The current trend of exosome in epithelial ovarian cancer studies: A bibliometric review

Background: Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer. About 90% of ovary tumors are epithelial. The current treatment for EOC involves surgical debulking of the tumors followed by a combination of chemotherapy. While most patients achieve complete remission, many EOCs will recur and develop chemoresistance. The cancer cells can adapt to several stress stimuli, becoming resistant. Therefore, new ways to fight resistant cells during the disease are being studied. Recently, exosomes, which reflect cell behavior in normal and pathological conditions such as epithelial ovarian cancer, are of academic interest as new biomarkers for diagnosis and therapy. Consequently, the current study aimed to investigate the research output of exosomes in EOC. Method: A bibliometric method was used for analyzing publications on exosome and epithelial ovarian cancer from the beginning to 15 October 2022 by searching keywords in Scopus, PubMed and Google scholar. Annual scientific publications, authors, citations, journals, co-authorships, and keywords co-occurrence were analyzed and plotted using Microsoft Office Excel and VOS viewer. 39 original journal articles and 3 reviews have been published since 2015 up to 15 October 2022. Results: The findings showed that China is the top country in research output, international collaborations, organization, author, and sponsorship. The top journals were the Journal of Ovarian Research, Oncotarget, and Tumor Biology, all in the United States. The top institution was Shanghai Jiao Tong University in China. The top author was Xipeng Wang. Co-occurrence analysis showed that academics’ interest is toward:1) 1) Exosomes as prognostic biomarkers of EOC as well as their role in the proliferation and migration of cells. 2) The role of exosomes in metastasis through different mechanisms; 3) The role of exosomes in epithelial-mesenchymal transition of ovarian cancer cells; 4) The diagnostic role of EVs in EOC; and 5) Conferring chemoresistance in EOC through the exosomal transfer of miRNAs. Conclusion: Research on the exosome and EOC has an increasing trend, and China is much more involved than other countries in research, financial support, and international cooperation. These findings could aid researcher in understanding novel ideas and subjects interested by sponsors in this field.


Introduction
Despite decades of efforts for improving the effectiveness of treatment approaches, epithelial ovarian cancer (EOC) is still the most lethal of all gynecological malignancies (Obermair et al., 2021). From a clinical point of view, the standard approach of EOC management is still debulking surgery and chemotherapy (Gadducci et al., 2022;Lodewijk et al., 2022). However, innovative surgical and medical developments were associated with only marginal survival improvements. The negative prognosis of patients suffering from OCE is normal because of late-stage diagnosis and the chemoresistance development during the illness period (Ma et al., 2014;Akter et al., 2022;Wanyama et al., 2022). Overdiagnosed, EOC remains an asymptomatic disease until the development of diffuse peritoneal carcinomatosis, including abdominal disease (van Baal et al., 2018). In addition, the transvaginal ultrasound combined with tumor markers carbohydrate antigen 125 (CA-125) serum level dosage as a promising screening method attracted attention, but yet had limitations in identifying EOC as an early-stage disease (Fishman et al., 2005;Olivier et al., 2006). Accordingly, 70% of patients diagnosed with EOC are frequently at the end stage of the disease with a 5-year survival rate of less than 40% (Meng et al., 2016a), so the necessity of developing non-invasive tools with highly sensitive for ensuring an early-stage diagnosis is one of the main challenges in biomarker investigate. Drug resistance development is another significant point in EOC investigations (Liu et al., 2018;Bukowski et al., 2020). In this regard, new advanced methods have been presented to date, precise approaches for detecting and treating different cancers (Bartosh et al., 2016;Baghban et al., 2022;Miri et al., 2022). One of the most newly known biomarkers of diseases is extracellular nano-vesicles, called exosomes (Hubert et al., 2015;Nawaz et al., 2016;Yousafzai et al., 2018;Ghafourian et al., 2022). Exosomes are produced by cells and carry several genetic materials and proteins playing key roles in the signaling and crosstalk of cells (Mashouri et al., 2019;Afshar et al., 2021;Bayat et al., 2021;Zhankina et al., 2021;Akbar et al., 2022). It has been reported that exosomes and their cargoes are an appropriate tool for maintaining the homeostasis of cancer tissues as they are able to mediate intercellular communication (Salido-Guadarrama et al., 2014;Caruso Bavisotto et al., 2019). Moreover, researchers propose that a panel of exosome-derived circulating miRNAs may aid to come for diagnosing early-onset of cancer and monitoring disease over cancer therapy (Wang and Chen, 2014). In this regard, increasing attention has been concentrated on the function of exosomes and their molecular cargo in EOC .
In light of the above-mentioned, the present bibliometrics study focuses on analyzing and examining the scientific productivity developed specifically on exosomes in EOC up to 15 October 2022 to observe its evolution. In this context, the scientific productivity by year, countries, subject areas, organizations, sponsors, authors, citations, keyword co-occurrence, and coauthorships mapping related to exosomes and EOC were extracted from the titles and keywords of the included documents and analyzed. According to the best of our knowledge, there is no similar study on the subject of the exosome in EOC. The findings and statistics attained are of great value for academics working on this topic or beginning their initial steps.

