Skip to main content

Current status of research on exosomes in general, and for the diagnosis and treatment of kidney cancer in particular

Abstract

Kidney cancer is a common urological tumour. Owing to its high prevalence and mortality rate, it is the third most malignant tumour of the urinary system, followed by prostate and bladder cancers. It exerts a high degree of malignancy, and most of the distant metastasis occurs at an early stage; it is insensitive to chemoradiotherapy and easily develops drug resistance. The current treatment for kidney cancer mainly includes surgery, interventional embolization and targeted therapy; however, the treatment efficacy is poor. In recent years, the role of exosomes as mediators of intercellular communication and information exchange in the tumour microenvironment in tumour pathogenesis has attracted much attention. Exosomes are rich in bioactive substances such as nucleic acids, proteins and lipids and are involved in angiogenesis, immune regulation, drug resistance, formation of pre-metastatic niche, invasion and metastasis. This article reviews the ongoing research and applications of exosomes for the diagnosis and treatment of kidney cancer.

Background

Kidney cancer, also known as renal cell carcinoma (RCC), is one of the most common malignancies of the urinary tract, and its incidence has increased at a rapid rate of 2% per year over the past two decades [1, 2]. In 2018, approximately 400,000 new cases and 170,000 deaths owing to kidney cancer were reported worldwide [3]. In 2015, approximately 74,000 new cases and 27,000 deaths owing to kidney cancer were reported in China [4]. Kidney cancer is insensitive to radiotherapy and chemotherapy, and surgery remains the mainstay of treatment for kidney cancer. However, approximately 30% of patients with kidney cancer develop metastasis on initial diagnosis, and approximately 25% of patients with localized kidney cancer may develop local recurrence or distant metastasis after surgery [5, 6]. Owing to recurrence or distant metastasis, the 5-year survival rate of patients with advanced kidney cancer is extremely low, approximately 5–10% [7, 8].

Exosomes are small extracellular vesicles composed of a lipid bilayer membrane structure; they are actively secreted by normal and cancer cells in the body and contain proteins, nucleic acids, lipids and other bioactive substances [9, 10]. Exosomes play an important role in the exchange of information between cells by releasing bioactive substances that fuse with receptor cell membranes or bind to cell surface receptors [11, 12]. Studies have demonstrated that exosomes play an important role in the development, diagnosis and treatment of kidney, prostate, bladder and breast cancers and serve potential clinical applications as tumour markers, therapeutic targets and drug nanocarriers in clinical settings [13,14,15].

This article reviews the ongoing research and applications of exosomes for the diagnosis and treatment of kidney cancer.

Overview of exosomes

Exosomes are nanoscale biological vesicles released into surrounding body fluids upon fusion of multivesicular bodies and the plasma membrane; they are produced and secreted autonomously by living cells in vivo and are the smallest extracellular vesicles [16, 17]. Exosomes are subgroups of extracellular vesicles with an average diameter of about 30–100 nm [18, 19]. Exosomes originate from the intracellular body structure, which influences the composition of exosome contents after interaction with other intracellular vesicles and organelles [20]. Exosomes were previously considered non-functional substances until 2007, when it was discovered that exosomes may act as ‘messengers’ that carry genetic material for the exchange of intercellular information and act within the recipient cells, suggesting that exosomes can be involved in intercellular information exchange [21,22,23]. The membrane structure of exosomes is resistant to exogenous proteases and RNA enzymes, thus resulting in more stable intracellular functional proteins, messenger RNAs (mRNAs) and microRNAs (miRNAs) that make exosomes a sensitive marker for disease diagnosis [24, 25]. In many diseases, exosomes can function by altering cellular or tissue states, and exosome-related assays can be used as effective and non-invasive methods for disease diagnosis and monitoring [9, 10]. In addition, the study of molecular mechanisms related to exosome-mediated intercellular material exchange will also provide a theoretical basis for the development of exosome-related therapies [26, 27].

Composition of exosomes

As observed under the electron microscope, exosomes are hemispherical structures with a lipid bilayer membrane [28]. Exosomes are composed of various components, mainly including proteins, lipids and nucleic acids (Table 1), and are abundantly present in body fluids, including blood, tears, urine, saliva, milk and ascites [38] (Fig. 1). Proteins mainly include tetraspanin, heat shock proteins, MVB formation, membrane transport and fusion proteins, antigen presentation, adhesion molecules, lipid raft and cytoskeletal proteins, which participate in the fusion of cell membranes and release of exosomes [29,30,31]. Lipids mainly include cholesterol, ceramide, phosphatidylserine, phosphatidylinositol, phosphatidylcholine, sphingomyelin and ganglioside, which are involved in the biological activity of exosomes [32,33,34]. Nucleic acids mainly include DNA, mRNA, miRNA, long non-coding RNA (lncRNA) and circular RNA (circRNA), which participate in the transmission of genetic information and diagnosis of diseases [35,36,37]. The specific components of exosomes are displayed in Table 1.

Table 1 Composition of exosomes
Fig. 1
figure 1

The hallmarks and cargos of exosomes. Exosomes are hemispherical structures with lipid bilayer membrane under electron microscope. Exosomes are composed of various components, mainly including proteins, lipids and nucleic acids

Formation of exosomes

The exact mechanism of exosome formation remains poorly understood, and the endosomal sorting complex required for transport (ESCRT) is a classical pathway [39, 40] (Fig. 2). The two main steps in the formation of exosomes are as follows: First, the cell membrane sags inward to form the early endosomes with accumulated luminal vesicles (ILV), and the endosomes are wrapped with proteins, lipids and nucleic acids synthesised by the cells; the endosomal membrane is depressed to bud inward to form tubular vesicles (intraluminal vesicles), that is, early endosomes (EEs) [41, 42]. Subsequently, the depressed membrane matures into multivesicular bodies (MVBs) with dynamic subcellular structures, that is, late endosomes (LEs), which can expose the transmembrane protein domain of the cytoplasm and release multiple vesicle structures into the extracellular environment upon fusion with the plasma membrane to form exosomes. Rab27a and Rab27b direct the movement of LEs/MVBs toward the cell periphery, the SNARE complex helps LEs/MVBs fuse with the plasma membrane to release exosomes, and the rest of LEs/MVBs are degraded by lysosomes [43, 44].

Fig. 2
figure 2

Exosome biogenesis and secretion within endosomal system by the endosomal sorting complex required for transport (ESCRT) pathway. Early endosomes (EEs) are formed by the fusion of endsomes. Subsequently, EEs depend on ESCRT to form multivesicular late endosomes (LEs)/bodies (MVBs). Rab27a and Rab27b direct the movement of LEs/MVBs toward the cell periphery, the SNARE complex helps LEs/MVBs fuse with the plasma membrane to release exosomes, and the rest of LEs/MVBs are degraded by lysosomes

Secretion of exosomes

Exosomes are secreted extracellularly through exocytosis upon the fusion of intercalated compartments with plasma membrane, which is the most basic and common process in cells [45]. However, in T cells and mast cells, this fusion is dependent on calcium ions for activation [46]. Most intracellular membrane fusions occur through specific protein mechanisms, such as N-ethylmaleimide-sensitive factor (NSF) for soluble factors and soluble NSF adhesion protein (SNAP) and SNAP adhesion protein receptor (SNARE) for membrane complex factors [47]. The two membranes in which fusion occurs should contain the corresponding SNAREs, namely vesicular SNARE (v-SNARE) and target SNARE (t-SNARE) [48, 49]. In addition, exosome secretion is controlled by Ras-associated GTP-binding protein 27a (Rab27a) and Rab27b [50, 51]. Synaptic binding protein-like 4 (SYTL4) and exophilin 5 (EXPH5) can inhibit Rab27a and Rab27b, leading to exosome secretion [51]. The exact mechanism of regulation of exosome secretion remains unclear, and the role of the above-mentioned molecules in exosome secretion requires further investigation.

