Global research trends in tumor stem cell-derived exosomes and tumor microenvironment: visualization biology analysis

We selected the Scopus database (http://​www.​scopus.​com) for source publications retrieval as the target. Scopus is widely regarded as one of the best online databases for bibliometric research and is the largest abstract and citation database worldwide. Compared to other single abstract indexing databases, Scopus is more comprehensive and has a wider range of disciplines (Falagas et al. 2008; Sweileh 2020).

We used the “advanced search” function of the Scopus online database and inserted appropriate keywords to find relevant literature on exosomes and tumor microenvironments for the databases created before May 4, 2022. To prevent bias caused by the ongoing database update, document extraction and export should be completed within 1 day (May 4, 2022). Terms related to exosomes and tumor microenvironment were extracted from PubMed's Medical Subject Headings (MeSH) in the Scopus engine. To make the results more comprehensive and precise, we used the search strategy of [MeSH] + free terms (Entry Terms), which are synonyms and polysemous terms to MESH. The search formula was as follows: (exosomes OR exosome) AND TITLE-ABS-KEY (cancer AND stem AND cells OR tumor AND stem AND cells OR neoplastic AND stem AND cells OR tumor AND microenvironment OR microenvironment, AND tumor OR microenvironments, AND tumor OR tumor, AND microenvironments OR cancer AND microenvironment OR cancer, AND microenvironments OR microenvironment, AND cancer OR microenvironments, AND cancer).

Journal articles with research content related to the topic “Exosomes or exosome tumor stem cells and tumor microenvironment” were included by reading the titles, abstracts, and keywords of the detected articles. Articles with incomplete research information, conference articles, dissertations, book content, and duplicate articles were excluded. A total of 2077 publications were eventually included in the analysis, the basic information about which, including titles, abstracts, authors, affiliations, keywords, and references, were recorded on May 4, 2022.

An Excel spreadsheet was used to collect the following data as bibliometric indicators: total number of publications, year of publication, the distribution of authors, the distribution of countries/regions, the distribution of journals, and the distribution of top‑cited publications.

CiteSpace (version 5.8.R3) and VOSviewer (version 1.6.16) software tools were used to build, visualize and explore networks of countries, authors, and terms, as well as links between co-occurrence-based items, and to create network visualization maps of the most co-occurrence terms to identify the hotspots for frontier studies, as well as the most co-authorship of countries. Methodological workflow for this study as show in Fig. 1.

The total number of publications focusing on the relationship between exosomes and tumor microenvironment from 2009 to May 4, 2022, was 2077, increasing from 4 in 2009 to 271 in 2021. The overall trend is increasing yearly, as shown in Fig. 2. The growth in the number of publications of related studies was divided into two phases. The first phase (2009–2016) grew gently, while the second phase (2017–2021) went more rapidly, reaching a peak of 271 and declining sharply to 93 in 2022.

The co-occurrence analysis of the author collaboration network was performed by VOSviewer, as shown in Fig. 3. VOSviewer can be used to view the knowledge graph of the analysed domain in four views. In this study, we mainly use the labels view, which uses a circle and a label to represent an element, with the size of the circle representing the level of importance. Circles with the same colour belong to the same cluster. In order to avoid overlapping labels, the label view generally shows only a subset of labels, and the labels of each node on the graph can be viewed in detail by zooming in the software. Table 1 shows the top ten authors in terms of publication frequency, and the author with the highest number of publications is Wang, Y. The authors and their teams who published the most research in this field focused on the production and secretion of exosomes from tumours and tumour stem cells and their impact on cancer progression, emphasizing that exosomes secreted by tumour stem cells are regulated through the tumour stem cell-tumour microenvironment-target tissue interface, which can act as metastatic markers and are expected to serve as an entry point for blocking tumour metastasis. The author with the highest number of collaborative studies with other authors is ZHANG, Y.

The network mapping of countries/regions was created by CiteSpace visualization software, as shown in Fig. 4. Parameter settings for CiteSpace software to plot this figure: Slice Length = 2, Selection Criteria: g-index = (k = 5), LRF = 3.0, e = 2.0. The top five countries are China, the USA, Italy, Germany, and Japan, as shown in Table 2. Among them, China topped the list with 690 publications, accounting for about 33.22% of the total (2077). Centrality is an index to measure the importance of nodes in the network (Chen 2006) which is mainly used to measure the bridge function value of nodes in the whole network structure. Usually, nodes greater than 0.1 are considered relatively important. Majority of the EV research have been done in USA, China, Italy and many other researchers (top ten countries in Table 2). In addition, according to the results of the studies we included, the country with the least amount of relevant research in this area was Argentina, with a frequency of 2 and a centrality of 0.