Methods
The current research focuses on bibliometric analysis, which applies methods and software that allow identification, documentation and combination of diverse properties of the knowledge area (Donthu et al., 2021). Scientific mapping is performed according to the obtained data and different networks are resulted that define their relations between diverse factors. The proper expression of these networks will determine the upcoming lines of strengthening the scientific production of this field. Documents are tracked and selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( Figure 1) (Moher et al., 2009). The data for this study, dating from the beginning to (15 October 2022, will be extracted using the PoP software (version 8) from Scopus, PubMed and Google scholar using the following search terms in title and keywords: "epithelial ovarian cancer" and "exosomes" or "exosome" or "exosomal" or "extracellular vesicles" or "extracellular vesicle". Then, those articles investigating ovarian cancer in general (which also includes epithelial ones) or microvesicles and extracellular vesicles (which also contain exosomes) were excluded as this study aims to investigate the studies focusing on only EOC and only exosomes. All the information including metadata on citation information and abstract, among other information will be exported in CSV format to the Microsoft Office Excel software for data analysis after merging the obtained files. Additionally, the VOSviewer software bibliometric analysis software, which enabled to build diverse illustrations of scientific mapping, will be employed to generate the collaboration and word co-occurrence networks.

FIGURE 1
Steps of identifying and selecting documents according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.

FIGURE 2
Trend of productivity by years in terms of number of publications in the field of exosome and EOC.

Countries
A total of 14 countries including China, Germany, Sweden, Hungary, Japan, the United States, Italy, Iran, Thailand, South Korea, Taiwan, Australia, Saudi Arabia, and Chile had published at least one article related to the exosome and EOC from 2015 to 2022. As observed in Figure 4, China with 29 is the top country.
In order to analyze country co-authorship or international collaboration, all 14 countries were included in the analysis. This analysis resulted in 9 clusters that 3 of which contains only two or more country. These three clusters contain 8 countries and 2 out of these 3 clusters are linked together. These results have been illustrated in Figure 5. It shows that authors in eight countries have international collaboration. Among these countries, China has the best international collaboration.

Organizations
A total of 63 organizations including 25 hospitals and 38 universities and colleges published at least one journal article from 2015 up to 15 October 2022. Among these organizations, the Shanghai Jiao Tong University in China with 6 articles is ranked as Trend of productivity by subject areas in terms of number of publications in the field of exosome and EOC.

FIGURE 4
Trend of productivity by countries in terms of number of publications in the field of exosome and EOC.
Frontiers in Pharmacology frontiersin.org 04 the first producer university and the Tongji University in China with 5 articles is ranked as the second one. Table 1 shows the ranking of organizations with more than one journal article in this field between 2015 to 15 October 2022.
To analyze the organizations' collaboration, the organizations' coauthorship network was obtained using VOSviewer software ( Figure 6). All 63 identified organizations were included in the primary analysis and it resulted in 26 clusters that 9 of them has no collaboration with other organizations. The largest cluster contains 8 organizations including, which has been shown in detail in Figure 6.