Function of exosomes

Exosomes are released by different cell types and can regulate the biological activity of target cells by transporting proteins, lipids and nucleic acids. They play a role in various biological processes such as angiogenesis, antigen presentation, apoptosis and inflammation [17]. They act by transferring informative substances, thus influencing physiological and pathological processes involved in cancer, neurodegenerative diseases, infections and autoimmune diseases [52,53,54,55,56]. Exosomes affect the recipient cells through two pathways [57]. The first pathway involves ligand–receptor interactions between exosomes and recipient cells, without internalising the exosome or its contents into the target cell. This pathway can regulate the activation or inhibition of target cell signalling pathways. The second pathway involves the entry of exosomes into cells through membrane fusion or endocytosis, wherein their components are taken up and released into the cytoplasm, thus affecting the host cells by regulating specific gene expression and signalling pathways and ultimately leading to changes in the cell function or phenotype.

Detection of exosomes

In recent years, with the progress of research on exosomes in tumours, various technologies for exosome detection have been introduced that focus on the following three aspects: isolation and enrichment, identification and content analysis [58,59,60,61,62]. In addition, some researchers have developed various kits for the diagnosis and prognostic risk assessment of tumours based on the composition of exosomes [56, 63,64,65,66]. Development of such detection kits is a major clinical breakthrough in the field of early tumour diagnosis and provides an effective test for clinical diagnosis and the assessment of efficacy. However, there is a lack of a unified gold-standard method for exosome detection, which makes it difficult to be widely promoted in clinical settings. Therefore, it is necessary to discover a uniform and clinically recognised exosome detection technology.

Exosomes and kidney cancer

Involvement in the formation of tumour microenvironment

The tumour microenvironment is a key factor in the formation of tumours, and tumour cells can interact with their microenvironment to promote tumorigenesis and progression [67]. Exosomes exhibit certain characteristics of tissue and organ cellophilia, and the expression of this tendency is related to the expression of integrins on the surface of exosomes [68]. The establishment of pre-metastatic ecological niche is a complex process that involves the binding of exosomes secreted by cancer cells to the stromal cells of target organs, leading to the reprogramming of target cells, activation of signalling pathways and ultimately the establishment of a pre-metastatic microenvironment in target organs, thus providing the prerequisite for tumour metastasis [69, 70]. Exosomes are considered the main mediators of cell–cell interactions in the tumour microenvironment and are involved in promoting tumour cell invasion, angiogenesis and immunosuppression [71,72,73,74,75]. The role of exosomal constituents in kidney cancer are shown in Fig. 3.

Fig. 3
figure 3

Role of exosomal constituents in kidney cancer. Exosomal component sare involved in the proliferation, migration and invasion, metastasis, angiogenesis, drug resistance, and epithelial mesenchymal transition (EMT) of kidney cancer

Contribution to angiogenesis

During tumorigenesis, tumour cells require a large supply of nutrients and oxygen to maintain rapid cell growth and reproduction. The formation of new blood vessels in the primary tumour foci provides more nutrients for the growth and spread of tumour cells [76, 77]. Tumour cells promote angiogenesis by activating endothelial cells [78]. Endothelial cells secrete exosomes rich in vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietin-1 (ANGPT1), ephrin A3 (EFNA3), matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9) and azurocidin 1 (AZU1), which can stimulate the production of adjacent tumour blood vessels [78,79,80,81,82]. Grange et al. [70] verified that a subset of CD105-expressing tumour-initiating cells in human kidney cancer released microvesicles, which triggered angiogenesis and promoted the formation of pre-metastatic niches. Hou et al. [72] demonstrated that oncogenic miR-27a delivered by exosomes can bind to secreted frizzled-related protein 1 (SFRP1) and promote angiogenesis in kidney cancer. Tyrosine kinase inhibitor (TKI)-resistant kidney cancer can secrete low levels of exosomal miR-549a to induce vascular permeability and angiogenesis to promote kidney cancer metastasis [83]. Li et al. [84] found that ApoC1 transfer from kidney cancer cells to vascular endothelial cells through exosomes promoted angiogenesis and enhanced the migration and invasion of human umbilical vein endothelial cells (HUVEC) cells by activating signal transducer and activator of transcription 3 (STAT3). In addition, exosomes with high expression of carbonic anhydrase IX (CA IX) are associated with kidney cancer revascularisation [85]. The establishment of a vascular network is not only essential for the normal growth of tumour tissues but also provides an important channel for tumour invasion [86].

Contribution to immune escape

Myeloid-derived suppressor cells (MDSCs) exert potent inhibitory effects on several immune cells, and their high concentration aggregation in the tumour microenvironment is one of the reasons for the formation of tumour immune escape [87, 88]. It was found that Hsp70 was abundantly present in exosomes secreted by mouse kidney cancer cells (Renca cells), upregulated the expression of arginase 1 (ARG-1), iNOS, interleukin 6 (IL-6) and VEGF and induced the expression of MDSCs by phosphorylating STAT3 (p-STAT3) pathway, thus promoting tumour growth [75, 89].

Natural killer (NK) cells are the main host defence factors against kidney cancer cells and can exert anti-tumour effects by either directly mediating cytotoxic activity through degranulation or promoting anti-tumour activity and producing immunomodulatory cytokines [90,91,92]. Xia et al. [93] found that exosomes of kidney cancer origin induced defective NK cell function through transforming growth factor-beta (TGF-β)/SMAD signalling pathway to evade natural immunity.

Exosomes secreted by kidney cancer cells can induce immune responses in T cells to trigger apoptosis of activated T lymphocytes by activating the caspase pathway. They can diminish the cytotoxicity of NK cells and reduce the production of IL-2, interferon gamma (IFN-γ), IL-6 and IL-10, which contribute to the immune escape and promote the development of kidney cancer [77, 94, 95]. In addition, exosomes isolated from human renal adenocarcinoma ACHN cells contain Fas ligands, which inhibit the action of the human immune system by inducing apoptosis of CD8+ T cells and ultimately help cancer cells in achieving immune escape [96].

Involvement in cancer cell invasion and metastasis

A key molecular event in the development of target organ/tissue metastasis by tumours is the formation of tumour pre-metastatic niches [97]. Tumour pre-metastatic niches are defined as some molecular and cellular changes in metastatic-designated organs/tissues that can facilitate the colonisation of target organs/tissues by circulating tumour cells and promoting distant tumour metastasis [98]. In recent years, secretory components and cells found in distant metastatic tissues of different tumour animal models, including soluble factors, exosomes, vesicles and MDSCs, have confirmed the presence of tumour pre-metastatic niches in most types of malignancies [99, 100]. Exosomes can alter the target cell function through substances they carry; tumour-derived exosomes that act on epithelial cells lead to epithelial–mesenchymal transition (EMT), which is important in tumour metastasis [101].

