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1. Introduction

In 2020, global cancer statistics reported prostate cancer as the second most widespread cancer in American men, representing 7.3% of all cases. Lung cancer was the most prevalent cancer, accounting for 11.4% of all cases (1,2). These statistics indicate an estimate of 1,141,259 (7.3%) new cases and 375,304 mortalities worldwide attributed to prostate cancer among men (1). Prostate cancer affects a large number of men every year and the incidence and mortality rates can be influenced by various factors, such as age, ethnicity, genetic background and staging (3). Prostate cancer exhibits higher incidence and mortality rates in developed countries compared with developing countries (4). The improvement of prostate cancer treatment and the understanding of its pathogenesis are challenging tasks. Researchers have identified exosomes and the tumor microenvironment (TME) as crucial areas of study and active topics of current literature.

Exosomes are nano-sized organelles encased in a single membrane, typically ranging between 30 to 200 nanometers in diameter. These organelles contain various chemicals, including proteins, lipids, nucleic acids and other substances such as amino acids, and metabolites (5). Exosomes are essential for various cellular activities and have the capacity to transmit information between cells. These single-membrane organelles can be secreted by various cell types and mediate intracellular communication signaling (6). Exosomes are natural nanoparticles that facilitate communication between cells, aiding in the regulation of cancerous growth. These cellular messengers transfer proteins and other biological substances through tissue fluids, affecting the development of cancer (7). Exosomes have the potential to respond to the growth and progression of tumor cells and can also have an impact on the metastasis of tumor cells that are located in a remote location (8). Exosomes have a crucial function in controlling the TME by affecting various processes, such as metastasis, angiogenesis and immunity. These functions are crucial in altering the state of the TME (9). The scientific community and clinical practitioners have shown considerable interest in the mechanism of exosome function in tumors.

The TME encompasses tumor cells, surrounding cells and their cytokine secretions, creating a conducive and abundant environment for tumor survival and proliferation (10). It is important to highlight the intricate and constantly altering nature of the TME, as well as the influence that the type of tumor may have on its individual components (11). However, the essential components of the TME include immune and stromal cells, blood vessels and the extracellular matrix (12). The composition of the TME and its existence are critical for the tumor development, advancement and spread (13). The understanding of the impact of the TME on cancer development and progression is critical for identifying novel treatment strategies. This relationship can be considered similar to the connection between soil and seeds, with exosomes serving as essential messengers between the tumor and its environment (14). Previous research has revealed a strong interaction between TME and exosomes (15). The interaction between exosomes and TME remains unclear. As a result, the current review aimed to examine the role of exosomes on the regulation of prostate cancer cells within the TME.

2. Composition and role of exosomes in the TME

The structure of exosomes and their inherent biological activity render them significant to intercellular communication. Their discovery and significance first gained prominence in a 1983 article by Pan and Johnstone, which indicated that exosomes released alongside transferrin receptors are involved in sheep reticulocyte formation (16). Subsequent research has uncovered the ability of exosomes to transport various RNA molecules, including but not limited to mRNA, microRNA (miR), transfer RNA, ribosomal RNA, small nuclear RNA, small nucleolar RNA, piwi-interacting RNA and small Cajal body-specific RNA (17). As shown in Fig. 1A, exosomes consist of various components, such as miRs (miR-409, miR-141 and miR-375), mRNAs, DNAs, lipids and functional proteins including cluster of differentiation (CD) 9, CD81, CD82, CD83, actin, myosin and tubulin (18).

Figure 1 (A) The composition of exosomes. Exosomes include miRs (miR-409, miR-141 and miR-375), mRNAs, DNAs, lipids and relevant functional proteins (CD9, CD81, CD82, CD83, actin, myosin and tubulin). (B) Exosomes act as the mediator between tumor cells and the TME. Exosomes can originate from different types of cells, including cancer stem cells, macrophages and dendritic cells. Exosomes play a crucial role in regulating multiple physiological processes and the pathology of tumor cells. miR, microRNA; CD, cluster of differentiation; TME, tumor microenvironment.