Authors
245 authors are identified in 39 articles implying a productivity index of 0.16 articles per author. Authors with more than 2 articles  in the field of exosome and EOC have been presented in Table 2. Xipeng Wang (Ying et al., 2016;Chen et al., 2017;Wu et al., 2017;Chen et al., 2018;Zhou et al., 2018;Li et al., 2020), Xinjing Wang (Ying et al., 2016;Chen et al., 2017;Wu et al., 2017;Chen et al., 2018;Zhou et al., 2018;Li et al., 2020), and Qinyi Zhu (Ying et al., 2016;Chen et al., 2017;Wu et al., 2017;Zhou et al., 2018;Li et al., 2020) are the most productive author with 7, 6, and 5 articles in the field of exosome and EOC. Most citations are also related to the same authors with values of 887, 811, and 651, respectively. It is worth notable that these authors are in the same group.
Regarding the author collaboration trend in producing journal articles, there is no single authorship document and all articles display a contribution of two or more authors that authors in 25 of which have different affiliations. The participation of several authors with diverse affiliations in one manuscript displays thematic maturity (Berelson, 1952;López López, 1996).
For authors' co-authorship analysis, only the authors with at least 2 articles were included in this analysis; so, 25 of 246 authors were entered into the network analysis. As it was demonstrated in Figures 6, 7 groups were resulted by clustering the co-authorships among these 25 authors. Only 2 clusters link together and the rest of them have no link with each other. In this network, a total of 70 links were found between authors.

Citations
A primary analysis of citations showed that the selected articles had been cited 2,101 times, and the mean citation to each article was 53.87 times. 2018 is the year with the maximum number of citations, with 549 citations (26.13%). For articles with the maximum citations, three original articles by Ying et al. (Ying et al., 2016) with 272 citations, Zhou et al.  with 230 citations and Meng et al. (Meng et al., 2016b) with 220 citations were first, second, and third, respectively. Table 3 indicates ten articles with the maximum citations in detail. As observed 7 out of these 10 articles focused on the delivery of microRNAs (miRNAs) by exosomes.
On the other hand, the authors' co-citation analysis (ACA) indicates how often authors of the former articles are co-cited by authors of subsequent articles. These groups cause clusters with central nodes whose size shows the co-citation trend reached by each author. Figure 8 demonstrates a scientific mapping by ACA. The structure contains 10,504 authors, 15 of which meet the threshold recognized in fifteen citations, resulting in 3 clusters. The authors with the maximum citations were: Xipeng Wang (33 co-citations), Klaus Pantel (28 co-citations), and Heidi Schwarzenbach (27 cocitations).

FIGURE 6
Organization co-authorship network (criteria: organizations with at least 1 article in the field of exosome and OEC). In fact, each cluster in Figure 8 forms a "school of thought" (Zupic and Čater, 2015), which allows us to observe the methods shared between the authors. Cluster 1, which is red, is composed of 7 academics including Xin Chen (15 co-citations), Ahmedin Jemal (24 co-citations), Rebecca l. Siegel (18 co-citations), Xinjing Wang (19 co-citations), Xipeng Wang (33 co-

FIGURE 9
Bibliographic coupling of journals (criteria: journals with at least one article in the field of exosome and OEC).

Journals
According to the bibliographic coupling of resources, a total of 30 journals with five clusters were identified (Figure 9). The most productive ones are the Journal of ovarian research, Oncotarget, and Tumor biology, with three articles each. The Oncotarget has the maximum number of citations received by accumulating 492 (Table 4). A total number of 25 journals only published one article in the field of exosome and OEC. 9 out of which (15 out of 39 documents) were published mostly in the United States. 19 out of 25 journals are Q1 suggesting the high quality of the research in this field.

Funding sponsors
The main financial sponsors for "exosome and EOC" research was presented in Table 5. The obtained results showed that the National Natural Science Foundation of China was the top funding sponsor with sponsoring 20 projects on this topic. National health and medical research council 1

FIGURE 10
Co-occurrence author keyword (criteria: at least 2 author keyword co-occurrences).