We performed a visual analysis of published journals using the VOSviewer software and found that a total of 572 academic journals published 2077 articles on exosomes and tumor microenvironment. Among them, International Journal of Molecular Sciences had the highest output with an impact factor (IF) of 5.923, followed by Frontiers In oncology with an IF of 6.244. Among the top ten academic journals, Molecular Cancer has the highest IF of 27.401. Specially, Oncotarget ranked fifth, reflecting the impact factor of 2017; however, the journal has not been included in Science Citation Index (SCI) since 2018. According to the Journal Citation Reports (JCR), 70% of journals belong to Q2, as shown in Table 3. It is clear that the impact of journals depends on the number of times they are cited together, which reflects whether the journal has a significant influence in a specific research field.

We summarized the top ten most cited papers in the field of exosomal and tumor microenvironment since the establishment of the Scopus database, as shown in Table 4. Parameter settings for CiteSpace software to plot this figure: Slice Length = 1,Selection Criteria: LRF = 3.0, L/N = 10, LBY = 5, e = 1.0. The highest ten citations range from 161 to 65 (Hoshino et al. 2015; Costa-Silva et al. 2015; Niel et al. 2018; Chen et al. 2018; Melo et al. 2014; Melo et al. 2015; Zhou et al. 2014; Colombo et al. 2014b; Tkach and Théry 2016; Zhang et al. 2015). Hoshino A et al. (Hoshino et al. 2015), published in Nature in 2015, had the highest overall citation frequency (number of citations = 161). The publications co-citation network graph was created by CiteSpace visualization software, as shown in Fig. 5.

This study visualizes the overall situation and research hotspots of exosomes and tumor microenvironment-related studies and cases in the past decade through visual maps. A total of 2077 publications originating from the Scopus database were analyzed. According to several studies, Scopus is the world’s largest database of abstracts and citations from peer-reviewed scientific literature (Falagas et al. 2008; Kulkarni et al. 2009), which is a multidisciplinary database with more indexed journals than PubMed and WoS. CiteSpace and VOSviewer have been widely used visualization software with multiplicity, dynamism, and time-sharing that can present the development status and trends of a research field and help researchers grasp the hot spots and frontiers of scientific research.

The number and trend of publications per year can reflect the development rate and research progress of the study and indicate the concentration of research in the field. From 2009 to May 4, 2022, the number of published articles on the relationship between exosomes and tumor microenvironment has been increasing yearly. The growth in the number of publications of related studies was divided into two phases. The second phase (2017–2021) increased more quickly than the first phase (2009–2016), which developed more slowly. In the first stage, the growth rate is relatively slow. The primary explanation may be that as the area of miRNA and tumor microenvironment research continues to advance, researchers' focus is shifting inexorably toward the control of exosomes produced by tumor cells and miRNAs in the tumor microenvironment. The primary explanation for why the second stage of development occurs so quickly is that exosomes have a variety of immune regulatory functions that may both encourage and inhibit immunological response, according to an increasing number of studies (Zuo et al. 2022). Second, exosomes can change the sensitivity of cancer cells to chemotherapy drugs by regulating cell signaling pathways. Finally, exosomes have gradually attracted attention in tumor diagnosis and prognostic biomarkers, and the research results have provided new ideas for researchers. In addition, according to the results of the study, the related studies of exosomes and tumour microenvironment showed a decreasing trend in 2022. We considered that it might be related to the time of our search, which was from the time of library construction to 4 May 2022, and the related studies in the second half of 2022 have not been counted, so the results have a certain lag.

