Global trends and focuses of Integrins in Colorectal Cancer: a bibliometric analysis and visualization from 2007 to 2023

doi:10.21203/rs.3.rs-5255861/v1

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Global trends and focuses of Integrins in Colorectal Cancer: a bibliometric analysis and visualization from 2007 to 2023

https://doi.org/10.21203/rs.3.rs-5255861/v1

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Colorectal cancer is one of the most common tumors of the digestive system; however, current treatment methods still have certain limitations. In recent years, researchers have found that integrins play a crucial role in colorectal cancer, making them a hot topic in research. To gain a better understanding of the current status and trends of integrins in colorectal cancer research, this study conducted a bibliometric analysis for the first time to assess the development of integrin-related research in colorectal cancer. The study selected the core dataset from the Web of Science database and included relevant research on integrins and colorectal cancer published between 2007 and 2023. The CiteSpace, VoSviewer, and Bibliometrix R packages were utilized for analyzing the aspects of country/region, authors, institutions, journals, references, and keywords. The analysis revealed steady growth in research on integrins and colorectal cancer over the past 16 years, with a total of 1,339 articles published by 61 countries. Among them, China has the highest number of publications, followed by the United States. The most frequently cited journal is Cancer Research, followed by the Journal of Biological Chemistry and Oncogene. In conclusion, bibliometric analysis provided a comprehensive visualization of the current status and trends in research on integrins in colorectal cancer. These analytical results not only offer valuable insights for researchers but also provide useful information for decision-makers in the scientific and medical communities. This, in turn, can facilitate the improvement and development of treatment methods for colorectal cancer.

Colorectal cancer

Integrins

Trends

CiteSpace

VOSviewer

Bibliometric analysis

Colorectal cancer (CRC) ranks as the third most common cancer globally and the second leading cause of cancer-related deaths. In 2020, there were 19,292,789 new cases of cancer and 9,958,133 cancer-related deaths worldwide [1]. As CRC progresses globally, the number of new CRC cases is projected to reach 3.2 million by 2040 [2]. China is currently undergoing a cancer transition period, with a significant increase in new cases of colorectal cancer. The cancer mortality rate for colorectal cancer in China is higher than that in developed countries, contributing to a substantial cancer burden [3]. Thus, understanding the underlying mechanisms of CRC development and progression is crucial for developing precise preventive and therapeutic measures for this disease.

Integrin proteins are heterodimeric transmembrane glycoprotein receptors consisting of α and β subunits. There are 18 variants of α subunits and 8 variants of β subunits, resulting in 24 distinct heterodimers [4]. Through noncovalent interactions, the α and β subunits bind to ligand-binding sites at the interface, enabling integrin proteins to adhere to receptors and facilitating signal transduction [5]. Integrins maintain cell viability primarily through mechanical attachment to the extracellular matrix (ECM) and directly control cancer cell migration and invasion by binding to ECM components that drive the dynamics of cell movement and invasion [6]. In addition, activated integrins can bind to a variety of receptors on the cell membrane to form protein signaling complexes to regulate a variety of intracellular pathways, e.g., integrins regulate cell proliferation, migration, and survival through focal adhesion kinase (FAK) and downstream signaling cascades, such as phosphatidylinositol 3-kinase (PI3K)-AKT/PKB and mitogen-activated protein kinase (MAPK) pathways [7]. It is widely known that the extracellular matrix can guide the migration of cancer cells, particularly cancer-associated fibroblasts (CAFs) located in the tumor microenvironment. Integrins, in turn, play a role in regulating the interactions between cells and the extracellular matrix [8]. Currently, specific attention is given to the integrin proteins αvβ3, α5β1, and αvβ6 in tumors, while αvβ5, α6β4, and α4β1 are expressed at lower frequencies. Among these, αvβ6 activates transforming growth factor-beta (TGFβ) in CRC cells, promoting the invasion of CRC cells into fibroblasts [6]. Since integrins play a role in every stage of tumor development, targeted therapies against integrins may hold promise for the treatment of colorectal cancer. To elucidate the current mechanisms of action and therapeutic means of integrins in colorectal cancer, we conducted a bibliometric-based study that comprehensively analyzed studies related to colorectal cancer and integrins from 2007 to 2023 using visualization techniques.

Bibliometric analysis enables the assessment of individual researchers, publications, and institutions, providing insights into their research output. By employing scientific visualization techniques, bibliometrics can effectively depict the dynamic changes in these entities over time. Furthermore, one of the most significant advantages of bibliometric analysis is its ability to track emerging research topics and areas [9]. Bibliometric analysis has also been applied to other areas of CRC research, such as nanoparticles and the gut microbiota [10, 11]. However, to date, there have been no reported bibliometric analyses specifically focusing on integrins in relation to CRC. In this study, we employed bibliometric methods to perform a statistical analysis of integrin research in CRC over the past 16 years. The aim was to gain a better understanding of the current status, research hotspots, and future prospects in this field.