Role of exosomes in the diagnosis of kidney cancer

Proteins

Raimondo et al. [73] identified 261 and 186 proteins by isolating urinary exosomes from normal patients and patients with kidney cancer, respectively, and most proteins were membrane-associated or cytoplasmic. Among these proteins, the expression of MMP9, ceruloplasmin (CP), podocalyxin like (PODXL), carbonic anhydrase IX (CAIX) and dickkopf 4 (DKK4) in urinary exosomes was higher in patients with kidney cancer than that in normal patients, and the expression of CD10, extracellular matrix metalloproteinase inducer (EMMPRIN), dipeptidase 1 (DPEP1), syntenin 1 and aquaporin 1 (AQP1) in urinary exosomes was higher in normal patients than that in patients with kidney cancer. These proteins may serve as potential markers of kidney cancer. Wang et al. [68] investigated the effect of exosomes isolated from cancer stem cells (CSCs) of 76 patients with metastatic RCC and 133 patients with localised RCC and found that CD103+ played a role in directing CSC exosomes to target cancer cells and organs. In addition, Tsuruda et al. [102] found that Rab27b protein can play an oncogenic role in renal cancer and sunitinib resistance through exosome-independent function.

mRNA

mRNAs are a class of single-stranded RNAs that carry genetic information and can direct protein synthesis; they are transcribed from a strand of DNA as a template [103, 104]. Exosomes can carry and transport large amounts of mRNA to function in the recipient cells [23]. Grange et al. [70] identified mRNAs implicated in tumour progression and metastasis through molecular characterisation of microvesicles, including VEGF, FGF2, ANGPT1, EFNA3, MMP2 and MMP9. In addition, Palma et al. [105] reported that the mRNA levels of glutathione s-transferase alpha 1 (GSTA1), CCAAT enhancer binding protein alpha (CEBPA) and pterin-4 alpha-carbinolamine dehydratase 1 (PCBD1) in urinary extracellular vesicles were lower in patients with RCC than those in controls, and the mRNA levels of these three genes returned to normal 1 month after nephrectomy. This demonstrates that mRNA levels in urinary extracellular vesicles serve as potential molecular markers for the diagnosis of RCC.

miRNA

miRNAs are smaller endogenous non-coding RNAs (18–24 nucleotides) that regulate protein translation after gene transcription [106, 107]. They can act as oncogenes or tumour suppressors involved in tumorigenesis [108, 109]. Several exosomal miRNAs have been identified to be differentially expressed in patients with renal cancer and normal patients. Grange et al. [70] found that 24 miRNAs, including miR-200c and miR-650, were significantly upregulated in CD105+ microvesicles, and 33 miRNAs, including miR-100 and miR-296, were significantly downregulated, and several miRNAs such as miR-29a, miR-650, and miR-151 were associated with tumour invasion and metastasis. Zhang et al. [110] found that the expression levels of miR-210 and miR-1233 in blood exosomes were significantly higher in patients with RCC than those in healthy subjects, and the expression levels were significantly decreased after surgical removal of the tumour. Xiao et al. [111] sequenced exosomal miRNAs from plasma samples and found that the expression level of miR-149-3p and miR-424-3p was upregulated, whereas that of miR-92a-1-5p was significantly decreased. In addition, other miRNAs were reported to be potential diagnostic biomarkers of kidney cancer [68, 83, 112,113,114,115,116,117,118].

lncRNA

lncRNAs are RNAs that are longer than 200 nucleotides and cannot code for proteins [119]. They can control cellular transcription and protein translation by interacting with proteins, mRNAs or miRNAs [120]. Malignant tumour cells can express specific lncRNA markers, indicating that lncRNAs can be used as disease-specific markers that are important for cancer diagnosis [121]. lncRNAs are abundantly expressed in exosomes and can be protected by the exosomal tegument with higher stability [122, 123]. Similar to miRNAs, lncRNAs play an important role in the growth, proliferation, invasion and metastasis of cancer cells [124]. Qu et al. [125] demonstrated that exosome-transmitted lncARSR promoted AXL and c-MET expression in RCC cells by competitively binding to miR-34/miR-449, thereby promoting sunitinib resistance. Exosomal lncRNAs are important in tumour biology, and further studies are required to understand the role of exosomal lncRNAs in renal cancer.

circRNA

CircRNAs are a newly discovered type of non-coding RNAs that form a covalently closed continuous loop structure that originates from exons or introns by specific selective shearing [126,127,128]. It has been found that a large number of circRNAs can be detected in exosomes. circRNAs function as miRNA sponges during gene regulation [129, 130]. Based on the circRNA expression array data, Xiao et al. [131] found that circ_400068 was significantly upregulated in exosomes derived from RCC. At present, circRNAs in exosomes derived from renal cancer cells have been investigated in a relatively small number of studies, and therefore, further investigation is required. Potential biomarkers derived from exosomes that have been validated in kidney cancer are listed in Table 2. Figure 3 demonstrates the role of exosomal constituents in kidney cancer.

Table 2 Exosomes derived potential biomarker for kidney cancer

The role of exosomes in kidney cancer treatment

Tumour drug resistance

Tumour drug resistance is one of the main reasons for the failure of clinical treatment of tumours. Drug-resistant tumour cells can secrete exosomes that contain the genetic information of multiple drug resistance-associated proteins, which in turn cause other tumour cells to acquire drug resistance [132, 133]. Several receptor tyrosine kinases associated with angiogenesis and tumour microenvironment are overexpressed mainly owing to the inactivation of Von Hippel–Lindau (VHL) tumour suppressor genes in renal cancer; therefore, TKIs, including sunitinib, have become one of the first-line therapies for renal cancer [134]. However, sunitinib resistance has made the clinical benefit of sunitinib treatment limited at present [135]. Qu et al. [125] found that drug-resistant cells in nephropathy transmitted lncARSR to other cells through exosomes, causing them to develop drug resistance, and lncARSR promoted AXL/c-MET expression by competitively binding to miR-34/miR-449. MET expression, which in turn promoted lncARSR expression as positive feedback, further promoted drug resistance in renal cancer cells. In addition, Tsuruda et al. [102] found that Rab27b can play an oncogenic role in sunitinib resistance in renal cancer through exosome-independent function. The above-mentioned study demonstrates that exosomes mediate the development of drug resistance in tumour cells, which can not only provide novel therapeutic targets for patients but also predict the responsiveness of patients to anti-tumour drugs through the detection of exosomal markers, thus providing an important reference for individualised treatment of kidney cancer [44, 136].

Drug carriers

Owing to their lipid bilayer membrane structure, exosomes can protect RNA present inside the membranes from degradation by RNA enzymes, and owing to their smaller particle size and deformability, they can cross the biological membranes more easily, thus facilitating precise delivery of therapeutic genes to the target cells [137, 138]. Exosomes can mediate the transfer of genetic material, thus altering the biological activity of recipient cells [139]. Exosomes can carry various therapeutic substances, including RNAs and antisense oligonucleotides [24]. Exosomes can deliver therapeutic substances directly to target organs through different biological barriers, for example, macrophage-derived exosomes can effectively cross the blood–brain barrier to deliver protein-like substances [140]. Ligand enrichment on engineered exosomes can also be used to induce or inhibit signalling in the receptor cells for targeting exosomes to specific cells [141]. In addition, exosomes can be effectively loaded with chemotherapeutic drugs with low toxic side effects. Therefore, they can serve as well-tolerated and promising drug carriers [142, 143]. Currently, exosomes are considered important drug delivery carriers for the treatment of cardiovascular diseases and pancreatic cancer [35, 144]; however, their role in kidney cancer requires further investigation [145].

