v
Search
Advanced

Publications > Journals > Cancer Screening and Prevention> Article Full Text

  • Review Article
  • OPEN ACCESS

Exosomes: A Promising Tool for Liquid Biopsy in Prostate Cancer

  • Aixin Qiu#,
  • Zhen Luo#,
  • Xiaohui Liu,
  • Xiangchen Hou,
  • Yao Xiao,
  • Yue Zhang*  and
  • Yang Yu* 
 Author information 

Abstract

Prostate cancer (PCa) often manifests insidiously, with most patients being diagnosed at an advanced stage, leading to a poor prognosis. Early detection of PCa can significantly prolong overall survival by impeding the progression of metastasis. A commonly utilized screening method for detecting PCa is the prostate-specific antigen test. However, since the prostate-specific antigen lacks specificity and sensitivity for PCa identification, there is a paramount urgency to develop precise diagnostic biomarkers for early detection. Extracellular vesicles, known as exosomes, are released by cells into body fluids. Exosomes derived from cancer cells can carry genetic information about the tumor, including DNA, RNA, and proteins, which play crucial roles in tumor initiation, invasion, metastasis, and drug resistance. Studies have indicated that exosomes (including messenger RNAs, microRNAs, long noncoding RNAs and others) can enhance the sensitivity and specificity of PCa diagnosis, indicating their potential for early detection. This review highlights the biological characteristics and functions of exosomes, as well as recent advancements in their use for the diagnosis, prognosis, and treatment of prostate cancer.

Keywords

Exosomes, Prostate cancer, Diagnosis, Therapy, Prognosis, Extracellular vesicles

Introduction

Prostate cancer (PCa) is one of the most common cancers in males and a leading cause of cancer-related death globally. It is the most prevalent cancer and the second leading cause of cancer-related death among males in the United States.1 In recent years, its incidence in China has been steadily increasing, particularly in economically developed coastal regions. Prostate-specific antigen (PSA) is a common tumor marker used for PCa screening, diagnosis, and clinical monitoring. However, since PSA lacks specificity and sensitivity for PCa identification, benign prostate hyperplasia (BPH) or prostate inflammation can also result in elevated PSA levels. This can lead to up to 75% of patients undergoing unnecessary prostate biopsy, which may result in overdiagnosis and overtreatment.2 Patients who undergo prostate biopsy often experience severe discomfort from postoperative complications such as hematuria, infection, and pain at the site of the procedure. Some patients with an undetermined diagnosis may even require a second or third biopsy, increasing medical costs, particularly for patients whose PSA levels fall into the so-called “gray zone” of 4–10 ng/mL.3 Radical prostatectomy and radiotherapy are common treatment options for early-stage, localized prostate cancer. In contrast to traditional open surgery, minimally invasive or robot-assisted radical prostatectomy offers shorter operating times, less tissue trauma, fewer postoperative complications, and significant therapeutic benefits, all of which greatly improve patients’ quality of life in the postoperative period.4 Androgen deprivation therapy (ADT) is the primary first-line treatment for PCa, initially leading to tumor regression.5 However, despite an initial therapeutic response to ADT, the disease inevitably evolves into castration-resistant prostate cancer (CRPC) within 18 to 24 months.6 Once metastasis occurs, patients progress to metastatic castration-resistant prostate cancer, which is associated with a significantly increased mortality rate.7 Therefore, the development of novel biomarkers for PCa diagnosis, therapy, and prognosis is urgently needed. The study of exosomes has advanced rapidly in recent years. Exosomes are extracellular vesicles 30–150 nm in diameter that are released by cells. They can carry lipids, proteins, RNA, and DNA. Due to their lipid bilayer structure, exosomes can stably resist external interference, making them potential biomarkers for the diagnosis and treatment of diseases. Exosomes offer several diagnostic advantages, including high sensitivity, minimal invasiveness, low cost, and the ability to provide real-time insights into disease progression.

The structure and function of exosomes

Exosomes are extracellular vesicles characterized by lipid bilayer membranes, with a diameter ranging from 30 to 150 nanometers. They are ubiquitously found in diverse bodily fluids, such as blood, urine, ascitic fluid, and saliva.8 The primary constituents of exosomes include proteins, lipids, and nucleic acids.9 Their composition is influenced by the health status of the originating cells and organisms. Proteins are the predominant components of exosomal contents and can directly impact the invasion and migration capabilities of tumor cells, thereby promoting tumor progression and metastasis. The nucleic acids found in exosomes primarily consist of microRNAs (miRNAs), messenger RNAs, and long noncoding RNAs (lncRNAs). Among these, miRNAs have emerged as a focal point of research in recent years. miRNAs can be transferred to recipient cells via exosome-target cell membrane fusion, thereby modifying the signaling pathways of the recipient cells. The composition of exosomes secreted by different tissues varies significantly. Analysis of relevant studies has revealed that exosomes transport 4,563 proteins, 1,639 messenger RNAs, and 764 miRNAs out of cells, playing a pivotal role in intercellular communication. These molecules can influence target cells through various mechanisms, facilitating intercellular information transfer and participating in numerous physiological and pathological processes, including tumor development, antigen presentation, vascular remodeling, drug resistance, and metastasis (Fig. 1).10,11 In summary, exosomes are characterized by diverse and stable contents with multiple biological functions. Analyzing the composition of exosomes provides insights into the physiological and pathological states of their originating cells, establishing exosomes as one of the critical tools for “liquid biopsy.” A growing body of research indicates that exosomes not only serve as molecular markers for diagnosis and prognosis but also present novel therapeutic targets to halt the progression of PCa (Table 1).12–46

Role of tumor-derived exosomes in prostate cancer progression.
Fig. 1  Role of tumor-derived exosomes in prostate cancer progression.