Data sources and search strategies

We utilized the Web of Science Core Collection (WoSCC) database, which covers 9,000 of the world's most prestigious high-impact journals and more than 12,000 academic conferences, and is considered to be a highly authoritative platform and applicable to previous bibliometric studies, as the source of data[12, 13]. All searches were independently conducted by two researchers (YW and XL) on April 1, 2023, to avoid additional bias due to daily updates of the database. TSs were retrieved through the following formula: TS= (Colonic Neoplasm* OR Colon Neoplasm* OR Colon Cancer* OR Colonic Cancer* OR Colon Adenocarcinoma* OR Cancer of Colon OR Cancer of the Colon OR Rectal Neoplasm* OR Rectum Neoplasm* OR Rectal Tumor* OR Rectal Cancer* OR Rectum Cancer* OR Cancer of Rectum OR Cancer of the Rectum OR Colorectal Neoplasm* OR Colorectal Tumor* OR Colorectal Cancer* OR Colorectal Carcinoma*) AND TS=(integrin*). All English-language articles on integrin research in CRC published between January 1, 2007, and April 1, 2023 were retrieved. The selection criteria and literature screening process used in this study are depicted in Fig. 1. The exclusion criteria were as follows: (1) article types were conference abstracts, conference proceedings papers, letters, editorial material, book chapters, revisions, or withdrawn publications; and (2) articles that were not related to CRC and integrin content. The inclusion criteria were as follows: (1) studies focusing on integrins and CRC as the main topic; (2) articles including original research articles and reviews; and (3) articles published in English.

Data analysis

The complete records and cited references were downloaded from the database as plain text files and tab-separated files. These files were imported into CiteSpace (version 6.2. R2), VoSviewer (version 1.6.19), and the R Bibliometrix Package for analysis. The collected information included publication details, titles, author information, publication dates, keywords, cited references, journal citation reports (JCRs), and impact factors (IFs). R (version 4.2.2) was used for plotting, and Microsoft Excel 2019 was utilized for visualizing the annual publication output and creating tables.

CiteSpace (https://citespace.podia.com/) is a visual analytics software designed and developed by Dr. Chaomei Chen, an informatics professor at the College of Computing and Informatics, Drexel University in the United States. It is widely used for the visualization and analysis of the properties of scientific literature [14]. We used Citespace for collaborative analysis of countries, institutions, and authors; for reference cocitation analysis; and for keyword analysis of high interest over time.

VoSviewer (https://www.vosviewer.com/) is a widely used software for bibliometric analysis and is particularly known for its ability to visualize data in the form of maps [15]. It has three main functions: (1) Visualizing a citation network. (2) Drilling down into a citation network. (3) Searching for publications [16]. Each node on the map represents an element, and the size of the node represents the frequency. The connecting lines between the nodes represent the connections between the elements, and the width of the line represents the strength of the connection; nodes in different clusters are colored differently.

The bibliometrix R-package (https://www.bibliometrix.org/home/) is written in the R programming language and provides a wide range of statistical algorithms and integrated data visualization workflows. The analysis workflow of the bibliometrix R package is as follows: (1) study design; (2) data collection; (3) data analysis; (4) data visualization; and (5) interpretation [17].

Publication analysis

Analyzing the changes in the number of publications over time provides an objective picture of the overall research trend of integrins in colorectal cancer. From January 1, 2007, to April 1, 2023, a total of 1,339 publications related to integrins and colorectal cancer were retrieved from the WoSCC, including 1,141 articles and 198 reviews. Ninety-thirds of the records, including conference abstracts, conference proceedings, book chapters, and other types of papers, were excluded. Ultimately, 1,339 publications that met the inclusion and exclusion criteria were subjected to bibliometric analysis (Fig. 1).

Figure 2A shows the annual number of publications on integrins in colorectal cancer research, with the average number of first editions from 2015–2023 being greater than that between 2015, and the overall trend of first editions showing a slow increase. This trend is further shown by the curve fitted to Fig. 2B and the coefficient of determination (R²). In conclusion, the trend in the number of publications reflects the fact that researchers are still exploring, but further research may be needed to explore the potential for growth in the field.

From 2007 to 2023, research on integrins in CRC was published by 61 countries/regions across 6 continents. Close collaborations are observed among East Asia, North America, and Western Europe (Fig. 3A). Table 1 displays the top 10 most productive countries in this field. The country with the highest number of publications in this area is China (418 articles, 31.2% of all the articles), followed by the United States (345, 25.8%), Germany (123, 9.2%), Japan (111, 8.3%), and France (72, 5.4%). The country with the greatest number of citations is the United States (16934 citations), followed by China (10069 citations), Germany (5024 citations), Italy (3056 citations), and Japan (2970 citations). The United States and France have the highest average citation counts, and it is worth noting that although Canada has a relatively low publication output, its average citation rate is above 40, placing it fourth, indicating a high quality of published articles.