Tumour vaccines

Compared with conventional vaccines, the vaccines developed using exosomes derived from tumour cell secretion may exert incomparable effects with higher affinity [146]. Exosomes secreted by tumour cells can present tumour-associated antigens and induce the development of immunity against tumours [94]. Zhang et al. found that IL-12-anchored kidney cancer cell-derived exosomes induced the production of more cytotoxic T lymphocytes specific for kidney cancer antigens and improved anti-tumour effects [147]. They further constructed an enhanced immunogenic EXO-IL-12 vaccine capable of stably expressing kidney cancer-specific antigen G250, immune-associated protein and GPI-IL-12, which can significantly enhance the proliferation and activation of T lymphocytes in vitro and exert an induced antigen-specific killing effect [74, 148]. Another study found that mice with kidney cancer vaccinated with tumour exosome-loaded dendritic cell (DC-TEX) vaccine had a longer survival period than that of mice vaccinated with tumour cell lysate-loaded dendritic cell vaccine [149]. Exosomes that are loaded and delivered with tumour suppressor genes that inhibit tumour cell growth provide necessary conditions for the development of exosomal tumour vaccines [150,151,152].

Conclusion

Early diagnosis of kidney cancer is one of the key factors in improving the survival rate of patients. Exosomes may benefit early diagnosis. Exosomes secreted by kidney cancer cells are abundantly present in blood, urine and other body fluids, thus providing advantages such as easy availability, non-invasive examination and tumour specificity. Owing to their small size, high mobility and lipid bilayer structure, they can easily passthrough biological membranes and protect rich bioactive substances present inside the membranes from degradation; therefore, exosomes have become a prime focus of research. Tumour-derived exosomes carry a large number of substances, including proteins, nucleic acids and lipids, which can alter the biological behaviour of target cells and participate in the development of kidney cancer. Numerous studies have found that the expression of exosomes is significantly different in patients with kidney cancer and normal subjects. Exosomes play an important role in the infiltration and metastasis of kidney cancer and also participate in tumour drug resistance and immune escape. Studies related to exosomes provide new ideas for the diagnosis and treatment of kidney cancer and offer adequate developmental prospects. However, studies on exosomes derived from renal cancer cells are mostly retrospective, and the tissue types mostly include renal clear cell carcinoma. To promote the application of exosomes in clinical settings, more extensive studies combined with clinical trials are required, and future studies should include increased sample sizes and different tissue types and adopt a prospective study design, which will be more convincing and provide substantial medical data support for clinical translation. In addition, the study of exosomes in kidney cancer is relatively independent and none of the molecules identified seem to have been repeatedly validated in different studies, which requires more prospective clinical trials leading to more reproducible biomarkers. Moreover, further investigation is required for developing exosome-mediated tumour vaccines and understanding the effect and mechanism of drug resistance on targeted therapy for kidney cancer.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ALIX:

ALG-2 interacting protein X

ANGPT1:

Angiopoietin-1

AQP1:

Aquaporin 1

ARG-1:

Arginase 1

AZU1:

Azurocidin 1

CA IX:

Carbonic anhydrase IX

CEBPA:

CCAAT enhancer binding protein alpha

circRNA:

Circular RNA

CP:

Ceruloplasmin

CSCs:

Cancer stem cells

DKK:

4dickkopf 4

DPEP1:

Dipeptidase 1

EEs:

Early endosomes

EFNA3:

Ephrin A3

EMMPRIN:

Extracellular matrix metalloproteinase inducer

EMT:

Epithelial–mesenchymal transition

ESCRT:

Endosomal sorting complex required for transport

EXPH5:

Exophilin 5

FGF:

Fibroblast growth factor

FLOT1:

Flotillin-1

GSTA1:

Syntenin 1 and glutathione s-transferase alpha 1

Hsp:

Heat shock proteins

HUVEC:

Human umbilical vein endothelial cells

ICAM-1:

Intercellular adhesion molecule-1

IFN-γ:

Interferon gamma

IL-6:

Interleukin 6

LEs:

Late endosomes

lncRNA:

Long non-coding RNA

MDSCs:

Myeloid-derived suppressor cells

MHC:

Major histocompatibility complex

miRNAs:

microRNAs

MMP2:

Matrix metallopeptidase 2

MMP9:

Matrix metallopeptidase 9

mRNAs:

Messenger RNAs

MVBs:

Multivesicular bodies

NK:

Natural killer

NSF:

N-ethylmaleimide-sensitive factor

PCBD1:

Pterin-4 alpha-carbinolamine dehydratase 1

PODXL:

Podocalyxin like

Rab:

Ras-associated GTP-binding

RCC:

Renal cell carcinoma

SFRP1:

Secreted frizzled-related protein 1

SNAP:

Soluble NSF adhesion protein

SNARE:

SNAP adhesion protein receptor

STAT3:

Signal transducer and activator of transcription 3

SYTL4:

Synaptic binding protein-like 4

TGF-β:

Transforming growth factor-beta

TKI:

Tyrosine kinase inhibitor

TSG101:

Tumour susceptibility gene 101

t-SNARE:

Target SNARE

VEGF:

Vascular endothelial growth factor

VHL:

Von Hippel–Lindau

v-SNARE:

Vesicular SNARE

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.

    Article  PubMed  Google Scholar 

  2. Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67(5):913–24.

    Article  PubMed  Google Scholar 

  3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  4. Zhang S, Sun K, Zheng R, Zeng H, Wang S, Chen R, et al. Cancer incidence and mortality in China. J Nat Cancer Cent. 2015;2020.

  5. Tannir NM, Pal SK, Atkins MB. Second-line treatment landscape for renal cell carcinoma: a comprehensive review. Oncologist. 2018;23(5):540–55.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mao W, Wang K, Zhang H, Lu H, Sun S, Tian C, et al. Sarcopenia as a poor prognostic indicator for renal cell carcinoma patients undergoing nephrectomy in China: a multicenter study. Clin Transl Med. 2021;11(1):e270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yong C, Stewart GD, Frezza C. Oncometabolites in renal cancer. Nat Rev Nephrol. 2020;16(3):156–72.

    Article  CAS  PubMed  Google Scholar 

  8. Bianchi M, Sun M, Jeldres C, Shariat SF, Trinh QD, Briganti A, et al. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol. 2012;23(4):973–80.

    Article  CAS  PubMed  Google Scholar 

  9. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478).

  10. Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016;126(4):1208–15.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mathieu M, Martin-Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21(1):9–17.

    Article  CAS  PubMed  Google Scholar 

  12. Li I, Nabet BY. Exosomes in the tumor microenvironment as mediators of cancer therapy resistance. Mol Cancer. 2019;18(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nawaz M, Camussi G, Valadi H, Nazarenko I, Ekstrom K, Wang X, et al. The emerging role of extracellular vesicles as biomarkers for urogenital cancers. Nat Rev Urol. 2014;11(12):688–701.