Exosomes participate in drug resistance, vascular remodeling, and antigen presentation. Exosomes not only impair the function of immune cells but also reshape the tumor microenvironment, thereby contributing to tumor growth and facilitating metastasis. (This is made by FigDraw.) circRNA, circular RNA; lncRNA, long noncoding RNA; miRNA, microRNA.

Table 1

Exosomal biomarkers and functions in prostate cancer

Exosomal miRNAsExpression levelExosome sourceRole in PCaReferences
circTFDP2↑CellPromotes PCa cell progression via modulating the PARP1/DNA damage axis12
miR-153↑PlasmaRegulates the proliferation, migration, and invasion of prostate cancer cells13
hsa-miR-19b-3p↑PlasmaDiscriminate between tumor and NAT14
hsa-miR-101-3p↑PlasmaDiscriminate between tumor and NAT14
miR-20b-5p↑Prostatic fluidEarly diagnoses PCa15
miR-2909↑UrinePromotes tumor cell invasion16
miR-888↑CellPromotes proliferation and migration17
miR-141-3p↑PlasmaEarly diagnoses PCa18
miR-125a-5p↓PlasmaEarly diagnoses PCa18
PSMA↑PlasmaEarly diagnoses PCa19
caveolin-1↑PlasmaEarly diagnoses PCa19
lncRNA↑UrineEarly diagnoses PCa20
miR-423-5p↑CellInhibits GREM2 through the TGF-β pathway and increases PCa resistance to taxane21
miR-146a-5p↓CellRegulates the EGFR/ERK pathway and promotes EMT22
miR-432-5p↑CellIncreases PCa resistance to DTX by suppressing ferroptosis via targeting CHAC123
miR-34a↓UrineRegulates BCL-2 expression and partly modulates the response of cancer cells to docetaxel24
lincROR↑CellInitiates a β-catenin/HIF1α positive feedback loop through targeting the MYH9 protein25
ZNF667-AS1↓CellSuppresses PCa cell growth, inhibit tumor progression, and reduce DTX resistance26
miR-222-3p↑CellEnhances cell proliferation, migration, and invasion ability27
miR-375↑PlasmaInterferes with the expression of PTPN, stabilizes phosphorylated STAT3, and promotes osteoblastic metastasis28,34,44,45
miR-217↑PlasmaInfluences the proliferation and invasion of cancer cells29
miR-23b-3p↓PlasmaInfluences the proliferation and invasion of cancer cells29
miR-95↑CellCombines its downstream gene, JunB, and enhances proliferation, invasion, and EMT30
HOXD-AS1↑PlasmaPromotes PCa cell metastasis31
PGAM1↑PlasmaPromotes angiogenesis32
hsa-miR-184↑PlasmaPromotes angiogenesis33
miR-21↑PlasmaAssesses PCa aggressiveness34
HSPH1↑CellPromotes the growth of CD8+ T cells and exerts anti-tumor effects35
miR-150-5p↓PlasmaRegulates the Wnt pathway and bone metastasis36
miR-500a-3p↑CellDrives PCa metastasis37
miR-425-5p↑TissuePromotes PCa cell bone metastasis38
miR-196a-5p↓UrineInfluences PCa cell proliferation, invasion, and migration39
miR-501-3p↓UrineInfluences the invasion of PCa cells39
miR-1246↓PlasmaPromotes apoptosis of tumor cells, and reduces tumor cell proliferation, invasion, and migration40
miR-532-5p↑UrinePredicts BCR of PCa41
hsa-miR-148a-3p↓PlasmaPromotes PCa progression42
miR-1290↑PlasmaPredicts the survival prognosis of CRPC patients43,44
miR-1275↑CellEnhances osteoblast proliferation and activity via modulation of SIRT2/Runx2 signaling46

BCL-2, B cell lymphoma-2; BCR, biochemical recurrence; CHAC1, cation transport regulator-like protein 1; CRPC, castration-resistant prostate cancer; DTX, docetaxel; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; ERK, extracellular signal-regulated kinase; GREM2, Gremlin 2; HIF, hypoxia-inducible factor; HOXD-AS1, HOXD cluster antisense RNA 1; lncRNA, long noncoding RNA; miRNA, microRNA; NAT, normal adjacent tissues; PARP1, poly(ADP-ribose) polymerase 1; PCa, prostate cancer; PGAM1, phosphoglycerate mutase 1; PSMA, prostate-specific membrane antigen; PTPN, protein tyrosine phosphatase nonreceptor; Runx2, runt-related protein 2; TGF-β, transforming growth factor β.