Table 1

The top 10 productive countries/regions related to integrin in CRC
Rank	Country	Publications n (%)	Total citations	Average citations	Centrality
1	CHINA	418 (31.2)	10069	24.09	0.07
2	USA	345 (25.8)	16934	49.08	0.13
3	GERMANY	123 (9.2)	5024	40.85	0.33
4	JAPAN	111 (8.3)	2970	26.76	0
5	FRANCE	72 (5.4)	2966	41.19	0.14
6	ENGLAND	70 (5.2)	2746	39.23	0.31
7	SOUTH KOREA	67 (5.0)	2035	30.37	0
8	ITALY	60 (4.5)	3056	50.93	0.42
9	CANADA	56 (4.2)	2258	40.32	0.07
10	AUSTRALIA	40 (3.0)	1273	31.83	0.03

The network of cooperation between these countries is shown in Fig. 3B, where the size of the circles indicates the volume of publications by the country, and the connecting lines between the circles indicate the cooperation between the countries, with China, the most productive country, and the United States working most closely together. China mainly collaborates with Australia, the United Kingdom, and South Korea, while the United States mainly collaborates with Germany, Italy, and South Korea. Although China has the highest publication output, its intermediary centrality is 0.07, indicating a lower ranking in terms of collaboration centrality. The purple color in the outermost part of the circle indicates high intermediate centrality, and the top five countries in terms of centrality ranking are Finland (0.85), Italy (0.42), Argentina (0.41), Hungary (0.37), and Germany (0.33).

Contribution of institutions and authors

Over the course of the past 17 years, a total of 1,795 institutions have been involved in the publication of research articles on the topic of integrins in CRC. Among these institutions, 150 have contributed to at least 5 publications, forming 7 distinct clusters that are visually represented using different colors (Fig. 4A). The top 10 most productive institutions are listed in Table 2. Shandong University is the most prolific institution in terms of publication output, followed by Seoul National University and the German Cancer Research Center. The top ten universities in terms of ranking include five Chinese universities, two German institutions, one Korean university, one American university, and one Australian university. The Huazhong University of Science and Technology exhibits the highest betweenness centrality, underscoring its pivotal role in the investigation of integrins in CRC.

Table 2

Top 10 institutions that contributed to publications on integrin in CRC
Rank	Institution	Country	Publications n(%)	Total citations	Average citations	Centrality
1	Shandong University	China	37 (2.8)	962	26.00	0.07
2	Seoul National University	Korea	19 (1.4)	680	35.79	0.08
3	German Cancer Research Center	Germany	18 (1.3)	824	45.78	0.02
4	Huazhong University of Science and Technology	China	16 (1.2)	213	13.31	0.16
5	Inserm	Germany	15 (1.1)	565	37.67	0.06
6	Sun Yat-Sen University	China	15 (1.1)	462	30.80	0.02
7	Vanderbilt University	USA	14 (1.0)	1085	77.50	0.08
8	Peking University	China	14 (1.0)	371	26.50	0.01
9	Taipei Medical University	China	14 (1.0)	634	45.29	0
10	Monash University	Australia	13 (0.9)	477	36.69	0

Among the top ten most prolific authors (Table 3), seven are from China. The author with the highest number of published papers is Professor Niu Jun from Shandong University, who has published a total of 24 papers. Peng Cheng (15 articles) and Niu Weibo (14 articles) followed closely. In addition, Professor Niu Jun has the highest total citation count and h-index (630, 17). Figure 4B illustrates the timeline of paper publications from 2007 to 2023 for the top 10 most productive authors. In addition, we plotted the network analysis of authors' cooperation, which is roughly divided into six clusters, among which the cluster dominated by Liu Jun is the densest, the thickness of the connecting lines reflects the degree of cooperation between authors, and the authors with whom they cooperate most closely are Peng Cheng, Niu Weibo, Liu Ey, and Wang JY (Fig. 4C). Notably, Prof. Liu Jun is affiliated with Shandong University, which confirms the accuracy of the institutional contribution. The above data demonstrate that Chineseresearchers and authors have been continuously conducting research in the field of integrins and colorectal cancer.

Table 3

Top 10 most productive authors on integrins in CRC
Rank	Author	Institution	Country	Publications n (%)	Total citations	Average citations	H-index
1	Niu, jun	Shandong University	China	24 (1.8)	630	26.25	17
2	Peng, cheng	Shandong University	China	15 (1.1)	391	26.07	13
3	Niu, weibo	Emory University	USA	14 (1.0)	429	30.64	14
4	Wang, jiayong	Shanghai Qiangzhi Hospital	China	13 (0.97)	402	30.92	15
5	Liu, enyu	Xi'an University of Technology	China	12 (0.9)	354	29.5	12
6	Gao, huijie	Jining Medical University	China	10 (0.7)	277	27.7	8
7	Beaulieu, Jean-Francois	University of Sherbrooke	Canada	10 (0.7)	222	22.2	10
8	Liang, benjia	University of California San Francisco	USA	9 (0.7)	239	26.56	8
9	Liu, song	Shandong University	China	8 (0.6)	294	36.75	10
10	Wang, ben	Shandong University	China	8 (0.6)	262	32.75	7