    Article  PubMed  Google Scholar 

  14. Thongboonkerd V. Roles for exosome in various kidney diseases and disorders. Front Pharmacol. 2019;10:1655.

    Article  CAS  PubMed  Google Scholar 

  15. Halvaei S, Daryani S, Eslami SZ, Samadi T, Jafarbeik-Iravani N, Bakhshayesh TO, et al. Exosomes in Cancer liquid biopsy: a focus on breast Cancer. Mol Ther Nucleic Acids. 2018;10:131–41.

    Article  CAS  PubMed  Google Scholar 

  16. Tkach M, Kowal J, Thery C. Why the need and how to approach the functional diversity of extracellular vesicles. Philos Trans R Soc Lond B Biol Sci. 2018;373:1737.

    Article  CAS  Google Scholar 

  17. Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9:19.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262(19):9412–20.

    Article  CAS  PubMed  Google Scholar 

  19. Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5(1):8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164(6):1226–32.

    Article  CAS  PubMed  Google Scholar 

  21. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161–72.

    Article  CAS  PubMed  Google Scholar 

  22. Shimaoka M, Kawamoto E, Gaowa A, Okamoto T, Park EJ. Connexins and Integrins in Exosomes. Cancers (Basel). 2019;11:1.

    Article  CAS  Google Scholar 

  23. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.

    Article  CAS  PubMed  Google Scholar 

  24. Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.

    Article  CAS  PubMed  Google Scholar 

  25. Xu L, Gimple RC, Lau WB, Lau B, Fei F, Shen Q, et al. The present and future of the mass spectrometry-based investigation of the exosome landscape. Mass Spectrom Rev. 2020;39(5–6):745–62.

    Article  CAS  PubMed  Google Scholar 

  26. Muluhngwi P, Valdes R Jr, Fernandez-Botran R, Burton E, Williams B, Linder MW. Cell-free DNA diagnostics: current and emerging applications in oncology. Pharmacogenomics. 2019;20(5):357–80.

    Article  CAS  PubMed  Google Scholar 

  27. Giallombardo M, Chacartegui Borras J, Castiglia M, Van Der Steen N, Mertens I, Pauwels P, et al. Exosomal miRNA analysis in non-small cell lung Cancer (NSCLC) Patients' plasma through qPCR: a feasible liquid biopsy tool. J Vis Exp. 2016;111.

  28. Weidle UH, Birzele F, Kollmorgen G, Ruger R. The multiple roles of Exosomes in metastasis. Cancer Genomics Proteomics. 2017;14(1):1–15.

    Article  CAS  PubMed  Google Scholar 

  29. Faught E, Henrickson L, Vijayan MM. Plasma exosomes are enriched in Hsp70 and modulated by stress and cortisol in rainbow trout. J Endocrinol. 2017;232(2):237–46.

    Article  CAS  PubMed  Google Scholar 

  30. Yunusova NV, Tugutova EA, Tamkovich SN, Kondakova IV. The role of exosomal tetraspanins and proteases in tumor progression. Biomed Khim. 2018;64(2):123–33.

    Article  CAS  PubMed  Google Scholar 

  31. Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem. 2019;88:487–514.

    Article  CAS  PubMed  Google Scholar 

  32. Skotland T, Hessvik NP, Sandvig K, Llorente A. Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology. J Lipid Res. 2019;60(1):9–18.

    Article  CAS  PubMed  Google Scholar 

  33. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319(5867):1244–7.

    Article  CAS  PubMed  Google Scholar 

  34. Kajimoto T, Okada T, Miya S, Zhang L, Nakamura S. Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes. Nat Commun. 2013;4:2712.

    Article  PubMed  CAS  Google Scholar 

  35. Ibrahim A, Marban E. Exosomes: fundamental biology and roles in cardiovascular physiology. Annu Rev Physiol. 2016;78:67–83.

    Article  CAS  PubMed  Google Scholar 

  36. Wei Z, Batagov AO, Schinelli S, Wang J, Wang Y, El Fatimy R, et al. Coding and noncoding landscape of extracellular RNA released by human glioma stem cells. Nat Commun. 2017;8(1):1145.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009;11(9):1143–9.

    Article  CAS  PubMed  Google Scholar 

  38. Zaborowski MP, Balaj L, Breakefield XO, Lai CP. Extracellular vesicles: composition, biological relevance, and methods of study. Bioscience. 2015;65(8):783–97.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Tang XH, Guo T, Gao XY, Wu XL, Xing XF, Ji JF, et al. Exosome-derived noncoding RNAs in gastric cancer: functions and clinical applications. Mol Cancer. 2021;20(1):99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sun W, Ren Y, Lu Z, Zhao X. The potential roles of exosomes in pancreatic cancer initiation and metastasis. Mol Cancer. 2020;19(1):135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fujita Y, Kosaka N, Araya J, Kuwano K, Ochiya T. Extracellular vesicles in lung microenvironment and pathogenesis. Trends Mol Med. 2015;21(9):533–42.

    Article  CAS  PubMed  Google Scholar 

  42. Frydrychowicz M, Kolecka-Bednarczyk A, Madejczyk M, Yasar S, Dworacki G. Exosomes - structure, biogenesis and biological role in non-small-cell lung cancer. Scand J Immunol. 2015;81(1):2–10.

    Article  CAS  PubMed  Google Scholar 

  43. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer. 2019;18(1):75.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Conlan RS, Pisano S, Oliveira MI, Ferrari M, Mendes PI. Exosomes as reconfigurable therapeutic systems. Trends Mol Med. 2017;23(7):636–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yue P, Zhang Y, Mei K, Wang S, Lesigang J, Zhu Y, et al. Sec3 promotes the initial binary t-SNARE complex assembly and membrane fusion. Nat Commun. 2017;8:14236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wei Y, Wang D, Jin F, Bian Z, Li L, Liang H, et al. Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nat Commun. 2017;8:14041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang Y, Li L, Hou C, Lai Y, Long J, Liu J, et al. SNARE-mediated membrane fusion in autophagy. Semin Cell Dev Biol. 2016;60:97–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lepore DM, Martinez-Nunez L, Munson M. Exposing the elusive exocyst structure. Trends Biochem Sci. 2018;43(9):714–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pfeffer SR. Two Rabs for exosome release. Nat Cell Biol. 2010;12(1):3–4.

    Article  CAS  PubMed  Google Scholar 

  51. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12(1):19–30 sup pp 1–13.

    Article  CAS  PubMed  Google Scholar 

  52. Zeng Y, Yao X, Liu X, He X, Li L, Liu X, et al. Anti-angiogenesis triggers exosomes release from endothelial cells to promote tumor vasculogenesis. J Extracell Vesicles. 2019;8(1):1629865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Beatriz M, Vilaca R, Lopes C. Exosomes: innocent bystanders or critical culprits in neurodegenerative diseases. Front Cell Dev Biol. 2021;9:635104.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wang J, Yao Y, Chen X, Wu J, Gu T, Tang X. Host derived exosomes-pathogens interactions: potential functions of exosomes in pathogen infection. Biomed Pharmacother. 2018;108:1451–9.

    Article  CAS  PubMed  Google Scholar 

  55. Baharlooi H, Azimi M, Salehi Z, Izad M. Mesenchymal stem cell-derived Exosomes: a promising therapeutic ace card to address autoimmune diseases. Int J Stem Cells. 2020;13(1):13–23.