Exosomes and prostate cancer

Exosomes and early diagnosis of prostate cancer

Early detection and treatment of PCa are crucial for improving patient prognosis and long-term survival rates. Exosomes offer several advantages for the early diagnosis of tumors: (1) Exosomes are produced and secreted by nearly all cells in the body and can be readily obtained from various body fluids, including blood, urine, semen, prostatic fluid, saliva, and ascitic fluid. This makes exosome detection minimally invasive and clinically feasible.47 (2) Tumor-derived exosomes are well protected from degradation by nucleases and proteases, preserving their contents, including proteins, lipids, and nucleic acids. The separation and detection of these exosomal contents provide strong indications of tumor development, offering a certain level of sensitivity for tumor diagnosis.48 (3) Exosomes carry a variety of specific markers on their membranes that reflect their cellular origin. These markers enhance the specificity of exosome-based tumor detection, improving diagnostic accuracy. Clinically, Gleason scores are well correlated with the biological behavior of PCa. Elevated levels of circTFDP2 are directly linked to an increased Gleason score. Moreover, exosomes containing circTFDP2 play a pivotal role in promoting PCa progression both in vivo and in vitro. Mechanistically, circTFDP2 promotes PCa cell progression by modulating the PARP1/DNA damage axis, highlighting circTFDP2 as a promising target for PCa.12 Bertoli et al.13 demonstrated that miR-153 exhibits elevated expression levels in patients with high Gleason score PCa, playing a critical role in regulating the proliferation, migration, and invasion of PCa cells. Notably, miR-153 is secreted by exosomes within the tumor microenvironment, and upon entering peritumoral tissues, it significantly impacts tumor cell growth. Exosomal miRNAs have the potential to predict invasive versus localized metastasis and can distinguish between normal tissue, BPH, and aggressive prostate cancers. Duca et al.14 reported that both hsa-miR-19b-3p and hsa-miR-101-3p were significantly elevated in the bloodstream of PCa patients compared to the control group, and were markedly increased in prostate tumors compared with normal adjacent tissues. Further receiver operating characteristic analysis demonstrated that hsa-miR-19b-3p could reliably differentiate tumor tissues from normal adjacent tissues, whereas hsa-miR-101-3p was effective in distinguishing metastatic prostate cancer from nonmetastatic prostate cancer.14 Zhai et al.15 utilized reverse transcription-quantitative PCR (RT-qPCR) to evaluate the expression of miR-20b-5p in PCa and BPH tissues. Their findings revealed significantly increased expression levels of miR-20b-5p in PCa, which suppressed the expression of RB1, suggesting that RB1 may serve as a crucial target gene for miR-20b-5p.15 Exosomal miR-2909 is upregulated in the urine of PCa patients compared to healthy individuals, promoting tumor cell invasion.16 Additionally, miR-888 has emerged as a novel oncogenic factor in PCa, stimulating migration and proliferation that drive tumor progression. Mouse xenograft studies further confirmed that miR-888 functions as a pro-oncogenic factor, enhancing prostate tumor growth in vivo.17 Moreover, elevated plasma exosomal miR-141-3p expression and reduced miR-125a-5p expression in PCa patients may serve as potential biomarkers for specific tumor traits associated with PCa.18 These findings suggest that miRNAs in exosomes extracted from PCa patients’ bodily fluids hold significant potential as diagnostic markers for PCa and as promising tools to guide prostate biopsy decisions. Nucleic acids and proteins are the primary targets for exosome content detection. Nucleic acid markers such as miR-375, PCA3, TMPRSS2: ERG, and miR-107 are elevated in the exosomes of prostate cancer patients.49,50 Biomarkers such as FOLH1, XPO1, SFN, and GDF15 indicate that both receptors and transmembrane proteins have the potential to serve as effective indicators of PCa at the protein level.51 Prostate-specific membrane antigen (PSMA )and caveolin-1, which are membrane proteins overexpressed in PCa, are integral to tumor growth and contribute significantly to increased tumor aggressiveness.52,53 Compared to exosomes from men with BPH, investigations show that the plasma of PCa patients contains more PSMA and caveolin-1 exosomes.19 Li et al.20 reported that a lncRNA assay showed superior diagnostic performance compared to PSA, detecting clinically significant PCa. Thus, in addition to exosomal miRNAs, urinary exosomal lncRNAs also exhibit strong potential for the early diagnosis of PCa. The combination of various exosomal biomarkers in body fluids can enhance diagnostic accuracy, thereby assisting physicians in formulating more effective treatment plans.

Exosomes and the treatment of prostate cancer

Targeted therapy

Exosomes are playing an increasingly significant role in PCa therapy. They can deliver various substances, including proteins and nucleic acids, while effectively crossing biological barriers with minimal immunogenicity, making them highly promising as natural vectors for drug or gene delivery. Currently, ultracentrifugation is the primary method for exosome extraction; however, it is costly, requires large sample volumes, and has a low yield. Alternative methods, such as exosome sedimentation, immunoaffinity capture, and ultrafiltration, are also available, but further development of efficient and reliable isolation techniques is necessary. Additionally, elucidating the composition and mechanisms of substances within exosomes is essential, as well as establishing methods for obtaining high-purity exosomes and determining appropriate dosages for clinical application.54 Current treatment approaches for PCa include endocrine therapy, chemotherapy, radiation therapy, and surgery. While these approaches can substantially delay or suppress disease progression, chemoresistance remains a major challenge, often leading to patient mortality.55 Shan et al.21 demonstrated that exosomes derived from cancer-associated fibroblasts (CAFs) reduce the chemosensitivity of PCa cells and enhance the chemoresistance of drug-resistant cells. They also reported that PCa resistance to taxanes is increased by exosomes from PCa-associated fibroblasts carrying miR-423-5p, which inhibit Gremlin 2 (GREM2) via the transforming growth factor β (TGF-β) pathway.21 Interestingly, this mechanism was found to partially increase drug sensitivity in vivo. ADT remains the primary treatment for advanced prostate cancer. Zhang et al.22 reported that miR-146a-5p expression levels were substantially reduced in exosomes derived from ethanol-treated CAFs (to mimic the castration level of the PCa microenvironment after ADT), potentially accelerating tumor metastasis by regulating the EGFR/ERK pathway and promoting epithelial-mesenchymal transition (EMT). A major challenge in the treatment of CRPC is the resistance of PCa cells to drugs such as docetaxel (DTX). miR-432-5p, originating from CAF exosomes, increases PCa resistance to DTX by suppressing ferroptosis via targeting CHAC1.23 Additionally, miR-34a in prostate cancer cells can modulate BCL-2 expression, potentially influencing the sensitivity of cancer cells to DTX.24 In DTX-resistant PCa cell lines, lincROR has been shown to be significantly expressed and linked to a poor response to DTX treatment. Mechanistically, targeting the MYH9 protein, exosome-mediated lincROR initiates a β-catenin/HIF1α positive feedback loop.25 Notably, ZNF667-AS1 was shown to suppress PCa cell growth, inhibit tumor progression in mice, and reduce DTX resistance. Furthermore, increased exogenous expression of ZNF667-AS1 in tumor-derived exosomes interacts with U2AF1 to reduce the expression of TGFBR1, leading to attenuated Treg expansion associated with DTX resistance.26 Moreover, miR-222-3p is elevated in CRPC cells, significantly enhancing cell proliferation, migration, and invasion.27 Gan et al.28 demonstrated that miR-375 interferes with the expression of PTPN4, thereby stabilizing phosphorylated STAT3. Compared to plasma exosomes from healthy controls, the level of miR-217 expression was significantly upregulated, while miR-23b-3p expression was significantly downregulated in PCa patients.29 These miRNAs are thought to influence the proliferation and invasion of cancer cells. In the tumor microenvironment (TME), tumor-associated macrophages are essential for mediating intercellular communication. Guan et al.30 analyzed microRNA sequences in exosomes derived from macrophages and reported that miR-95 expression in exosomes derived from tumor-associated macrophages was significantly increased, indicating that recipient PCa cells directly take up miR-95. In vitro and in vivo assays further demonstrated that miR-95 directly interacts with its downstream gene JunB, thereby increasing proliferation, invasion, and EMT in PCa cells. These findings suggest that detecting exosomal miRNAs could provide novel therapeutic strategies and lay the groundwork for developing personalized treatments for PCa patients. However, these studies are still in the experimental stage, and the role of exosomes in PCa treatment requires further clinical studies with larger cohorts. In recent years, scholars have proposed the innovative concept of “radiolabeled exosomes”, which involves the use of radiation and nuclear medicine technologies to study the distribution of exosomes in vivo.56 This approach has the potential to visualize responses to PCa therapy, offering clinicians effective tools for the treatment of the disease.