These vesicles serve as important players in various physiological and pathological processes, posing challenges for researchers to fully comprehend their functions. Exosome formation encompasses initiation, endocytosis, multivesicular formation and secretion (19). Early endosomes are formed during the initiation stage through the invagination of cell membrane sites that contain ubiquitination surface receptors. This process allows for membrane fusion, which creates a platform for the detection of Fab1-YOTB-Vac1-EEA1 domain-containing proteins, facilitated by the protein Rad5(20). As multivesicular bodies mature, they can either undergo degradation by lysosomes or be secreted from the cell via Golgi processing or exosomal release. The proteins Rab GTPase (Rab) 6 and Rab7 have significant influence on multivesicular bodies; Rab6 directs them towards lysosomal degradation, while Rab7 guides them towards Golgi processing (21). The involvement of the Rad protein family is crucial in various stages of exosome biogenesis.

Within the TME, tumor-related fibroblasts represent a prominent cell population (22). The functioning mechanism of fibroblasts associated with tumors remains unknown. Fig. 1B demonstrates the significant role of exosomes in enabling communication between tumor cells and the neighboring microenvironment. A study conducted by Baroni et al (23) revealed that exosomes can transport miR-9, which in turn transforms human breast fibroblasts into cells resembling cancer-associated fibroblasts. Zhu et al (24) discovered that breast cancer cells can trigger cancer-associated fibroblast-like characteristics in human breast fibroblasts through exosomal miR-425-5p. The TGFβ1/reactive oxygen species (ROS) signaling pathway is the mediator of this process (24). According to Yan et al (25), exosomal miR-18b derived from cancer-related fibroblasts can stimulate invasion and metastasis of breast cancer by modulating transcription elongation factor A-like 7.

Exosomes have been identified as significant players in various cancers and diseases, including breast cancer. Kang et al (26) reported that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) can boost neural function restoration in rats with spinal cord injuries. According to their findings, exosomes obtained from hucMSCs have potential therapeutic benefits in enhancing motor function through their antiapoptotic and anti-inflammatory properties. It is hypothesized that hucMSC exosomes may exert their protective effects through modulation of the Bcl2/Bax and Wnt/β-catenin signaling pathways, which are implicated in spinal cord injury (26).

Wang et al (27) indicated that the application of exosomes sourced from hucMSCs containing miR-326 can alleviate symptoms of bowel disease in mice by inhibiting neural communication. The findings suggest that the therapeutic potential of exosomes derived from hucMSCs are enhanced when they contain high levels of miR-326, as demonstrated by the substantial improvements observed in inflammatory bowel disease mouse models treated with these exosomes in comparison to those treated with regular hucMSC-derived exosomes (27). Zhang et al (28) indicated that exosomes obtained from hucMSCs can enhance the development of diabetic cardiomyopathy by adjusting autophagy through the signaling pathway of AMP-activated protein kinase-Unc-51-like autophagy-activating kinase 1. More recent findings have revealed that exosomes obtained from hucMSCs selectively target the miR-138-5p/SRY-related HMG-box-4 pathway for regulation, resulting in the suppression of human melanoma cell survival (29).

Moreover, endometrial cancer is impacted by exosomes, as evidenced by a previous research study (30). Pan et al (30) demonstrated that exosomes containing miR-503-3p from hucMSCs can impede the advancement of endometrial cancer cells by suppressing mesoderm-specific transcripts. Exosomes have been shown by numerous studies to enhance the functions of tumor stromal cells in the microenvironment, leading to the promotion of tumor progression (31,32).

3. Interactions between the TME and prostate cancer cells are mediated by exosomes

Earlier studies have suggested that exosomes are involved in the growth of tumors. A previous study conducted by Giovannelli et al (33) indicates that exosomes derived from prostate cancer cells can affect the TME, leading to tumor progression. Nevertheless, low oxygen levels and acidic conditions in the TME can influence the production and absorption of exosomes by cancer cells (34,35). Low pH will increase the yield of exosome separation (36,37).

A previous study has shown that an increase in the pH levels in the TME can enhance the therapeutic effects of pharmacological ascorbic acid on castration-resistant prostate cancer cells (38). Xi et al (39) have demonstrated that hypoxia-induced activation of ataxia-telangiectasia mutated regulates the secretion of exosomes that are involved in autophagy by cancer-associated fibroblasts, thereby promoting cancer cell invasion. Tumor-derived related exosomes can induce immunosuppressive macrophages to promote the progression of intrahepatic cholangiocarcinoma; however the specific underlying mechanisms have not been fully elucidated (40). The intracellular signaling mechanism of macrophages, the processes involving exosome uptake and the regulatory payload of the TME have not been specifically elucidated.