    Article  CAS  PubMed  Google Scholar 

  56. Yu W, Hurley J, Roberts D, Chakrabortty SK, Enderle D, Noerholm M, et al. Exosome-based liquid biopsies in cancer: opportunities and challenges. Ann Oncol. 2021;32(4):466–77.

    Article  CAS  PubMed  Google Scholar 

  57. French KC, Antonyak MA, Cerione RA. Extracellular vesicle docking at the cellular port: extracellular vesicle binding and uptake. Semin Cell Dev Biol. 2017;67:48–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Vaswani K, Koh YQ, Almughlliq FB, Peiris HN, Mitchell MD. A method for the isolation and enrichment of purified bovine milk exosomes. Reprod Biol. 2017;17(4):341–8.

    Article  PubMed  Google Scholar 

  59. Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Witwer KW, Soekmadji C, Hill AF, Wauben MH, Buzas EI, Di Vizio D, et al. Updating the MISEV minimal requirements for extracellular vesicle studies: building bridges to reproducibility. J Extracell Vesicles. 2017;6(1):1396823.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Baek R, Jorgensen MM. Multiplexed Phenotyping of small extracellular vesicles using protein microarray (EV Array). Methods Mol Biol. 2017;1545:117–27.

    Article  CAS  PubMed  Google Scholar 

  62. Sina AA, Vaidyanathan R, Dey S, Carrascosa LG, Shiddiky MJ, Trau M. Real time and label free profiling of clinically relevant exosomes. Sci Rep. 2016;6:30460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. He YD, Tao W, He T, Wang BY, Tang XM, Zhang LM, et al. A urine extracellular vesicle circRNA classifier for detection of high-grade prostate cancer in patients with prostate-specific antigen 2-10 ng/mL at initial biopsy. Mol Cancer. 2021;20(1):96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ocansey DKW, Zhang L, Wang Y, Yan Y, Qian H, Zhang X, et al. Exosome-mediated effects and applications in inflammatory bowel disease. Biol Rev Camb Philos Soc. 2020;95(5):1287–307.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Hu Q, Su H, Li J, Lyon C, Tang W, Wan M, et al. Clinical applications of exosome membrane proteins. Precis Clin Med. 2020;3(1):54–66.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Chen KB, Chen J, Jin XL, Huang Y, Su QM, Chen L. Exosome-mediated peritoneal dissemination in gastric cancer and its clinical applications. Biomed Rep. 2018;8(6):503–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013;91(4):431–7.

    Article  CAS  Google Scholar 

  68. Wang L, Yang G, Zhao D, Wang J, Bai Y, Peng Q, et al. CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p. Mol Cancer. 2019;18(1):86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Choi D, Lee TH, Spinelli C, Chennakrishnaiah S, D'Asti E, Rak J. Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation. Semin Cell Dev Biol. 2017;67:11–22.

    Article  CAS  PubMed  Google Scholar 

  70. Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, et al. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 2011;71(15):5346–56.

    Article  CAS  PubMed  Google Scholar 

  71. Chen G, Zhang Y, Wu X. 786-0 renal cancer cell line-derived exosomes promote 786-0 cell migration and invasion in vitro. Oncol Lett. 2014;7(5):1576–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hou Y, Fan L, Li H. Oncogenic miR-27a delivered by exosomes binds to SFRP1 and promotes angiogenesis in renal clear cell carcinoma. Mol Ther Nucleic Acids. 2021;24:92–103.

    Article  CAS  PubMed  Google Scholar 

  73. Raimondo F, Morosi L, Corbetta S, Chinello C, Brambilla P, Della Mina P, et al. Differential protein profiling of renal cell carcinoma urinary exosomes. Mol BioSyst. 2013;9(6):1220–33.

    Article  CAS  PubMed  Google Scholar 

  74. Zhang Y, Luo CL, He BC, Zhang JM, Cheng G, Wu XH. Exosomes derived from IL-12-anchored renal cancer cells increase induction of specific antitumor response in vitro: a novel vaccine for renal cell carcinoma. Int J Oncol. 2010;36(1):133–40.

    Article  PubMed  CAS  Google Scholar 

  75. Gao Y, Xu H, Li N, Wang H, Ma L, Chen S, et al. Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression. Cell Commun Signal. 2020;18(1):106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Demircioglu F, Hodivala-Dilke K. alphavbeta3 integrin and tumour blood vessels-learning from the past to shape the future. Curr Opin Cell Biol. 2016;42:121–7.

    Article  CAS  PubMed  Google Scholar 

  77. Zhang L, Wu X, Luo C, Chen X, Yang L, Tao J, et al. The 786-0 renal cancer cell-derived exosomes promote angiogenesis by downregulating the expression of hepatocyte cell adhesion molecule. Mol Med Rep. 2013;8(1):272–6.

    Article  CAS  PubMed  Google Scholar 

  78. Audia A, Conroy S, Glass R, Bhat KPL. The impact of the tumor microenvironment on the properties of Glioma stem-like cells. Front Oncol. 2017;7:143.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Urabe F, Kosaka N, Kimura T, Egawa S, Ochiya T. Extracellular vesicles: toward a clinical application in urological cancer treatment. Int J Urol. 2018;25(6):533–43.

    Article  PubMed  Google Scholar 

  80. Xue C, Shen Y, Li X, Li B, Zhao S, Gu J, et al. Exosomes derived from hypoxia-treated human adipose Mesenchymal stem cells enhance angiogenesis through the PKA signaling pathway. Stem Cells Dev. 2018;27(7):456–65.

    Article  CAS  PubMed  Google Scholar 

  81. Grange C, Brossa A, Bussolati B. Extracellular Vesicles and Carried miRNAs in the Progression of Renal Cell Carcinoma. Int J Mol Sci. 2019;20:8.

    Article  CAS  Google Scholar 

  82. Jingushi K, Uemura M, Ohnishi N, Nakata W, Fujita K, Naito T, et al. Extracellular vesicles isolated from human renal cell carcinoma tissues disrupt vascular endothelial cell morphology via azurocidin. Int J Cancer. 2018;142(3):607–17.

    Article  CAS  PubMed  Google Scholar 

  83. Xuan Z, Chen C, Tang W, Ye S, Zheng J, Zhao Y, et al. TKI-resistant renal Cancer secretes low-level Exosomal miR-549a to induce vascular permeability and angiogenesis to promote tumor metastasis. Front Cell Dev Biol. 2021;9:689947.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Li YL, Wu LW, Zeng LH, Zhang ZY, Wang W, Zhang C, et al. ApoC1 promotes the metastasis of clear cell renal cell carcinoma via activation of STAT3. Oncogene. 2020;39(39):6203–17.

    Article  CAS  PubMed  Google Scholar 

  85. Horie K, Kawakami K, Fujita Y, Sugaya M, Kameyama K, Mizutani K, et al. Exosomes expressing carbonic anhydrase 9 promote angiogenesis. Biochem Biophys Res Commun. 2017;492(3):356–61.

    Article  CAS  PubMed  Google Scholar 

  86. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. 2020;77(9):1745–70.

    Article  CAS  PubMed  Google Scholar 

  87. Umansky V, Blattner C, Fleming V, Hu X, Gebhardt C, Altevogt P, et al. Myeloid-derived suppressor cells and tumor escape from immune surveillance. Semin Immunopathol. 2017;39(3):295–305.

