived exosomes as hsa_circ_0001610 vectors transfer hsa_circ_0001610 to endometrial cancer cells to compete for miR-139-5p and release expression of cyclin B1, thereby impairing radiosensitivity of endometrial cancer cells. 74
Prostate Cancer
Prostate cancer is the most common malignancy of the male genital system and is prone to bone metastasis. Prostate cancer cell-derived exosomes miR-125b, miR-130b and miR-155 cause tumor transformation and mesenchymal-epithelial transformation (MET) in adipose tissue stem cells from prostate cancer patients. 75 Human prostate cancer cell-derived exosome miR-183 promotes prostate cancer cell proliferation, migration and invasion through down-regulation of tropomyosin 1 (TPM1). 76 One study found that miR-1275 enhanced osteoblast activity by downregulating NAD-dependent protein deacetylase sirtuin-1 (SIRT1) and increasing the expression of Runt-related transcription factor 2 (RUNX2) through exosomal transfer from prostate cancer cells to osteoblasts. 77 Exosomal miR-205 from human bone marrow mesenchymal stem cells may potentially metastasize to prostate cancer cells, thereby inhibiting the proliferation, invasion and migration of prostate cancer cells and promoting their apoptosis by inhibiting Rho GTPase binding protein 2 and inhibiting tumor cell growth. 78 Prostate cancer cell-derived exosome miR-26a shows significant inhibitory effects on cancer cell proliferation, migration and invasion. 79 Prostate cancer cell-derived exosomal miR-375 targets disconnected interacting protein homolog 2C (DIP2C) to promote osteoblast metastasis and prostate cancer progression by regulating Wnt signaling. 80
Long non-coding RNAs (lncRNAs) are also involved in some aspects of prostate cancer. lncRNA PCSEAT exhibits oncogenic properties in prostate cancer and acts as a competitive endogenous RNA associated with the Enhancer of Zeste Homolog 2 (EZH2) recombinant protein. 81 Exosomal lncAY927529 can activate autophagy of bone marrow mesenchymal stem cells, regulate bone microenvironment, and enhance the proliferation and invasion of prostate cancer cells. 82 Exosomal circRNA HIPK3 inhibits cell proliferation and metastasis of prostate cancer by regulating miR-212/ BMI-1 pathway. 83
Studies have shown that exosomal circ_0044516 promotes the proliferation and metastasis of prostate cancer cells and can be used as a potential biomarker. 84
Kidney Cancer
Renal cell carcinoma (RCC) is one of the tumors with immune infiltration. The tumor microenvironment influences tumor biology and response to therapy, 85 and much evidence suggests that specific metabolic pathway activation plays a role in renal cancer angiogenesis, inflammatory response and modulation of immune infiltration. 86 Several studies have shown that activation of specific metabolic pathways may lead to the development of renal cell carcinoma. 87 Certain pathway components can be used as biomarkers for renal cell carcinoma.88,89 Understanding the interactions between cells in the tumor microenvironment and cancer cells may provide new ideas for the prognostic and predictive characterization of RCC patients and for future drug development90ā92.
Cancer-associated fibroblasts (CAFs) can enhance cancer stemness by delivering exosomes to renal cell carcinoma (RCC) cells. The exosomal miR-181d-5p transferred from CAFs to RCC cells directly inhibits the expression of RNF43 and activates the Wnt/Ī²-catenin signaling pathway, thereby promoting cancer stemness and tumor progression. 93 MicroRNA-1 (miR-1) acts as a tumor suppressor in renal cell carcinoma. Exosomal miR-1 significantly inhibits cell proliferation, migration and invasion. Compared with normal kidney samples, the expression of miR-1 in clinical renal cell carcinoma samples was significantly down-regulated. Compared with patients with high expression, patients with low miR-1 expression had poor overall survival. 94 M2 macrophages carry miR-21-5p to promote migration and invasion in RCC cells through PTEN/Akt signaling. 95 MiR-193a-5p in tumor-associated macrophage (TAM) -derived exosomes can down regulate tissue inhibitor of metalloproteinase 2 (TIMP2) gene to promote the development of renal cell carcinoma. 96
As a competitive endogenous RNA of miR-613 / 206 / 1-1-3p, lncHILAR can up-regulate Jagged-1 and C-X-C chemokine receptor 4 (CXCR4), activate Jagged-1 / Notch / CXCR4 axis, induce metastasis of renal cell carcinoma, and promote cell invasion and migration. Exosomal lncHILAR from hypoxic renal cell carcinoma cells is taken up by recipient normoxic renal cell carcinoma cells thereby enhancing the cell-invasion phenotype. 97 miR-155-5p is transferred from hypoxic TAM to renal cancer cells via exosomes, and the renal cell carcinoma-derived exosome LncARSR interacts with miR-34 / miR-449 to increase STAT3 expression and mediate macrophage polarization in RCC cells, promoting tumor progression. 98
Renal cell carcinoma-derived exosomal circSAFB2 mediates the polarization of M3 macrophages through the miR-2 / JAK620 / STAT1 axis to promote renal cell carcinoma metastasis. 99 Circ-PRKCI can be transferred from highly malignant RCC cells to relatively low malignant RCC cells through exosomes. The up-regulation of RCC cell-derived exosome circ-PRKCI can inhibit miR-545-3p. As a target of miR-545-3p, cyclin D1 (CCND1) is a major regulator of cell cycle and participates in the proliferation of tumor cells. Therefore, regulating the miR-545-3p / CCND1 axis can promote the proliferation, migration and invasion of RCC cells while inhibiting their apoptosis. 100 Exosomal circ_400068 regulates the proliferation of RCC cells by targeting the miR-2-210p / SOCS1 axis. Circ_400068 acts on the potential downstream molecule miR-210-5p. Suppressor of cytokine signaling 1 (SOCS1) is the target of miR-210-5 p and affects cell proliferation and apoptosis. 101
Potential in Clinical Diagnosis and Treatment