Exosome-mediated drug delivery

Extracellular vesicles can deliver multiple therapeutic molecules to tumor cells, enhancing drug accumulation in tumor tissues and thereby improving therapeutic efficacy while reducing systemic toxicity.57,58 PCa cell-derived extracellular vesicles function as efficient delivery vehicles for paclitaxel to their parental cells, facilitating intracellular drug delivery via an endocytic mechanism.59 Interestingly, fluorescence lifetime imaging microscopy investigates the interaction attributes of extracellular vesicles (EVs) and living cells.60 The study used fluorescence lifetime imaging microscopy to explore how microvesicles and exosomes loaded with the chemotherapeutic agent paclitaxel are taken up by cells, revealing differences in their uptake mechanisms. Exosomes primarily facilitate drug delivery through endocytosis, whereas microvesicles gain access to cells via both direct fusion with the cellular membrane and endocytosis.61 miR-let-7c has been identified as a tumor suppressor in PCa, and exogenous let-7c therapy inhibits the growth and spread of CRPC by targeting both cancer cells and mesenchymal stem cells.62 Exosomes from mesenchymal stem cells could function as a therapeutic delivery system for let-7c to target CRPC.63 Berbamine, derived from the root of Berberis amurensis, has demonstrated antitumor activities in various cancers.64,65 In PCa, berbamine increased the exosomal levels of let-7 family members and miR-26b, indicating that it may modulate their expression via exosome delivery.66 Additionally, exosome-mediated delivery of TGFβRI kinase inhibitors and TLR7/8 agonists may be a potential treatment option for PCa.67 EV-based drug delivery systems not only offer novel strategies to overcome tumor drug resistance but also hold significant potential for broader clinical applications. Despite their promising therapeutic prospects, the clinical translation of EV-based therapies still requires further research and appropriate regulatory frameworks to ensure their safety and efficacy.

Exosomes and the prognosis of prostate cancer

Exosomes, which carry diverse lipids, proteins, and RNAs, play a major role in the survival, angiogenesis, and proliferation of cancer cells, as well as their capacity to evade immune surveillance.68 Exosomes are closely linked to the invasion of PCa and the formation of micrometastases. Metastasis is responsible for approximately 50% of PCa-related deaths. The five-year overall survival (OS) rate for distant metastatic prostate cancer (mPCa) is only 31%, indicating a poor prognosis.69 Through the miR-361-5p/FOXM1 axis, exosomal lncRNA HOXD-AS1 induces metastasis-associated phenotypes both in vitro and in vivo, thereby driving PCa metastasis.31 TME is essential for cancer metastasis. Podosome development, a crucial element of neovascularization, and cancer metastasis are both significantly influenced by angiogenesis in the TME.70 Notably, exosomal PGAM1 may attach to γ-actin, promoting neovascular sprouting and facilitating podosome formation. In the in vivo study, exosomal PGAM1 was found to significantly enhance lung metastasis.32 Moreover, hsa-miR-184 has been identified as a promising regulator associated with the proangiogenic effects of PCa exosomes.33 The TME also facilitates the transport of miRNAs by exosomes. One study analyzed the expression of exosomal miR-21 and miR-375, revealing that exosomal miR-21 levels were elevated in PCa patients with high PSA levels and those with invasive prostate cancer.34 Furthermore, heat shock protein family genes are highly expressed in the T cell stress response state, a distinct stress response state.71 HSPH1, a gene associated with extracellular vesicles and a member of the heat shock protein family, may contribute to T cell stress response state in PCa. Through the IL2-MYC-IL2RA pathway, HSPH1 stimulates the differentiation of conventional T cells, thereby promoting CD8+ T cell proliferation and exerting anti-tumor effects.35 Exosomes exhibit differential expression levels across various samples. Cruz-Burgos et al.36 identified differences in the expression of miRNAs (miR-140-3p, miR-23b-3p, and miR-150-5p) in tissues and plasma. Moreover, these miRNAs were evaluated in exosomes from PCa cells and plasma samples. Notably, the expression of miR-150-5p was lower in high Gleason score samples compared to control samples. In a hypoxic microenvironment, exosomes from CAFs drive PCa metastasis via the miR-500a-3p/FBXW7/HSF1 pathway.37 Exosomes are also strongly associated with PCa metastasis. Rode et al.38 reported the expression profiles of exosomal miRNAs in mPCa cell lines (LNCaP and PC-3), identifying fourteen miRNAs as potential noninvasive biomarkers for mPCa. They confirmed the differential expression of five miRNAs—miR-205-5p, miR-148a-3p, miR-125b-5p, miR-183-5p, and miR-425-5p—in mPCa exosomes.38 Rodríguez et al.39 demonstrated that the expression levels of miR-196a-5p and miR-501-3p were both downregulated in PCa. Similarly, miR-1246 was downregulated in PCa tissues and cell lines and released into exosomes.40 Notably, high expression of miR-1246 inhibited xenograft tumor growth, promoted tumor cell apoptosis, and reduced cell proliferation, invasion, and migration. Additionally, miR-1246 inhibited the activity of N-cadherin and vimentin, thereby suppressing EMT. Biochemical recurrence is a marker of poor prognosis in patients with intermediate-risk prostate cancer. Kim et al.41 reported that miR-532-5p expression was elevated in biochemical recurrence patients based on RT-PCR analysis. With the inevitable progression of mPCa to CRPC, CRPC represents the terminal stage of the disease, characterized by a median survival of less than two years and resistance to treatments targeting the androgen signaling pathway. In CRPC, biochemical and radiological progression are the primary indicators for diagnosis. High-throughput miRNA sequencing of plasma samples collected from CRPC patients during treatment revealed downregulation of hsa-miR-148a-3p expression.42 Furthermore, miR-375 and miR-1290 have been identified as prognostic markers for survival in CRPC patients.43 Huang et al.44 demonstrated associations between miR-1290, miR-1246, and miR-375 with OS through Cox regression analysis in a cohort of 100 CRPC patients. Higher expression levels of miR-1290 and miR-375 were significantly associated with lower OS in this cohort.44 Bone metastasis is the most common, occurring in approximately 90% of patients with mPCa and primarily of the osteoblastic bone-forming type.72,73 Notably, exosomal miR-375 from PCa cells specifically targets DIP2C, which activates the Wnt signaling pathway, thereby facilitating osteoblastic metastasis and promoting PCa progression.45 Additionally, exosomal miR-1275 from PCa patients enhances osteoblast proliferation by modulating SIRT2/Runx2 signaling.46 In summary, detecting the relevant components of miRNAs in exosomes derived from PCa patients can effectively indicate the biological behavior of tumors and provide valuable insights into patient prognosis. These findings are important for guiding the development of treatment strategies for PCa.