    Article  CAS  PubMed  Google Scholar 

  88. Shao L, Zhang B, Wang L, Wu L, Kan Q, Fan K. MMP-9-cleaved osteopontin isoform mediates tumor immune escape by inducing expansion of myeloid-derived suppressor cells. Biochem Biophys Res Commun. 2017;493(4):1478–84.

    Article  CAS  PubMed  Google Scholar 

  89. Diao J, Yang X, Song X, Chen S, He Y, Wang Q, et al. Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3. Med Oncol. 2015;32(2):453.

    Article  PubMed  CAS  Google Scholar 

  90. Frankenberger B, Noessner E, Schendel DJ. Immune suppression in renal cell carcinoma. Semin Cancer Biol. 2007;17(4):330–43.

    Article  CAS  PubMed  Google Scholar 

  91. Hinkel A, Tso CL, Gitlitz BJ, Neagos N, Schmid I, Paik SH, et al. Immunomodulatory dendritic cells generated from nonfractionated bulk peripheral blood mononuclear cell cultures induce growth of cytotoxic T cells against renal cell carcinoma. J Immunother. 2000;23(1):83–93.

    Article  CAS  PubMed  Google Scholar 

  92. Yang SH, Lee JP, Jang HR, Cha RH, Han SS, Jeon US, et al. Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury. J Am Soc Nephrol. 2011;22(7):1305–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Xia Y, Zhang Q, Zhen Q, Zhao Y, Liu N, Li T, et al. Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway. Oncotarget. 2017;8(23):37783–95.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Yang C, Robbins PD. The roles of tumor-derived exosomes in cancer pathogenesis. Clin Dev Immunol. 2011;2011:842849.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Yu DD, Wu Y, Shen HY, Lv MM, Chen WX, Zhang XH, et al. Exosomes in development, metastasis and drug resistance of breast cancer. Cancer Sci. 2015;106(8):959–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang L, Wu X, Wang D, Luo C, Chen L. Renal carcinoma cell-derived exosomes induce human immortalized line of Jurkat T lymphocyte apoptosis in vitro. Urol Int. 2013;91(3):363–9.

    Article  PubMed  Google Scholar 

  97. Sceneay J, Smyth MJ, Moller A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 2013;32(3–4):449–64.

    Article  CAS  PubMed  Google Scholar 

  98. Liu Y, Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell. 2016;30(5):668–81.

    Article  CAS  PubMed  Google Scholar 

  99. Ingangi V, Minopoli M, Ragone C, Motti ML, Carriero MV. Role of microenvironment on the fate of disseminating Cancer stem cells. Front Oncol. 2019;9:82.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Valcz G, Buzas EI, Szallasi Z, Kalmar A, Krenacs T, Tulassay Z, et al. Perspective: bidirectional exosomal transport between cancer stem cells and their fibroblast-rich microenvironment during metastasis formation. NPJ Breast Cancer. 2018;4:18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Whiteside TL. Tumor-derived Exosomes and their role in Cancer progression. Adv Clin Chem. 2016;74:103–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tsuruda M, Yoshino H, Okamura S, Kuroshima K, Osako Y, Sakaguchi T, et al. Oncogenic effects of RAB27B through exosome independent function in renal cell carcinoma including sunitinib-resistant. PLoS One. 2020;15(5):e0232545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rhoads RE. Synthetic mRNA: production, introduction into cells, and physiological consequences. Methods Mol Biol. 2016;1428:3–27.

    Article  CAS  PubMed  Google Scholar 

  104. Gilbert WV, Bell TA, Schaening C. Messenger RNA modifications: form, distribution, and function. Science. 2016;352(6292):1408–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. De Palma G, Sallustio F, Curci C, Galleggiante V, Rutigliano M, Serino G, et al. The three-gene signature in urinary extracellular vesicles from patients with clear cell renal cell carcinoma. J Cancer. 2016;7(14):1960–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annu Rev Pathol. 2014;9:287–314.

    Article  PubMed  CAS  Google Scholar 

  107. Hirschberger S, Hinske LC, Kreth S. MiRNAs: dynamic regulators of immune cell functions in inflammation and cancer. Cancer Lett. 2018;431:11–21.

    Article  CAS  PubMed  Google Scholar 

  108. Frixa T, Donzelli S, Blandino G. Oncogenic MicroRNAs: key players in malignant transformation. Cancers (Basel). 2015;7(4):2466–85.

    Article  CAS  Google Scholar 

  109. Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  110. Zhang W, Ni M, Su Y, Wang H, Zhu S, Zhao A, et al. MicroRNAs in serum Exosomes as potential biomarkers in clear-cell renal cell carcinoma. Eur Urol Focus. 2018;4(3):412–9.

    Article  PubMed  Google Scholar 

  111. Xiao CT, Lai WJ, Zhu WA, Wang H. MicroRNA derived from circulating Exosomes as noninvasive biomarkers for diagnosing renal cell carcinoma. Onco Targets Ther. 2020;13:10765–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Song S, Long M, Yu G, Cheng Y, Yang Q, Liu J, et al. Urinary exosome miR-30c-5p as a biomarker of clear cell renal cell carcinoma that inhibits progression by targeting HSPA5. J Cell Mol Med. 2019;23(10):6755–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Du M, Giridhar KV, Tian Y, Tschannen MR, Zhu J, Huang CC, et al. Plasma exosomal miRNAs-based prognosis in metastatic kidney cancer. Oncotarget. 2017;8(38):63703–14.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Kurahashi R, Kadomatsu T, Baba M, Hara C, Itoh H, Miyata K, et al. MicroRNA-204-5p: a novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma. Cancer Sci. 2019;110(6):1897–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Crentsil VC, Liu H, Sellitti DF. Comparison of exosomal microRNAs secreted by 786-O clear cell renal carcinoma cells and HK-2 proximal tubule-derived cells in culture identifies microRNA-205 as a potential biomarker of clear cell renal carcinoma. Oncol Lett. 2018;16(1):1285–90.

    PubMed  PubMed Central  Google Scholar 

  116. Li DY, Lin FF, Li GP, Zeng FC. Exosomal microRNA-15a from ACHN cells aggravates clear cell renal cell carcinoma via the BTG2/PI3K/AKT axis. Kaohsiung J Med Sci. 2021.

  117. Wang X, Wang T, Chen C, Wu Z, Bai P, Li S, et al. Serum exosomal miR-210 as a potential biomarker for clear cell renal cell carcinoma. J Cell Biochem. 2018.

  118. Butz H, Nofech-Mozes R, Ding Q, Khella HWZ, Szabo PM, Jewett M, et al. Exosomal MicroRNAs are diagnostic biomarkers and can mediate cell-cell communication in renal cell carcinoma. Eur Urol Focus. 2016;2(2):210–8.

    Article  PubMed  Google Scholar 

  119. Chan JJ, Tay Y. Noncoding RNA:RNA Regulatory Networks in Cancer. Int J Mol Sci. 2018;19:5.

    Article  Google Scholar 

  120. Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell. 2014;157(1):77–94.