From the perspective of national and regional distribution, China has the most significant number of publications, followed by the United States, demonstrating that American and Chinese academics are the primary research forces in this area. Among the top ten countries, the United States has the highest centrality (0.55), meaning it plays a key role in the global network of national cooperation, followed by Italy (0.16) and China (0.04). The diversity of the researchers with this knowledge and the sizeable financial support for researchers are two factors that contribute to the success of research in these nations. Given that the nations involved have better developed infrastructures, greater availability of scientific services, and a long tradition in the general study of exosomes and the tumor microenvironment, the research output is not surprising. However, there is still a dearth of deep cooperation and information sharing, and country research is still mostly independent. Therefore, strengthening cooperation and exchange among research institutions and researchers in different countries is beneficial to the flow of information, innovation of research methods and breakthrough of current research bottlenecks.

We discovered from the distribution of journals that 572 academic publications published 2077 papers about exosomes and the tumor microenvironment. The journals with the most articles about exosomes and tumor microenvironment were International Journal of Molecular Sciences, followed by Frontiers In Oncology and Cancers. Among the top ten academic journals, Molecular Cancer has the highest impact factor of 27.401. Finding the key journals that published research on exosomes and the cancer microenvironment is made easier by analyzing the distribution of literature sources. From the distribution of top‑cited publications, we summarized the top ten most cited papers in the field of exosomal and tumor microenvironment since the Scopus database was built; the highest ten citations range from 161 to 165. Among the top ten publications with the highest total citation frequency, Hoshino A et al. published in Nature in 2015 had the highest total citation frequency (number of citations = 161).

Keywords are the research themes and core contents of the literature. Using term co-occurrence analysis, it is feasible to comprehend the distribution and growth of various research hotspots in a specific topic. It can be seen in Fig. 6. Keywords with high frequency are extracellular vesicles, biomarker, molecule, cell communication, expression, effect, pathway, phenotype, migration, immune response, immune system, cancer treatment, etc. Based on keywords co-occurrence analysis map, cluster analysis, burst word analysis and time zone diagram analysis of the relationship between exosomes and tumor microenvironment were mapped by CiteSpace, and the research hotspots and development frontiers in this field were further determined.

CSCs have the capacity to reverse differentiation, self-replenishment, and self-renewal in tumor tissues, and have potential migration and drug resistance characteristics. They are regarded as cancer-causing agents because they facilitate the development, spread, and recurrence of cancer as well as treatment resistance (Clara et al. 2020; Ayob and Ramasamy 2018). Exosomes produced by tumor stem cells have been shown to be essential for tumor development and progression in recent years due to their ability to control TME elements locally or remotely in an autocrine or paracrine manner (Peitzsch et al. 2017). According to our study, the connection between CSC-Exos and TME is mainly reflected in the fact that exosomes regulate the growth and metastasis of tumor cells, participate in tumor angiogenesis and have potential value as tumor diagnostics (Tan et al. 2020; Zhao et al. 2022; He et al. 2019; Zeng et al. 2018). In addition, it has also been shown that because CSC-Exos deliver key molecules that are responsive to chemotherapy and immunotherapy, they may also contribute to tumor drug resistance and impede effective responses to antitumor immunotherapy, leading to poor clinical outcomes (López de Andrés et al. 2020; Han et al. 2020). Therefore, the targeting of CSC-Exos as therapeutic agents and drug delivery vehicles to inhibit or remove cancer cells may offer promise for future applications in cancer therapy (Liu et al. 2022a; Aramini, et al. 2022).