Journals, Cocited journals and Cocited references

Subsequently, we conducted an assessment of the top ten journals with the highest quantity of published papers (Table 4). Plos One (34 citations, 2.5%) emerged as the most prolific journal in the field, followed by Cancer Research (30 citations, 2.2%), Oncogene (28 citations, 2.1%), Oncotarget (27 citations, 2.0%), and Journal of Biological Chemistry (27 citations, 2.0%). Notably, Cancer Research had the highest citation count, average citation count, and impact factor, underscoring its prominent status as the most influential journal in the field. Among the 4446 indexed journals, 537 have been cited at least 20 times. The most cited journal is Cancer Research, followed by the Journal of Biological Chemistry, Oncogene, Proceedings of the National Academy of Sciences of the United States of America, and Cell. They have been cited 3482, 3297, 1783, 1632, and 1552 times, respectively. In addition, the number of citations of the top ten cited journals exceeded 1000. The IFs of these journals, including Proceedings of the National Academy of Sciences of the United States of America (12.779), Cancer Research (13.312), Clinical Cancer Research (13.801), Cell (66.85), Nature (69.504), and Nature Reviews Cancer (69.8), are greater than 10. Except for the Journal of Biological Chemistry, the other journals are in Q1 (Table 5).

Table 4

The top 10 core journals in terms of integrin in CRC
Rank	Journal	Publications n (% ,1339)	Total citations	Average citations	2022 JCR category quartile	2022 IF
1	Plos One	34 (2.5)	982	28.88	Q3	3.752
2	Cancer Research	30 (2.2)	2674	89.13	Q1	13.312
3	Oncogene	28 (2.1)	1381	49.32	Q1	8.756
4	Oncotarget	27 (2.0)	1057	39.15	/	/
5	Journal of Biological Chemistry	26 (1.9)	1613	62.04	Q2	5.486
6	Cancer Letters	23 (1.7)	700	30.43	Q1	9.756
7	International Journal of Molecular Sciences	23 (1.7)	342	14.87	Q2	6.208
8	International Journal of Cancer	22 (1.6)	972	44.18	Q1	7.316
9	Scientific Reports	21 (1.5)	463	22.05	Q3	4.996
10	International Journal of Oncology	18 (1.3)	281	15.61	Q2	5.884

Table 5

The top 10 most highly cocited journals about integrin in CRC from 2007 to 2023
Rank	Cited Journal	Citation	2022 JCR category quartile	2022 IF
1	Cancer Research	3482	13.312	Q1
2	Journal of Biological Chemistry	3297	5.486	Q2
3	Oncogene	1783	8.756	Q1
4	Proceedings of the National Academy of Sciences of the United States of America	1632	12.779	Q1
5	Cell	1552	66.85	Q1
6	Clinical Cancer Research	1318	13.801	Q1
7	Nature	1296	69.504	Q1
8	Journal of Cell Biology	1269	8.077	Q1
9	International Journal of Cancer	1267	7.316	Q1
10	Nature Reviews Cancer	1070	69.8	Q1

Cocited references refer to references that are cited in two or more papers. When two or more papers cite the same reference, these citations are called "cocitations". In Table 6, we list the top 10 cocited references related to the study of integrins in CRC. The most cited article is Integrins: bidirectional, allosteric signaling machines by Richard O. Hynes, published in Cell, with 126 citations. This is followed by Integrins in cancer: biological implications and therapeutic opportunities", which were published in Nature Reviews Cancer, with 100 citations. The remaining eight papers had fewer than 100 citations at this time. Notably, two of the cocited documents were written by Richard O. Hynes.

Table 6

Top 10 most highly cited studies
Rank	Author	Journal	Title	Co-Citation	Year of publication
1	Richard O Hynes	Cell	Integrins: bidirectional, allosteric signaling machines	126	2002
2	Desgrosellier, JS	Nature Reviews Cancer	Integrins in cancer: biological implications and therapeutic opportunities	100	2010
3	Bates, Richard C	The Journal of Clinical Investigation	Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma	62	2005
4	John D. Hood	Nature Reviews Cancer	Role of integrins in cell invasion and migration	53	2002
5	Siegel, Rebecca L.	CA-A Cancer Journal for Clinicians	Colorectal cancer statistics, 2017	48	2017
6	Guo, Wenjun	Nature Reviews Molecular Cell Biology	Integrin signaling during tumor progression	45	2004
7	Livak, K J	Methods	Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.	44	2001
8	Giancotti, F G	Science	Integrin signaling.	41	1999
9	Richard O Hynes	Cell	Integrins: Versatility, modulation, and signaling in cell adhesion	41	1992
10	Yang, Guang-Yun	Cancer Science	Integrin alphavbeta6 mediates the potential for colon cancer cells to colonize in and metastasize to the liver	40	2008

Citation bursts refer to instances in which papers in a field of research receive a large number of citations over a period of time, indicating that they were very influential during that time, perhaps because they posed important research questions, addressed research problems in the field, or opened up new research directions. Figure 5 shows the "Top 25 References with the Strongest Citation Bursts" chart generated by CiteSpace. The strongest citation burst since 2007 was published by Siegel, Rebecca L. et al. in the CA-A Cancer Journal for Clinicians [18], with a burst time from 2019 to the present. The earliest eruption was in 2007, with three citations, and the most recent eruption was in 2023, with seven citations.