Conclusions and future directions

Through research on prostate cancer-derived exosomes, we have gained new insights into the mechanisms of prostate cancer progression and metastasis from a novel perspective. All cells within tumors and the surrounding microenvironment can secrete exosomes. These exosomes provide valuable information about tumor heterogeneity. As a result, exosomes can serve as diagnostic biomarkers for prostate cancer screening, monitoring progression, assessing treatment response, and predicting survival prognosis. Notably, exosomes exhibit high sensitivity, specificity, and tissue specificity. Their detection is minimally invasive, cost-effective, and provides real-time insights into disease progression. These attributes position exosomes as promising noninvasive biomarkers for detecting tumors in the urinary and male reproductive systems, including PCa, kidney cancer,74 and bladder cancer.75 Emerging studies have confirmed the involvement of exosomes in the pathogenesis of PCa and highlighted their significant potential in its diagnosis, treatment, and prognosis. However, higher-level evidence is needed to establish the clinical value of this novel biomarker. Currently, exosome-related research is limited by relatively small sample sizes. Future studies should aim to expand both the quantity and diversity of research samples to substantiate the positive roles of these newly identified exosome biomarkers in the early diagnosis, treatment, and prognostic evaluation of PCa. These advancements have the potential to reduce treatment costs and mortality rates among patients.

Declarations

Acknowledgement

Not applicable.

Funding

This study was supported by the “1+X” program for Clinical Competency Enhancement – Clinical Research Incubation Project of the Second Hospital of Dalian Medical University (2022LCYJZD02) and the Basic Scientific Research Project of the Liaoning Provincial Education Department (LJKZ0873).

Conflict of interest

The authors have no conflicts of interest related to this publication.

Authors’ contributions

Conceptualization (AQ, YY, YZ), literature search and analysis (YX), drafting of the manuscript (AQ, ZL), and critical revision of the manuscript (XL, XH). All authors have approved the final version and publication of the manuscript.