Dendritic cells are an important component present in the TME. A previous study has shown that tumor-derived exosomes can promote tumor metastasis and development by acting on dendritic cells through the heat shock protein (HSP) 72/HSP105-toll-like receptor (TLR) 2/TLR4 pathway (41). Pancreatic cancer is characterized by a reduction in the number and function of dendritic cells, which affects antigen presentation and contributes to immune tolerance (42). Concomitantly, hypoxia-induced exosome secretion promotes the survival of prostate cancer cells in both African-American and native American populations in the USA (43). Three distinct pathways have been elucidated by which exosomes can enter prostate cancer cells (44). One mechanism of prostate cancer cell communication involves direct fusion with the recipient cell membrane (45). The second pathway involves the entrance of several molecules in the prostate cancer cell by binding to its membrane surface (46). The third pathway involves the process of endocytosis of prostate cancer cells that allows exosomes to enter and secrete exosome contents (2). It should be mentioned that p53 has a significant function in enhancing the dispersion of exosomes (47,48). In the following sections, the role of exosomes is examined in regulating intercellular communication between prostate cancer cells and TME, focusing on three crucial perspectives.

4. Cancer metastasis and cancer progression

Prostate cancer-related mortality is predominantly attributed to metastasis (49). Prostate cancer cells detach from the primary tumor during metastasis, navigate in the bloodstream, and eventually establish secondary colonies. During metastasis the prevalent site for colonized prostate cancer cells is the bone (50). Three distinct categories of bone metastasis in cancer have been determined as follows: Osteolytic, osteoblastic and mixed lesions (51,52). A previous investigation has demonstrated that exosomes derived from prostate cancer cells can merge with and transmit signals to the bone stromal cells in the bone tissue. The results indicate that exosomes can have a possible function in promoting prostate cancer metastasis to the bone (53).

Normal prostate epithelial cells secrete exosomes that prevent bone metastasis by failing to transport them to bone stromal cells (54). A study conducted by Karlsson et al (55) revealed that exosomes extracted from the TRAMP-C1 mouse prostate cancer cell line can considerably impede the advancement of mononuclear osteoclast precursors by obstructing their maturation, leading to a deceleration in their progression. Zhang et al indicated (2) that exosomes play a crucial role in the progression of androgen-independent prostate cancer by activating heme oxygenase 1. Exosomes have multiple functions, which facilitate the spread of prostate cancer and promote the proliferation of prostate cancer cells through the activity of miRs. Therefore, the presence of miRs in exosomes may provide a novel diagnostic method for prostate cancer (56,57). The circ_0044516 exosome is highly promising as a biomarker, as it has the capacity to increase the proliferation and metastasis of prostate cancer cells (58). The contribution of exosomes to prostate cancer metastasis is yet not fully understood, indicating a need for further research in this area.

5. Related regulation of immunity

The immune system plays a crucial role in the growth of cancer. Effective communication between tumors and the immune system is imperative for the development and spread of the tumor, as well as its metastasis. Exosomes present in the environment surrounding the tumor, can cause both chemotherapy resistance, as well as immune system suppression (59). A detailed comprehension of the way by which exosomes mediate immune responses in cancer is essential to further examine the development of exosome-based immunotherapies. Notably, the binding of programmed death-ligand-1 (PD-L1) to programmed cell death protein 1 (PD-1) and the subsequent signaling to CD8+ cells aims to alleviate immunosuppression (60). Numerous research studies have revealed that prostate cancer cells increase PD-1 expression to evade the immune system (61,62). Simultaneously, the findings of Liu et al (63) have corroborated this assertion. This study suggests that exosomes originating from gastric cancer cells can elicit immune suppression by altering the gene expression levels in CD8+ cells and the patterns of cytokine secretion (63).

Exosome immunotherapy has gained significant attention in recent years, particularly with regard to the impact of nasopharyngeal carcinoma cell-derived exosome PD-L1 on CD8+ T cell activity and immune evasion (64). The exosome PD-L1 has been identified as a mechanism of immune resistance in non-small cell lung cancer, which promotes the progression of tumors (65). Exosomal miRs serve as mediators in the process of immune evasion in neuroblastoma (66). The immune evasion of breast cancer is facilitated by the increase of exosome miR-27a-3p, which is induced by endoplasmic reticulum stress. These exosomes regulate PD-L1 expression in macrophages, thus reducing immune response (67).