Keyword analysis

Keyword analysis is one of the most commonly used analytical methods for identifying a research field and can be used to describe the subject and content of literature and understand the development of a research field. Figure 6A shows the keyword trend analysis in the Bibiometric R package, which sorts the keywords in the literature in chronological order and then combines them into a time series to study the research hotspots and trends in a group of literature. Early (2007–2011) research in this area focused on (1) alpha-3-beta-1 integrin, a protein-tyrosine kinase in nude mice; (2) laminin, a plasminogen- activator, rna; and (3) tyrosine kinase, a protein-kinase, and colon- carcinoma cells. The middle term (2011–2017) mainly focused on (1) motility, signaling pathways, and carcinoma cells; (2) binding, cancer cells, and the extracellular matrix; (3) in vitro, colon cancer, and adhesion; (4) integrin-linked kinase, angiogenesis, and cancer; (5) activation, breast cancer, and metastasis; and (6) growth, colorectal cancer, and expression. The focus of research in 2017–2021 shifted to (1) inhibition, epithelial- mesenchymal transition, and progression; (2) therapy, proliferation, and cell proliferation; (3) ulcerative colitis, inflammatory bowel disease, and promotion; (4) exosomes, tumorigenesis, and biomarkers; and (5) linked kinase ilk and macrophages.

Table 7 presents the 20 most frequently occurring related keywords, with "expression" having the highest frequency of co-occurrence. Figure 6B shows a visual analysis of cooccurring keywords based on VOSviewer, where all keywords have appeared at least 10 times and are categorized into five clusters represented by different colors. The size of the nodes corresponds to the frequency of keywords, while the thickness of the connections indicates the strength of co-occurrence between keywords. Notably, the two clusters headed by "expression" and "colorectal- cancer" appeared most frequently. In addition, Fig. 6C, which is based on the keyword outbreak analysis of CiteSpace, sheds light on recent research hotspots. Keywords such as "ulcerative colitis", "inflammatory bowel disease", "proliferation", "therapy", "promotes", and "tumor microenvironment" have been the focus of recent research efforts and have sustained relevance until 2023.

Table 7

Top 20 keywords with the highest number of integrins in CRC research
Rank	Keyword	Count
1	expression	392
2	colorectal-cancer	265
3	metastasis	254
4	integrin	226
5	colorectal cancer	201
6	migration	187
7	invasion	167
8	adhesion	161
9	cancer	154
10	breast-cancer	149
11	activation	148
12	growth	139
13	integrins	116
14	progression	108
15	apoptosis	104
16	proliferation	102
17	angiogenesis	102
18	colon-cancer	100
19	cells	97
20	epithelial-mesenchymal transition	95

The effect of integrins on CRC has long been a hot topic of research, and as biological targets they provide new ideas for the treatment of CRC. Activation of integrins is a transition from a low-affinity ligand-bound state to a high-affinity ligand-bound state triggered by "inside-out" signaling by integrins, and the affinity switch requires the binding of the junction proteins talin and kindlin to the cytoplasmic tail. Integrin-bound ligands also signal in an "outside-in" manner, facilitating the assembly of integrin complexes that lead to cell migration and spreading [19, 20]. FAK is a signaling protein that interacts with integrins. For example, integrin α1β1 regulates the activation of the FAK/Src and p130Cas/c-Jun signaling pathways and promotes colon cancer cell invasion [21, 22]. Activated β4 integrin interacts with FAK and induces FAK phosphorylation at Tyr397, contributing to CRC cell proliferation [23]. Recent clinical trials of FAK have recommended FAK inhibitors (GSK2256098, PF-00562271, VS-6063, and BI 853520) for use in combination with cytotoxic chemotherapy, targeted therapies, or immunotherapy [24]. Integrin-linked kinase (ILK), another hotly researched signaling protein of integrins, was shown to be overexpressed in colorectal cancer and to regulate the β-catenin, e-cadherin, and Akt pathways in human colon cancer [25]. Recent studies have shown that bone marrow ILK deficiency reduces the tumor burden in mouse models of colorectal cancer, suggesting that targeting ILK may be a potential therapeutic option for advanced colorectal cancer [26]. ILK acts as a central regulator of signaling cascades and participates in various signaling pathways including the NF-κB, Hippo, HIF-1, and PI3K/AKT pathways. ILK can upregulate EMT-related proteins such as E-cadherin and vimentin through NF-κB signaling, thereby promoting the migration and invasion of colorectal cancer cells [27]. In addition, downregulation of Thymosin β4, a 43- amino acid peptide, has been shown to significantly reduce ILK/AKT/β-catenin signaling cascade activity and upregulate E-cadherin expression in colorectal cancer cells [28]. Although significant progress has been made in the study of integrins in the field of colorectal cancer, the redundancy of integrin functions and the complexity of the mechanisms involved are because integrin functions are closely related to the onset and progression of cancer and that different integrin subunits are involved in different signaling pathways. Therefore, to advance the discipline, it is necessary to use bibliometric methods to conduct a scientifically oriented analysis of the field, to assess the current state of research and to identify more valuable research directions.