Epithelial–mesenchymal transition (EMT) is a critical step in cancer metastasis and infiltration. CSC-Exos acts as a transporter of EMT initiation signals and delivers these signals to tumor cells, leading to cancer metastasis and infiltration (Jiang et al. 2022). In addition, angiogenesis refers to the ability of an organism to form a new vascular system based on the primitive vascular system. Tumor growth requires blood vessels to provide various nutrients and is a key step in tumor development (Du et al. 2020). Exosomes can regulate intercellular communication through proteins and RNA, leading to alterations in tumor heterogeneity and ultimately promoting malignant proliferation and an aggressive cellular phenotype of tumor cells (Zhao et al. 2022). Or exosomes regulate vascular permeability by increasing the level of angiogenic factors in TME. Hepatocellular carcinoma (HCC) is a highly angiogenic cancer. Lin found that miR-210 secreted by HCC cells can promote tumor angiogenesis by targeting SMAD4 and STAT6 to endothelial cells (Lin et al. 2018). Sarcoma delivers miRNA to endothelial cells via exosomes to increase the expression of angiogenic factors including VEGF-A, IL-6 and IL-8 (Raimondi et al. 2020). Due to advances in liquid biopsy technology for early cancer detection, exosomes may become an important tool for early cancer diagnosis and prognosis (Kok and Yu 2020; Kumar et al. 2015). Circulating exosomal circRNAs and exosomal proteins have also been shown to reflect the progressive and malignant features of cancer, and they have great potential as non-invasive biomarkers for cancer diagnosis and prognosis (Wang et al. 2020; Seimiya et al. 2020; Li et al. 2017). Pan (Pan et al. 2018) found eight miRNAs in the plasma exosomes of ovarian cancer patients compared with healthy women. Among them, four miRNAs (miR-21, miR-100, miR-200 b, and miR-320) were significantly enriched in the plasma exosomes of ovarian cancer patients, while the other four miRNAs (miR-16, miR-93, miR-126 and miR-223) were insufficiently expressed in the exosomes of ovarian cancer patients. This research reveals that exosome metastasis is a mechanism through which miRNAs produced from ovarian cancer influence the local and distant environment. They are not only involved in tumor growth, angiogenesis, invasion, metastasis, and immunosuppression but also can be used as a new biomarker for early diagnosis of ovarian cancer. Yang (Yang et al. 2020) found that the plasma exosomes of colorectal cancer patients were rich in circ133, and the expression of circ133 increased with the progression of the disease and was related to cell hypoxia. Hypoxia cell exosome circ133 promotes tumor cell metastasis by targeting the miR-133a/GEF-H1/RhoA signaling pathway, and exosome circ133 is expected to become a biomarker for monitoring the progression of colorectal cancer. Based on the evidence of these research, the combination of multiple components involved in exosomes may help enhance the specificity and sensitivity of cancer diagnosis, while further research is still needed.

They are natural nanocarriers secreted by various cells, making them suitable candidates for diverse drug delivery and therapeutic applications from a material standpoint. They have a phospholipid bilayer decorated with functional molecules and an enclosed parental matrix, which has attracted interest in developing designer/hybrid engineered exosome nanocarriers. The structural versatility of exosomes allows the modification of their original configuration using various methods, including genetic engineering, chemical procedures, physical techniques, and microfluidic technology, to load exosomes with additional cargo for expanded biomedical applications. Thus, such research has great potential for future application in personal medicine (Mondal et al. 2023; Li et al. 2019).In addition, chemotherapy, as a frontline treatment option for cancer, is associated with limitations such as low tumor penetration efficiency, low bioavailability, local toxicity, and poor solubility in fluids. To address these challenges, utilizing the delivery properties of exosomes to load chemotherapy drugs has emerged as a potential solution. This cancer-specific drug delivery technology holds the potential to improve patient survival rates and greatly reduce the need for high-dose drug injections. Currently, researchers have been exploring the application of exosomes in drugs such as doxorubicin, paclitaxel, and cabazitaxel (Rezakhani et al. 2022). Moreover, exosomes have emerged as the most promising miRNA carriers due to their high permeability, long half-life across biological barriers, and natural ability to transport cargo as shuttle carriers under physiological and pathological conditions (Boorn et al. 2013). However, exosomes are cell heterogeneous and differences in their size give them different contents and functions as well as limited drug delivery efficiency, raising questions regarding their safety (Chen et al. 2022; Nicolini et al. 2021). Therefore, the development and clinical application of exosomes as drug delivery systems remains challenging and deserves further research and investigation.

In recent years, SPR (Surface Plasmon Resonance technology, SPR), AFM (Atomic Force Microscopy, AFM), and microfluidic device, as advanced biosensing tools, have been increasingly used to analyse the binding specificity between biomolecules. For example, SPR technology can be used for real-time detection of interactions between DNA and proteins, protein molecules, drugs and proteins, nucleic acids and nucleic acids, antigens and antibodies, and receptors and ligands, among other biomolecules. AFM, is an analytical instrument that can be used to study the surface structure of solid materials, including insulators. It investigates the surface structure and properties of substances by detecting the very weak interatomic interaction forces between the surface of the sample to be examined and a miniature force-sensitive element (i.e. the probe). Microfluidic systems, on the other hand, are used in precision medicine, and functional microfluidic assays as therapeutic predictors are promising and valuable for exploring the relationship between exosomes and the tumour microenvironment (Ayuso et al. 2022).