In patients with prostate cancer, myeloid suppressor and dendritic cells have been observed in the TME and are known to exhibit immunosuppressive effects. A previous study has indicated that these cells may contribute significantly to the proliferation and metastasis of cancer cells (68). Previous studies have indicated that a large quantity of PD-L1 within exosomes can potentially signify the advanced stages of prostate cancer, leading to a lower rate of survival and negative outcome (69,70). It should be emphasized that exosomes originating from prostate cancer cells have the potential to alter the behavior of macrophages and adjust the immune response (71).

6. Angiogenesis

Hypoxia-induced angiogenesis is a critical process that drives the advancement and dissemination of prostate cancer (72). Three stages of angiogenesis have been identified: i) The formation of blood vessels; ii) the angiogenesis stage; iii) and the maturation stage (73). Angiogenesis requires the synchronization of regulatory factors and activating signals (74). Exosomes are known to carry angiogenic factors, including VEGF and fibroblast growth factors, which promote the growth of new blood vessels (75,76). Early detection of prostate cancer is possible by utilizing biomarkers that are derived from proteins present in plasma exosomes associated with survival (77).

The Src tyrosine kinase is crucial for the development and growth of prostate cancer (78). Src tyrosine kinases impact the process of angiogenesis by activating signaling pathways through integrin (79). Earlier investigations have indicated that exosomes can contain Src tyrosine kinases and facilitate the progression of prostate cancer (80,81). Alcayaga-Miranda et al (82) revealed that exosomes extracted from menstrual stem cells have the ability to effectively suppress angiogenesis caused by prostate cancer. A previous study has indicated that exosomes can decrease ROS production and promote VEGF release, while also lowering NF-κB activity (83). Exosomes have been shown to possess an impact on the formation of blood vessels and as a result influence the multiplication of cells in prostate cancer. However, the precise mechanisms responsible for this effect require further investigation. The in-depth understanding of the angiogenesis mechanisms can be beneficial in improving prostate cancer treatment and prognosis.

7. Conclusion

Exosomes have been found to impact cancer metastasis and progression and regulate immunity and angiogenesis, which are involved in the spread of prostate cancer cells (Fig. 2). Nonetheless, the specific mechanisms underlying this correlation are currently uncertain. Further analysis of these mechanisms has the potential to advance the management and prediction of prostate cancer outcomes (Table I). Exosomes play a key inhibitory role in the progression of androgen-independent prostate cancer by activating heme oxygenase-1(2). Effective communication between tumors and the immune system is essential for tumor development and spread, as well as metastasis. Exosomes in the tumor microenvironment promote the progression of prostate cancer by secreting PD-L1, but macrophages in the immune system are able to slow this process. Exosomes in the prostate cancer microenvironment can promote the release of VEGF by reducing the production of ROS, and at the same time reduce the activity of NF-κB, inhibit angiogenesis, and effectively reduce the proliferation of prostate cancer.

Figure 2 Exosomes play an important role in the communication between the TME and prostate cancer cells. Exosomes mainly play a role in cancer metastasis, related immune regulation and angiogenesis. TME, tumor microenvironment.

Table I Role of exosomes in TME and prostate cancer.

Table I

Role of exosomes in TME and prostate cancer.

Author	TME	Exosomes	Mechanism	(Refs.)
Li et al	Low PH	Exosomal proteins	Acidic microenvironment may facilitate exosomes to fuse with prostate cancer cells.	(27)
Panigrahi et al	Hypoxia	Unique proteins and triglycerides	Hypoxic microenvironment can promote the secretion of exosomes in prostate cancer cells.	(31)
Li et al	Hypoxia	Circ0044516	Promote bone metastasis of prostate cancer.	(58)
Hosseini et al	Myeloid suppressor and dendritic cells	PD-L1	PD-L1 in exosomes inhibits immune cells in TME and promotes the progression of prostate cancer.	(71)
Alcayaga et al	Hypoxia	VEGF and FGF	VEGF and FGF carried by exosomes promote angiogenesis in a hypoxic microenvironment and accelerate the spread of prostate cancer cells.	(82)

[i] TME, tumor microenvironment; PD-L1, programmed death-ligand-1; FGF, fibroblast growth factors.

Acknowledgements

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Funding

Funding: No funding was received.

Availability of data and materials

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Authors' contributions

YQW and XHL wrote the manuscript and made substantial contributions to conception and design. XW and YZ drew the pictures and analyzed and interpretated the data. YQW revised the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

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Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References