4.1 Overview of Essential Research Trends for Integrins in Colorectal Cancer Disease, 2007 to 2023

We performed a bibliometric analysis of publications related to integrin research in colorectal cancer over the past 16 years using the visualization software CiteSpace and VoSviewer and the Blbiometric R package. In terms of annual publications, the number of annual publications showed a trend of slow growth. We evaluated them in terms of country/region, institution and authors, journals and references, and keywords.

Among the 61 countries analyzed, China and the United States are the two countries with the most published articles, and they are also active countries in this field, but the total number of citations, average citations and centrality of the United States exceed those of China. In addition, Chinese universities accounted for 50% of the top ten institutions with the largest research contributions, while American universities accounted for 10%. Among them, Huazhong University of Science and Technology (0.16) from China has the highest centrality, and Shandong University is the most productive university in the world. However, Vanderbilt University in the United States has the highest total and average citations, indicating that these institutions have played an important role in promoting academic development in this field.

In the journal analysis, Plos One, Cancer Research, Oncogene, OncoTarget, Journal of Biological Chemistry, Cancer Letters, International Journal of Molecular Sciences, International Journal of Cancer, Scientific Reports, and International Journal of Oncology are the top ten active journals. It is worth noting that Cancer Research, Journal of Biological Chemistry, and Oncogene are the three journals with the most citations, which indicates that their research in this field is more comprehensive and that resources are the most abundant. According to the results shown in Fig. 4, Niu Jun from Shandong University is the most prolific author, and he and his colleague Peng, Cheng (ranked second), have made important contributions to the research on integrins and CRC [29–34]. Professors Beaulieu and Jean-Francois of the University of Sherbrooke have also promoted the development of this field. His main research directions include integrin and laminin, colorectal cancer, signal transduction and anoikis research. His team first identified MYC as a key regulator of ITGA1 expression in colorectal cancer cells [35]. Subsequently, a novel mechanism by which the proto-oncogene MYC can directly control the promoter activity of ITGA6 and ESRP2 in colorectal cancer cells was discovered. This study demonstrated that MYC can regulate the promoter activation and splicing of the ITGA6 integrin gene through ESRP2, thereby promoting the generation of pro-proliferative ITGA6A variants in colorectal cancer cells [36].

4.2 Research history, research hotspots and future trends of integrins in colorectal cancer

The top 10 articles with the most citations focused on (1) the role of integrins in cancer, including their effects on tumor cell proliferation, migration, invasion, and survival; (2) the role of specific integrins in cancer; and (3) integrin-mediated signaling pathways and potential targets for preventing cancer development. This means that the focus of integrin research has shifted from the mechanism of cancer metastasis to the search for effective targets for clinical treatment. Figure 5 lists the top 25 articles with strong citations over time and identifies articles with milestone landmarks [5, 21, 37–48] (Fig. 7). Bates, R. C. et al. broke out in 2007–2010 with their study demonstrating the impact of high β6 expression on survival in patients with early- stage colorectal cancer, independent of tumor stage. In addition, αvβ6 integrins were identified as independent risk factors and potential therapeutic targets for early stage colorectal cancer [49]. In addition, integrin αvβ6 affects the apoptosis signaling pathway in colorectal cancer cells. Blocking integrin αvβ6 with a monoclonal antibody significantly increased the number of apoptotic cells, as well as the activities of the key enzymes involved in apoptosis, caspase-3 and caspase-9 [50]. Recent studies have shown that tumor integrin αvβ6 activates TGF-βsignaling in T cells, thereby reducing cytotoxic CD8 + T-cell activity and infiltration. Thus, blocking integrin αvβ6 leads to T-cell antitumor responses and enhances the effectiveness of immune checkpoint blockade therapy in colorectal cancer [51]. Desgrosellier, J. S. & Cheresh, D. A., whose research exploded in 2011–2015, summarized the progress made in targeting integrins in cancer, where the efficacy of integrin antagonists has been demonstrated in preclinical and clinical studies, and mentioned the initiation of the first phase III clinical trial using the integrin antagonist cilengitide, which showed clinical activity with few side effects in glioblastoma patients [40]. Liu, S. et al.'s research exploded in 2014–2016, and their study further demonstrated that β6 integrin not only promotes colon cancer extracellular matrix invasion, but also promotes 5FU resistance through the ERK/MAP kinase pathway and direct binding of β6-ERK2 in colon cancer cells [42]. Wang, J. et al. demonstrated the occurrence of integrin recycling in colorectal cancer cells and reported that the inhibition of ERK2 phosphorylation interrupted the internalization of integrin αvβ6 but had no effect on its recycling and that the activation of PKC significantly accelerated the internalization and recycling of integrin αvβ6 [41]. Interestingly, the corresponding author of both studies is Prof. Jun Niu of Shandong University, whose team has made significant progress in the study of integrins in CRC, effectively advancing research in this area. In 2017–2020, Hoshino, A. et al. used quantitative mass spectrometry to identify six integrins among the 40 most abundant adhesion molecules in metastatic exosomes in the brain, lungs, and liver, suggesting a correlation between exosomal integrins and metastatic potential. These findings suggest that exosomal integrins, particularly integrin α2β1, can serve as markers and drivers of metastasis in all cancers [44]. Exosomes have been applied in various diseases as a novel drug delivery method in recent years. Mesenchymal stem cell-derived exosomes carry miR-3940-5p into colorectal cancer cells, which binds directly to integrin α6 (ITGA6) and inhibits colorectal cancer cell invasion and EMT, as well as tumor growth and metastasis, through downregulation of ITGA6 and subsequently TGF-β1[52]. The most recent outbreak in the last few years, 2021–2023, was a review authored by Hamidi, H. & Ivaska, J. They outlined each step of cancer cell proliferation and metastasis, the specific aspects of integrin involvement in cancer cell activity, and the role of the RGD integrins in cancer immunotherapy, particularly as tumor-associated antigens for the selective delivery of antitumor drugs [53]. In conclusion, integrins not only act as facilitators of chemotherapy resistance, but also as targets involved in immunotherapy and exosome delivery therapy for CRC. However, further studies are needed to explore the molecular mechanisms and interactions of different integrin subunits with other factors in CRC, which will help to discover new areas of integrin research, as well as more precise therapies.