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021;71(1):7-33 View Article PubMed/NCBI
  2. Lavallée LT, Binette A, Witiuk K, Cnossen S, Mallick R, Fergusson DA, et al. Reducing the Harm of Prostate Cancer Screening: Repeated Prostate-Specific Antigen Testing. Mayo Clin Proc 2016;91(1):17-22 View Article PubMed/NCBI
  3. Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, Gulati R, et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst 2009;101(6):374-383 View Article PubMed/NCBI
  4. Yu HY, Hevelone ND, Lipsitz SR, Kowalczyk KJ, Hu JC. Use, costs and comparative effectiveness of robotic assisted, laparoscopic and open urological surgery. J Urol 2012;187(4):1392-1398 View Article PubMed/NCBI
  5. Akoto T, Saini S. Role of Exosomes in Prostate Cancer Metastasis. Int J Mol Sci 2021;22(7):3528 View Article PubMed/NCBI
  6. Wong YN, Ferraldeschi R, Attard G, de Bono J. Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat Rev Clin Oncol 2014;11(6):365-376 View Article PubMed/NCBI
  7. Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev 2010;24(18):1967-2000 View Article PubMed/NCBI
  8. 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):9412-9420 PubMed/NCBI
  9. Lai RC, Tan SS, Yeo RW, Choo AB, Reiner AT, Su Y, et al. MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA. J Extracell Vesicles 2016;5:29828 View Article PubMed/NCBI
  10. De Luca S, Bertetto O, Ciccone G, Rosato R, Galassi C, Bollito E, et al. Anxiety levels at diagnosis and after 6 months in localized low-risk prostate cancer who choose radical treatment or active surveillance: results of the start study group. Eur Urol Suppl 2018;17(8):221-222 View Article
  11. Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-Based Cell-Cell Communication in the Tumor Microenvironment. Front Cell Dev Biol 2018;6:18 View Article PubMed/NCBI
  12. Ding L, Zheng Q, Lin Y, Wang R, Wang H, Luo W, et al. Exosome-derived circTFDP2 promotes prostate cancer progression by preventing PARP1 from caspase-3-dependent cleavage. Clin Transl Med 2023;13(1):e1156 View Article PubMed/NCBI
  13. Bertoli G, Panio A, Cava C, Gallivanone F, Alini M, Strano G, et al. Secreted miR-153 Controls Proliferation and Invasion of Higher Gleason Score Prostate Cancer. Int J Mol Sci 2022;23(11):6339 View Article PubMed/NCBI
  14. Duca RB, Massillo C, Dalton GN, Farré PL, Graña KD, Gardner K, et al. MiR-19b-3p and miR-101-3p as potential biomarkers for prostate cancer diagnosis and prognosis. Am J Cancer Res 2021;11(6):2802-2820 PubMed/NCBI
  15. Zhai TY, Dou M, Ma YB, Wang H, Liu F, Zhang LD, et al. miR-20b-5p is a novel biomarker for detecting prostate cancer. Oncol Lett 2022;24(6):426 View Article PubMed/NCBI
  16. Wani S, Kaul D, Mavuduru RS, Kakkar N, Bhatia A. Urinary-exosomal miR-2909: A novel pathognomonic trait of prostate cancer severity. J Biotechnol 2017;259:135-139 View Article PubMed/NCBI
  17. Hasegawa T, Glavich GJ, Pahuski M, Short A, Semmes OJ, Yang L, et al. Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate. Mol Cancer Res 2018;16(4):669-681 View Article PubMed/NCBI
  18. Li W, Dong Y, Wang KJ, Deng Z, Zhang W, Shen HF. Plasma exosomal miR-125a-5p and miR-141-5p as non-invasive biomarkers for prostate cancer. Neoplasma 2020;67(6):1314-1318 View Article PubMed/NCBI
  19. Matijašević Joković S, Korać A, Kovačević S, Djordjević A, Filipović L, Dobrijević Z, et al. Exosomal Prostate-Specific Membrane Antigen (PSMA) and Caveolin-1 as Potential Biomarkers of Prostate Cancer-Evidence from Serbian Population. Int J Mol Sci 2024;25(6):3533 View Article PubMed/NCBI
  20. Li Y, Ji J, Lyu J, Jin X, He X, Mo S, et al. A Novel Urine Exosomal lncRNA Assay to Improve the Detection of Prostate Cancer at Initial Biopsy: A Retrospective Multicenter Diagnostic Feasibility Study. Cancers (Basel) 2021;13(16):4075 View Article PubMed/NCBI
  21. Shan G, Gu J, Zhou D, Li L, Cheng W, Wang Y, et al. Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-β signaling pathway. Exp Mol Med 2020;52(11):1809-1822 View Article PubMed/NCBI
  22. Zhang Y, Zhao J, Ding M, Su Y, Cui D, Jiang C, et al. Loss of exosomal miR-146a-5p from cancer-associated fibroblasts after androgen deprivation therapy contributes to prostate cancer metastasis. J Exp Clin Cancer Res 2020;39(1):282 View Article PubMed/NCBI
  23. Zhao J, Shen J, Mao L, Yang T, Liu J, Hongbin S. Cancer associated fibroblast secreted miR-432-5p targets CHAC1 to inhibit ferroptosis and promote acquired chemoresistance in prostate cancer. Oncogene 2024;43(27):2104-2114 View Article PubMed/NCBI
  24. Corcoran C, Rani S, O’Driscoll L. miR-34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression. Prostate 2014;74(13):1320-1334 View Article PubMed/NCBI
  25. Jiang X, Xu Y, Liu R, Guo S. Exosomal lincROR Promotes Docetaxel Resistance in Prostate Cancer through a β-catenin/HIF1α Positive Feedback Loop. Mol Cancer Res 2023;21(5):472-482 View Article PubMed/NCBI
  26. Shi Z, Pu W, Li M, Aihemaitijiang M, Li S, Zhang X, et al. Prostate cancer cell-derived exosomes ZNF667-AS1 reduces TGFBR1 mRNA stability to inhibit Treg expansion and DTX resistance by binding to U2AF1. Mol Med 2024;30(1):179 View Article PubMed/NCBI
  27. Wang W, Kong P, Feng K, Liu C, Gong X, Sun T, et al. Exosomal miR-222-3p contributes to castration-resistant prostate cancer by activating mTOR signaling. Cancer Sci 2023;114(11):4252-4269 View Article PubMed/NCBI