Discussion
The present research mainly purposed to study the international research activities in the field of exosome and EOC from the start of data published in this field up to 15 October 2022. It is emphasized that this research included studies focused on EOC, not ovarian cancer in general and exosomes alone, not microvesicles and extracellular vesicles.  Exosomes as a potential tool for a specific delivery of functional molecules Germany 2013 28 Nazarenko et al. (2013) Exploring the potential of engineered exosomes as delivery systems for tumor-suppressor microRNA replacement therapy in ovarian cancer United States 2020 37 Kobayashi et al. (2020) Human CAP cells represent a novel source for functional, miRNA-loaded exosome production Germany 2019 -Zeh et al. (2019) The passenger strand, miR-21-3p, plays a role in mediating cisplatin resistance in ovarian cancer cells UK 2015 85 Pink et al. (2015) Frontiers in Pharmacology frontiersin.org There are several bibliometric reviews on different aspects of ovarian cancer El Bairi et al., 2021;Gupta et al., 2021;Khedkar et al., 2021;Liu et al., 2022;Xu and Li, 2022) but there is no bibliometric review on EOC and applications of exosomes in EOC. The analysis of productivity by year showed that despite the growth of research interest in exosomes in different fields, research on exosomes and EOC has opened up in recent decades, and it is in the early stages. According to the findings of the current study, China is ranked the first publisher of journal articles in this field. This can be contributed to a large number of highly ranked institutions in publication and more funding sponsors in this region. However, Wang B et al., in 2019 andWang Y et al., in 2017 stated that the United States ranked as the first producer in the field of exosomes and China ranked second at that time Wang et al., 2019). Moreover, Yuanxia Liu et al. reported that the United States and UK are the first and second article producer from inception to 2021 (Liu et al., 2022). When it comes to funding sponsors of the research, Chinese sponsors especially the National Natural Science Foundation of China are impressive. This is since China efforts to impact high-tech technologies and promote their research and development sections and businesses.
Regarding the journal that publishes the articles, the Journal of Ovarian Research is the top publisher of journal articles in the field of exosome and EOC based on our analysis. Wang Y et al. and Wang B et al. stated that Plos One, Journal of Biological Chemistry, and Scientific Reports are the top publishers of articles in the exosome field Wang et al., 2019). Furthermore, Bernardo Pereira Cabral et al. reported that Oncotarget led published most cancer-related articles between 2012-2017 (Cabral et al., 2018). All of these journals are among high-ranking journals showing the field of study is novel and high-tech.
Citation analysis showed that 7 out of these 10 most cited articles focused on the delivery of microRNAs (miRNAs) by exosomes. The maximum co-occurrence author keywords showed the research flashpoints in the studied area over the study period. According to this analysis, the academics are interested to work on: 1) Exosomes as prognostic biomarkers of EOC and their role in the proliferation and migration of cells. 2) The role of exosomes in metastasis through different mechanisms; 3) The role of exosomes in epithelial-mesenchymal transition of ovarian cancer cells; 4) The diagnostic role of EVs in EOC; and 5) Conferring chemoresistance in EOC through Exosomal transfer of miRNAs.

Study limitations and sampling bias
The sampling bias is one of the key limitations of this study. As mentioned, this study focuses on research investigating specifically EOC and exosome. Therefore, sampling criteria excluded the published reports on extracellular vesicles, microvesicles and ovarian cancer, while exosomes are a subclass of extracellular vesicles and microvesicles. Moreover, EOC is one type of ovarian cancer. Therefore, considering exosome and EOC alone cannot make a general conclusion for highly cited or most productive authors in this field of ovarian cancer.
To reduce this limitation, according to citation analysis results which showed most cited articles focused on the delivery of miRNAs by exosomes, an extra search was conducted using the PubMed database on studies in the field of ovarian cancer and exosomal miRNA. 20 other articles other than those found above were found in this field. These articles are related to different countries including the United States, China, Hungary, Australia, Korea, Japan, Germany and the UK. The most cited article in this area is related to the United States with 487 citations, which is considerable. The information related to these articles has been listed in Table 6.

Conclusion
The present research findings showed the increasing trend of research activities in the field of exosomes and EOC. The scientific production was made up of 39 journal articles found in the international databases of Scopus, PubMed and Google scholar. China is the main contributor to the publications, institutions, funding, and international collaborations on the studied topic. The United States ranked first in terms of journals published articles on the studied topic. Moreover, results show that the scientists working in this area are mostly interested into apply microRNA delivery using exosomes in EOC contexts. However, it showed be noted that these results only related to studies in the field of EOC, not ovarian cancer in general or nanoscale extracellular vesicles, not all scales extracellular vesicles. These findings could be helpful for academics working in the field of exosomes and EOC to develop their studies and find new pipelines along the way.

Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Author contributions
Conceptualization, NB; methodology, NB; software, NB; validation, NB; formal analysis, NB; investigation, NB; resources, NB, MU, and IN; data curation, NB; writing-original draft preparation, NB; writing-review and editing, MU and IN; visualization, NB and MU; supervision, NB; project administration, NB All authors have read and agreed to the published version of the manuscript.

Conflict of interest
MU was employed by the company Department of Cancer Immunology, Genentech Inc.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.