From keyword trend analysis, keyword co-occurrence network analysis (Fig. 6), and keyword citation explosion, we found that researchers’ research on integrins in CRC from 2007 to 2011 mainly explored various proteins that interact with integrins or cytokines [54]. The mid-term (2011–2017) research direction is mainly the study of various signaling pathways mediated by integrins, and the possibility of integrins as a prognostic indicator of disease has been widely studied by researchers [55]. In recent years (2017–2023), research on the effects of integrins on the tumor microenvironment, macrophages, and therapeutic pathways targeting specific integrins has also been underway [56]. We focused on the keywords cited in the outbreak of research that will continue through 2023, including "proliferation", "tumor microenvironment", "biomarkers", and "therapy". "biomarkers", and "therapy".

The promotion of tumor proliferation has long been one of the roles of integrins, and early studies of integrins in CRC focused on combinations of α and β subunits, including: αvβ6, α5β1, and αvβ3 [6]. However, since many integrins show overlap in their ligand-binding profiles and downstream proteins can be recognized by more than one integrin, blocking the effect of one integrin can be compensated for by binding another integrin of the same ligand [57]. Recent studies have increasingly focused on targeting a particular subunit, e.g., resveratrol targets the β1-integrin receptor to inhibit EMT-associated transcription factor activation in colorectal cancer cells as well as inflammation in CRC cells and downregulates the invasion and metastasis of colorectal cancer cells [58]. Upregulated expression of ITGB5 enhances TGF-β/Smad signaling and promotes epithelial mesenchymal transition in colorectal cancer cells [48]. ITGB7 expression is correlated with a range of immune cell subsets that play important roles in tumor killing, such as effector memory CD8 + T cells, IFNγ + CD8 + T cells, CD103 + DCs, and IFNγ + NK cells [59]. However, the mechanism by which ITGB7 affects immune cells needs to be further investigated. The immune microenvironment is one of the key factors in the development of metastasis in CRC. Recent studies have demonstrated that some integrins have antitumor metastatic effects and that intestinal-derived α4β7 + CD8 + T lymphocytes are a key component of the antimetastatic effect [60]. In addition, resveratrol modulates chemosensitization to 5-FU via the β1-integrin/HIF-1α axis in the CRC tumor microenvironment [61]. In summary, significant breakthroughs have been made in the field of integrins, from promoting the proliferation and migration of cancer cells into the microenvironment of participating tumors to modulating cancer metastasis and tolerance to chemotherapeutic agents. However, the role of different integrin subunits in the tumor microenvironment is currently not well established and may be a mainstream direction for future research.

Notably, the involvement of integrins as biomarkers in various targeted therapies has become a hot research topic in the last two years. Therapeutic pathways targeting integrins currently include: inhibitor blockade, monoclonal antibodies, nanomaterials, exosome therapy, and radionuclide therapy. One of these monoclonal antibody treatments was studied as early as 2008, with a phase I clinical trial of etanercept, a humanized monoclonal antibody targeting the αvβ3 integrin receptor, in patients with advanced solid tumors [62]. Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. Recent findings suggest that patients with moderately to severely active ulcerative colitis who have been previously treated with anti-TNF medications have a significantly greater rate of remission at week 14 after treatment with etrolizumab[63]. With the rise of nanomedicine, drug-loaded nanotechnology has also been applied to the field of integrins. The arginine-glycine-glutamic acid (RGD) sequence is the 𝛼ν𝛽3 integrin (endothelial cell receptor) recognition site. This sequence is overexpressed in malignant tumors as well as in the new blood vessels required for tumor growth, making it a potential therapeutic target[64]. Another research team proposed chemo-PDT of tumor-targeting polysialic acid (PSA) nanoparticles by increasing their cellular uptake and cytotoxicity in cancer cells. Researchers have used a photosensitizer, chlorin e6 (Ce6), and an iRGD peptide(sequence; cCRGDKGPDC) conjugated to the amine of N-deacetylated PSA, which generates reactive oxygen species (ROS), especially singlet oxygen (¹O2), and targets Integrin αvβ3 on the surface of cancer cells[65]. The above studies further confirmed that biomarkers and therapies are current research hotspots in the field of CRC immunotherapy.