  28. Gan J, Liu S, Zhang Y, He L, Bai L, Liao R, et al. MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis. Exp Mol Med 2022;54(8):1290-1305 View Article PubMed/NCBI
  29. Zhou C, Chen Y, He X, Zheng Z, Xue D. Functional Implication of Exosomal miR-217 and miR-23b-3p in the Progression of Prostate Cancer. Onco Targets Ther 2020;13:11595-11606 View Article PubMed/NCBI
  30. Guan H, Peng R, Fang F, Mao L, Chen Z, Yang S, et al. Tumor-associated macrophages promote prostate cancer progression via exosome-mediated miR-95 transfer. J Cell Physiol 2020;235(12):9729-9742 View Article PubMed/NCBI
  31. Jiang Y, Zhao H, Chen Y, Li K, Li T, Chen J, et al. Exosomal long noncoding RNA HOXD-AS1 promotes prostate cancer metastasis via miR-361-5p/FOXM1 axis. Cell Death Dis 2021;12(12):1129 View Article PubMed/NCBI
  32. Luo JQ, Yang TW, Wu J, Lai HH, Zou LB, Chen WB, et al. Exosomal PGAM1 promotes prostate cancer angiogenesis and metastasis by interacting with ACTG1. Cell Death Dis 2023;14(8):502 View Article PubMed/NCBI
  33. Wang C, Zhou C, Wang D, Zhang YF, Lv HX, He H, et al. Proangiogenic potential of plasma exosomes from prostate cancer patients. Cell Signal 2024;124:111398 View Article PubMed/NCBI
  34. Joković SM, Dobrijević Z, Kotarac N, Filipović L, Popović M, Korać A, et al. MiR-375 and miR-21 as Potential Biomarkers of Prostate Cancer: Comparison of Matching Samples of Plasma and Exosomes. Genes (Basel) 2022;13(12):2320 View Article PubMed/NCBI
  35. Wu X, Zhu Y, Hu C, Du X, Xue W, Chen Y, et al. Extracellular vesicles related gene HSPH1 exerts anti-tumor effects in prostate cancer via promoting the stress response of CD8 + T cells. Cell Oncol (Dordr) 2024;47(3):1059-1064 View Article PubMed/NCBI
  36. Cruz-Burgos M, Cortés-Ramírez SA, Losada-García A, Morales-Pacheco M, Martínez-Martínez E, Morales-Montor JG, et al. Unraveling the Role of EV-Derived miR-150-5p in Prostate Cancer Metastasis and Its Association with High-Grade Gleason Scores: Implications for Diagnosis. Cancers (Basel) 2023;15(16):4148 View Article PubMed/NCBI
  37. Liu Z, Lin Z, Jiang M, Zhu G, Xiong T, Cao F, et al. Cancer-associated fibroblast exosomes promote prostate cancer metastasis through miR-500a-3p/FBXW7/HSF1 axis under hypoxic microenvironment. Cancer Gene Ther 2024;31(5):698-709 View Article PubMed/NCBI
  38. Rode MP, Silva AH, Cisilotto J, Rosolen D, Creczynski-Pasa TB. miR-425-5p as an exosomal biomarker for metastatic prostate cancer. Cell Signal 2021;87:110113 View Article PubMed/NCBI
  39. Rodríguez M, Bajo-Santos C, Hessvik NP, Lorenz S, Fromm B, Berge V, et al. Identification of non-invasive miRNAs biomarkers for prostate cancer by deep sequencing analysis of urinary exosomes. Mol Cancer 2017;16(1):156 View Article PubMed/NCBI
  40. Bhagirath D, Yang TL, Bucay N, Sekhon K, Majid S, Shahryari V, et al. microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer. Cancer Res 2018;78(7):1833-1844 View Article PubMed/NCBI
  41. Kim MY, Shin H, Moon HW, Park YH, Park J, Lee JY. Urinary exosomal microRNA profiling in intermediate-risk prostate cancer. Sci Rep 2021;11(1):7355 View Article PubMed/NCBI
  42. Pudova EA, Kobelyatskaya AA, Katunina IV, Snezhkina AV, Fedorova MS, Guvatova ZG, et al. Dynamic Profiling of Exosomal microRNAs in Blood Plasma of Patients with Castration-Resistant Prostate Cancer. Front Biosci (Schol Ed) 2022;14(2):15 View Article PubMed/NCBI
  43. Haflidadóttir BS, Ceder Y. Exosomal microRNAs as potential biomarkers in castration-resistant prostate cancer. Eur Urol 2015;67(1):42-43 View Article PubMed/NCBI
  44. Huang X, Yuan T, Liang M, Du M, Xia S, Dittmar R, et al. Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. Eur Urol 2015;67(1):33-41 View Article PubMed/NCBI
  45. Liu Y, Yang C, Chen S, Liu W, Liang J, He S, et al. Cancer-derived exosomal miR-375 targets DIP2C and promotes osteoblastic metastasis and prostate cancer progression by regulating the Wnt signaling pathway. Cancer Gene Ther 2023;30(3):437-449 View Article
  46. Zou Z, Dai R, Deng N, Su W, Liu P. Exosomal miR-1275 Secreted by Prostate Cancer Cells Modulates Osteoblast Proliferation and Activity by Targeting the SIRT2/RUNX2 Cascade. Cell Transplant 2021;30:9636897211052977 View Article PubMed/NCBI
  47. Deep G, Jain A, Kumar A, Agarwal C, Kim S, Leevy WM, et al. Exosomes secreted by prostate cancer cells under hypoxia promote matrix metalloproteinases activity at pre-metastatic niches. Mol Carcinog 2020;59(3):323-332 View Article PubMed/NCBI
  48. Wu W, Jiang J, Lv L, Liang J, Sun Y, Yuan J, et al. Role of exosomes in development and metastasis of prostate cancer. China Journal of Modern Medicine 2018;28(6):38-44 View Article
  49. Korzeniewski N, Tosev G, Pahernik S, Hadaschik B, Hohenfellner M, Duensing S. Identification of cell-free microRNAs in the urine of patients with prostate cancer. Urol Oncol 2015;33(1):16.e17-16.e22 View Article PubMed/NCBI
  50. Principe S, Jones EE, Kim Y, Sinha A, Nyalwidhe JO, Brooks J, et al. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 2013;13(10-11):1667-1671 View Article PubMed/NCBI