In recent years, more and more studies have shown that exosomes can be used as therapeutic strategies and tumor biomarkers, and become new important candidate technologies in the prevention and treatment of tumors. 102 Tumor cells secrete more exosomes. The composition of exosomes in the body fluids of tumor patients is different from that of healthy people (Table 1). According to these differences, some components in exosomes can be used as diagnostic biomarkers for tumors. Studies have shown that exosomal miR-30d-5p and let-7d-3p are valuable diagnostic biomarkers for screening cervical cancer. 42 The levels of exosomal microRNA-21 and microRNA-146a in cervical vaginal lavage fluid of women with cervical cancer are increased, which may suggest that exosomal microRNA-21 and microRNA-146a can be used as diagnostic biomarkers for cervical cancer. 103 The expression level of exosomal miR-125a-5p in cervical cancer patients was significantly lower than that in healthy controls, indicating that exosomal miR-125a-5p may be used as a biomarker for the diagnosis of cervical cancer.. 104 The level of serum exosomal lncRNA DLX6-AS1 in patients with cervical cancer was significantly increased, and its expression was positively correlated with lymph node metastasis, differentiation, FIGO stage and shortened survival. It is proved that serum exosomal lncRNA DLX6-AS1 can be used as an indicator to predict the survival time and prognosis of patients. 105 The expression of exosomal miR-93, miR-145 and miR-200c in serum of ovarian cancer patients was significantly increased, which could be used as molecular markers to support the diagnosis of ovarian cancer. 106 Urine-derived exosomal has-miR-200c-3p can be used for non-invasive liquid biopsy screening of endometrial cancer. 107 Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for prostate cancer patients, demonstrating the potential to diagnose and monitor the status of cancer patients. 108
Different Exosomal Non-Coding RNAs and Their Pathological Condition.
Exosomes can target content to specific cells, this feature can treat diseases by using exosomes to deliver ncRNAs. 109 Cervical cancer cells treated with miR-22-enriched exosomes showed increased radiosensitivity after being irradiated compared to untreated cervical cancer cells, which was achieved by inducing reduced levels of c-Myc binding protein (MYCBP) and human telomerase reverse transcriptase (hTERT). suggesting that treatment by increasing exosomal miR-22 may be able to aid cervical cancer radiotherapy. 110 miR-1246 released from ovarian cancer cells can metastasize to M2 macrophages and make cancer cells paclitaxel resistant by regulating Caveolin-1 (Cav1), and when miR-1246 inhibitors are used in combination with paclitaxel treatment, tumor cell proliferation can be reduced. 62 Exosome miR-499 inhibits endometrial cancer cell proliferation and endothelial tube formation by directly targeting VAV3. Studies have used mesenchymal stem cell (MSCs) -derived exosomes as a miR-499 delivery vehicle, which can be effectively absorbed by endometrial cancer cells, up-regulate the level of miR-499 in cancer cells, and help control cancer progression. 68 Overexpression of miR-1246 in prostate cancer cell lines can inhibit the growth of xenograft tumors in vivo, increase apoptosis, reduce proliferation, invasion and migration in vitro, and play a tumor suppressor role in prostate cancer. 111 Exosomes have also been used as drug delivery vehicles in recent years, and exosome encapsulated curcumin can be delivered intranasally to the brain to treat inflammatory brain diseases. 112 Exosomal delivery of adriamycin to tumor tissue is effective in inhibiting tumor growth and is not associated with significant drug toxicity. 113 Exosomes have made some progress as a treatment for the disease and hold great promise as an alternative clinical treatment to conventional therapiesļ¼Figure 2).
Exosomes are involved in gene, protein, and drug delivery.
Conclusions
Compared with imaging examination, pathological tissue biopsy and other drug-loading methods, exosomes have considerable advantages. Exosomes are non-invasive and can be extracted in body fluids, greatly reduce the detection time, do not cause patient discomfort, and can also reflect the patientās treatment and medication effectiveness; as a drug carrier, it can avoid the drug being decomposed in advance, improve the therapeutic effect, reduce the toxicity, and pass through the blood-brain barrier.
The relationship between various systemic diseases and exosomes has been confirmed by various studies, but there are still many unknown links and mechanisms to be discovered. Current research needs more clinical trials and data support. Exosomes have many challenges in clinical applications. For example, the process of extraction and detection is too cumbersome. The kits and equipment used for exosome extraction are expensive. The storage conditions and temperature of the extracted exosomes are strict. The degradation rate of exosomes is slightly faster and cannot be stored for a long time. The concentration and purity of exosomes extracted from tissues need to be further improved. Therefore, we need simpler and faster exosome extraction and purification methods to solve these problems, improve the clinical utilization of exosomes, and reduce the time and cost of patients.
In addition, there is now an exosomal and single-nucleus RNA-Seq (snRNA-Seq) technology that can simultaneously detect exosomal miRNA and single-cell transcriptome, which can not only understand the function of single cells, but also further discover the mechanism of action and communication transmission process between cells and tumor microenvironment. Therefore, it is necessary to invest in more research on exosomes. An in-depth understanding of the role of exosomes in the reproductive system can make exosomes play a role in clinical diagnosis and treatment, and provide a guarantee for the health of patients.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
This is a part research accomplishment of the project āeIF4E3 doubly regulates the translation of Snail/E-cad axis to suppress EMT, invasion and metastasis of cervical cancerā, which is supported by the National Natural Science Foundation of China.
xin-rong Hu, (grant number 81572566).