Future trends are likely to be combined with emerging research technologies in recent years, which could allow bioinformatics to discover the correlation between integrin subunits and disease, and machine learning to explore integrins to predict disease prognosis. Bioinformatics technology can help researchers to analyze the relationship between integrins and disease at the genetic level, Zhao, L. et al. analyzed the clinical information of colon cancer patients in The Cancer Genome Atlas database as well as the mRNA gene clusters related to ITGB3, and the results showed that low expression of ITGB3 is an independent prognostic factor for disease[66]. Therefore, the expression of integrins can be a marker of CRC prognosis, thus guiding the clinical assessment of this disease. A recent study used advanced molecular dynamics simulations and machine learning methods to investigate the interaction between cyclic RGD-coupled polyethylene glycolated titanium dioxide and extracellular fragments of integrin αvβ3[67].

In addition, gut microbes as well as metabolites intersect with the integrin field, which provides a larger research space for integrin studies. The current study suggested that gut flora-associated bile acid metabolism stimulating the FXR/TGR5 axis may be a potential mechanism influencing the anti-α4β7 integrin response in experimental colitis[68]. Another interesting finding suggests that gut microbiota-mediated alterations in bile acid metabolism may play a key role in modulating the anti-α4β7-integrin immunotherapeutic response in Crohn's disease[69]. Therefore, does gut microbe-mediated bile acid metabolism in CRC also modulate anti-α4β7 integrin therapy? Thus, future studies will be closely linked to the triad of gut microbes, bile acid metabolism, and anti-integrin therapy.

In summary, we summarized the current research status of integrins and colorectal cancer through bibliometric analysis and suggested several possible research directions. However, more molecular mechanisms and signaling pathways need to be continuously explored and continuously integrated with emerging technologies to advance the research progress on integrins.

This study has several limitations. First, we selected only the WoSCC database as the source of articles, which may have resulted in the omission of some articles. Second, we included only articles in English, so the number of articles may be insufficient. In addition, when conducting cocitation analysis, we mainly focused mainly on journals and references, which may have led to information bias.

To the best of our knowledge, this study represents the first comprehensive bibliometric evaluation of integrin in the context of CRC. Our findings indicate that China published the largest number of integrin-related studies, with Shandong University emerging as the leading institution in terms of collaborative research output. Notably, Professor Niu Jun from Shandong University has established an extensive network of collaborations in this field. We also observed that the focus of integrin research is shifting toward clinical practice, with emerging topics such as targeted therapy, nanoparticles, the tumor microenvironment, and inflammatory bowel disease. These areas represent promising avenues for future research, and drug design targeting integrins may hold the key to breakthrough treatments for this disease.

Funding

This study was supported by grants from the Science and Technology Planning Project of Sichuan Province (2022YFS0626), the "Luzhou Municipal People's Government-Southwest Medical University" Technology Strategy Project (2023LZXNYDJ001), the Sichuan Science and Technology Program (2023RCM198), and the Cooperation Project of Gulin County People’s Hospital and Southwest Medical University Affiliated Hospital (2022GLXNYDFY11).

Author Contribution

Wei Yin: Writing – review & editing, Writing – original draft, Conceptualization. Lijun Xiao: Writing – original draft, Visualization, Methodology, Data curation. Chao Zhang: Writing – review & editing, Visualization, Validation, Methodology, Data curation. Xu Zhang and Chengli Wen: Software, Resources, Methodology, Conceptualization. Hao Li and Yuan Yu: Project administration, Formal analysis. Zehui Yu: Writing – review & editing, Supervision, Conceptualization. Muhan Lü: Writing – review & editing, Writing – original draft, Visualization, Funding acquisition.

Acknowledgement

The authors sincerely thank the researchers who provided the bibliometrix package, the VOSviewer and CiteSpace open-source software, and the anonymous reviewers for their time and effort on this study.

Data Availability

Data is provided within the manuscript or supplementary information files.

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No competing interests reported.

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Reviewers invited by journal
04 Nov, 2024
Editor assigned by journal
25 Oct, 2024
Submission checks completed at journal
24 Oct, 2024
First submitted to journal
13 Oct, 2024

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Global trends and focuses of Integrins in Colorectal Cancer: a bibliometric analysis and visualization from 2007 to 2023

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Abstract

Figures

1 Introduction

2 Materials and methods

3 Results

4 Discussion

4.1 Overview of Essential Research Trends for Integrins in Colorectal Cancer Disease, 2007 to 2023

4.2 Research history, research hotspots and future trends of integrins in colorectal cancer

5 Limitations

6 Conclusion

Declarations

Funding

Author Contribution

Acknowledgement

Data Availability

References

Additional Declarations

Status:

Version 1