    Article  CAS  PubMed  Google Scholar 

  121. Qi P, Zhou XY, Du X. Circulating long non-coding RNAs in cancer: current status and future perspectives. Mol Cancer. 2016;15(1):39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Naderi-Meshkin H, Lai X, Amirkhah R, Vera J, Rasko JEJ, Schmitz U. Exosomal lncRNAs and cancer: connecting the missing links. Bioinformatics. 2019;35(2):352–60.

    Article  CAS  PubMed  Google Scholar 

  123. Wang Y, Zhang M, Zhou F. Biological functions and clinical applications of exosomal long non-coding RNAs in cancer. J Cell Mol Med. 2020;24(20):11656–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yang G, Lu X, Yuan L. LncRNA: a link between RNA and cancer. Biochim Biophys Acta. 2014;1839(11):1097–109.

    Article  CAS  PubMed  Google Scholar 

  125. Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, et al. Exosome-transmitted lncARSR promotes Sunitinib resistance in renal Cancer by acting as a competing endogenous RNA. Cancer Cell. 2016;29(5):653–68.

    Article  CAS  PubMed  Google Scholar 

  126. Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet. 2013;9(9):e1003777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495(7441):333–8.

    Article  CAS  PubMed  Google Scholar 

  128. Mao W, Huang X, Wang L, Zhang Z, Liu M, Li Y, et al. Circular RNA hsa_circ_0068871 regulates FGFR3 expression and activates STAT3 by targeting miR-181a-5p to promote bladder cancer progression. J Exp Clin Cancer Res. 2019;38(1):169.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25(8):981–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhang PF, Wei CY, Huang XY, Peng R, Yang X, Lu JC, et al. Circular RNA circTRIM33-12 acts as the sponge of MicroRNA-191 to suppress hepatocellular carcinoma progression. Mol Cancer. 2019;18(1):105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Xiao H, Shi J. Exosomal circular RNA_400068 promotes the development of renal cell carcinoma via the miR2105p/SOCS1 axis. Mol Med Rep. 2020;22(6):4810–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Sun W, Luo JD, Jiang H, Duan DD. Tumor exosomes: a double-edged sword in cancer therapy. Acta Pharmacol Sin. 2018;39(4):534–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013;32(3–4):623–42.

    Article  CAS  PubMed  Google Scholar 

  134. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.

    Article  CAS  PubMed  Google Scholar 

  135. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10(10):992–1000.

    Article  CAS  PubMed  Google Scholar 

  136. Qin Z, Xu Q, Hu H, Yu L, Zeng S. Extracellular vesicles in renal cell carcinoma: multifaceted roles and potential applications identified by experimental and computational methods. Front Oncol. 2020;10:724.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Barile L, Vassalli G. Exosomes: therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 2017;174:63–78.

    Article  CAS  PubMed  Google Scholar 

  138. He C, Zheng S, Luo Y, Wang B. Exosome Theranostics: biology and translational medicine. Theranostics. 2018;8(1):237–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Sun D, Zhuang X, Zhang S, Deng ZB, Grizzle W, Miller D, et al. Exosomes are endogenous nanoparticles that can deliver biological information between cells. Adv Drug Deliv Rev. 2013;65(3):342–7.

    Article  CAS  PubMed  Google Scholar 

  140. Yuan D, Zhao Y, Banks WA, Bullock KM, Haney M, Batrakova E, et al. Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials. 2017;142:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Record M, Carayon K, Poirot M, Silvente-Poirot S. Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta. 2014;1841(1):108–20.

    Article  CAS  PubMed  Google Scholar 

  142. Kim MS, Haney MJ, Zhao Y, Yuan D, Deygen I, Klyachko NL, et al. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. Nanomedicine. 2018;14(1):195–204.

    Article  CAS  PubMed  Google Scholar 

  143. Liang G, Zhu Y, Ali DJ, Tian T, Xu H, Si K, et al. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. J Nanobiotechnology. 2020;18(1):10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Qian L, Yu S, Chen Z, Meng Z, Huang S, Wang P. Functions and clinical implications of exosomes in pancreatic cancer. Biochim Biophys Acta Rev Cancer. 2019;1871(1):75–84.

    Article  CAS  PubMed  Google Scholar 

  145. Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B. 2016;6(4):287–96.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Zhong X, Zhou Y, Cao Y, Ding J, Wang P, Luo Y, et al. Enhanced antitumor efficacy through microwave ablation combined with a dendritic cell-derived exosome vaccine in hepatocellular carcinoma. Int J Hyperth. 2020;37(1):1210–8.

    Article  CAS  Google Scholar 

  147. Zhang Y, Wu XH, Luo CL, Zhang JM, He BC, Chen G. Interleukin-12-anchored exosomes increase cytotoxicity of T lymphocytes by reversing the JAK/STAT pathway impaired by tumor-derived exosomes. Int J Mol Med. 2010;25(5):695–700.

    CAS  PubMed  Google Scholar 

  148. Zhang Y, Wu XH, Chen G, Luo CL, Zhang JM. Preparation of renal cancer vaccine of IL-12-anchored exosomes and its antitumor effect in vitro. Zhonghua Zhong Liu Za Zhi. 2010;32(5):339–43.

    CAS  PubMed  Google Scholar 

  149. Gu X, Erb U, Buchler MW, Zoller M. Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice. Int J Cancer. 2015;136(4):E74–84.

    Article  CAS  PubMed  Google Scholar 

  150. Krause M, Samoylenko A, Vainio SJ. Exosomes as renal inductive signals in health and disease, and their application as diagnostic markers and therapeutic agents. Front Cell Dev Biol. 2015;3:65.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Xu HY, Li N, Yao N, Xu XF, Wang HX, Liu XY, et al. CD8+ T cells stimulated by exosomes derived from RenCa cells mediate specific immune responses through the FasL/Fas signaling pathway and, combined with GMCSF and IL12, enhance the antirenal cortical adenocarcinoma effect. Oncol Rep. 2019;42(2):866–79.

    CAS  PubMed  Google Scholar 

  152. Franzen CA, Blackwell RH, Foreman KE, Kuo PC, Flanigan RC, Gupta GN. Urinary Exosomes: the potential for biomarker utility, intercellular signaling and therapeutics in urological malignancy. J Urol. 2016;195(5):1331–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Home for Researchers (www.home-for-researchers.com) optimizing the figures and Bullet Edits (http://www.bulletedits.cn/) for editing this manuscript.

Funding

This study was supported by the Scientific Research Foundation of Graduate School of Southeast University (YBPY2173), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_0156), Jiangsu Provincial Key Research and Development Program (BE2019751), Innovative Team of Jiangsu Provincial (2017XKJQW07), and The National Key Research and Development Program of China (SQ2017YFSF090096).

Author information

Authors and Affiliations

Authors

Contributions

WM, KW and ZW contributed equally to this work and share first authorship. Conceptualization, WM, BX and MC; writing—original draft preparation, WM; writing—review and editing, BX and MC; visualization, KW and ZW; supervision, KW and ZW; funding acquisition, WM and MC. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Weipu Mao, Bin Xu or Ming Chen.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

We have obtained consents to publish this paper from all the participants of this study.

Competing interests

We declare that there are no conflicts of interest between authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mao, W., Wang, K., Wu, Z. et al. Current status of research on exosomes in general, and for the diagnosis and treatment of kidney cancer in particular. J Exp Clin Cancer Res 40, 305 (2021). https://doi.org/10.1186/s13046-021-02114-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13046-021-02114-2

Keywords