  51. Minciacchi VR, You S, Spinelli C, Morley S, Zandian M, Aspuria PJ, et al. Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles. Oncotarget 2015;6(13):11327-11341 View Article PubMed/NCBI
  52. Chang SS. Overview of prostate-specific membrane antigen. Rev Urol 2004;6(Suppl 10):S13-S18 PubMed/NCBI
  53. Chen P, Zhang YL, Xue B, Xu GY. Association of Caveolin-1 Expression With Prostate Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2020;10:562774 View Article PubMed/NCBI
  54. Di C, Zhang Q, Wang Y, Wang F, Chen Y, Gan L, et al. Exosomes as drug carriers for clinical application. Artif Cells Nanomed Biotechnol 2018;46(sup3):S564-S570 View Article PubMed/NCBI
  55. Sartor AO. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space. J Hematol Oncol 2011;4:18 View Article PubMed/NCBI
  56. Bakht MK, Oh SW, Hwang DW, Lee YS, Youn H, Porter LA, et al. The Potential Roles of Radionanomedicine and Radioexosomics in Prostate Cancer Research and Treatment. Curr Pharm Des 2017;23(20):2976-2990 View Article PubMed/NCBI
  57. Ming-Kun C, Zi-Xian C, Mao-Ping C, Hong C, Zhuang-Fei C, Shan-Chao Z. Engineered extracellular vesicles: A new approach for targeted therapy of tumors and overcoming drug resistance. Cancer Commun (Lond) 2024;44(2):205-225 View Article PubMed/NCBI
  58. Shan C, Liang Y, Wang K, Li P. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Cancer Therapy Resistance: from Biology to Clinical Opportunity. Int J Biol Sci 2024;20(1):347-366 View Article PubMed/NCBI
  59. Saari H, Lázaro-Ibáñez E, Viitala T, Vuorimaa-Laukkanen E, Siljander P, Yliperttula M. Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells. J Control Release 2015;220(Pt B):727-737 View Article PubMed/NCBI
  60. Becker W. Fluorescence lifetime imaging—techniques and applications. J Microsc 2012;247(2):119-136 View Article PubMed/NCBI
  61. Saari H, Lisitsyna E, Rautaniemi K, Rojalin T, Niemi L, Nivaro O, et al. FLIM reveals alternative EV-mediated cellular up-take pathways of paclitaxel. J Control Release 2018;284:133-143 View Article PubMed/NCBI
  62. Lee YS, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 2007;21(9):1025-1030 View Article PubMed/NCBI
  63. Kurniawati I, Liu MC, Hsieh CL, Do AD, Sung SY. Targeting Castration-Resistant Prostate Cancer Using Mesenchymal Stem Cell Exosomes for Therapeutic MicroRNA-let-7c Delivery. Front Biosci (Landmark Ed) 2022;27(9):256 View Article PubMed/NCBI
  64. Wang S, Liu Q, Zhang Y, Liu K, Yu P, Liu K, et al. Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action. Mol Cancer 2009;8:81 View Article PubMed/NCBI
  65. Nam S, Xie J, Perkins A, Ma Y, Yang F, Wu J, et al. Novel synthetic derivatives of the natural product berbamine inhibit Jak2/Stat3 signaling and induce apoptosis of human melanoma cells. Mol Oncol 2012;6(5):484-493 View Article PubMed/NCBI
  66. Wang L, Lyu C, Stadlbauer B, Buchner A, Nößner E, Pohla H. Berbamine targets cancer stem cells and reverses cabazitaxel resistance via inhibiting IGF2BP1 and p-STAT3 in prostate cancer. Prostate 2024;84(2):131-147 View Article PubMed/NCBI
  67. Lee JH, Song J, Kim IG, You G, Kim H, Ahn JH, et al. Exosome-mediated delivery of transforming growth factor-β receptor 1 kinase inhibitors and toll-like receptor 7/8 agonists for combination therapy of tumors. Acta Biomater 2022;141:354-363 View Article PubMed/NCBI
  68. Liu Y, Xiang X, Zhuang X, Zhang S, Liu C, Cheng Z, et al. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am J Pathol 2010;176(5):2490-2499 View Article PubMed/NCBI
  69. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70(1):7-30 View Article PubMed/NCBI
  70. Liu Y, Cao X. Characteristics and Significance of the Pre-metastatic Niche. Cancer Cell 2016;30(5):668-681 View Article PubMed/NCBI
  71. Chu Y, Dai E, Li Y, Han G, Pei G, Ingram DR, et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat Med 2023;29(6):1550-1562 View Article PubMed/NCBI
  72. Sturge J, Caley MP, Waxman J. Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol 2011;8(6):357-368 View Article PubMed/NCBI
  73. Lange PH, Vessella RL. Mechanisms, hypotheses and questions regarding prostate cancer micrometastases to bone. Cancer Metastasis Rev 1998-1 1999;17(4):331-336 View Article PubMed/NCBI
  74. 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):653-668 View Article PubMed/NCBI
  75. Geng H, Zhou Q, Guo W, Lu L, Bi L, Wang Y, et al. Exosomes in bladder cancer: novel biomarkers and targets. J Zhejiang Univ Sci B 2021;22(5):341-347 View Article PubMed/NCBI
Copyright © 2025 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

About this Article

Cite this article
Qiu A, Luo Z, Liu X, Hou X, Xiao Y, Zhang Y, et al. Exosomes: A Promising Tool for Liquid Biopsy in Prostate Cancer. Cancer Screen Prev. Published online: Mar 25, 2025. doi: 10.14218/CSP.2024.00029.
Copy        Export to RIS        Export to EndNote
Article History
Received Revised Accepted Published
December 21, 2024 February 27, 2025 March 19, 2025 March 25, 2025
DOI http://dx.doi.org/10.14218/CSP.2024.00029
  • Cancer Screening and Prevention
  • pISSN 2993-6314
  • eISSN 2835-3315
  • © 2025 Xia & He Publishing Inc.
  • Total visits : 3180273
  • Visits today : 3583
Back to Top

Exosomes: A Promising Tool for Liquid Biopsy in Prostate Cancer

Aixin Qiu, Zhen Luo, Xiaohui Liu, Xiangchen Hou, Yao Xiao, Yue Zhang, Yang Yu
  • Reset Zoom
  • Download TIFF