Abstract
Background
Cigarette smoking is a major contributor to the global burden of bladder cancer. Its carcinogenic effects result from the harmful substances in tobacco smoke, which induce genetic mutations and disrupt cellular processes. Understanding how smoking contributes to bladder cancer is essential for developing effective prevention and treatment strategies.
Objective
This study systematically reviews global research on the relationship between smoking and bladder cancer through bibliometric analysis, identifying research hotspots, trends and future directions.
Methods
Relevant literature on the relationship between cigarette smoking and bladder cancer published between 1999 and 2023 was retrieved from the Web of Science database. Visual analyses were conducted using VOSviewer and CiteSpace software, focusing on contributions from countries, institutions, journals, authors and keywords.
Results
Our analysis of 2,802 publications revealed an upward trend in annual output on the relationship between smoking and bladder cancer, with the United States and China as leading contributors. Notable institutions included the NIH, National Cancer Institute, University of Texas System and the International Agency for Research on Cancer. Key journals were Cancer Epidemiology, Biomarkers & Prevention and International Journal of Cancer. Rothman, Nathaniel and Zeegers, M.P.A. were the most productive and co-cited authors. Keyword analysis highlighted DNA repair, genome-wide association studies, and smoking cessation.
Conclusion
This bibliometric analysis has significantly advanced the field by highlighting current research directions and the application of specific mechanisms. These findings also have implications for clinical practice and public health policy, potentially improving patient outcomes through a comprehensive understanding of disease pathogenesis.
Keywords: Smoking, Bladder cancer, Bibliometrics, International collaboration, Citation analysis
Introduction
Bladder cancer (BC) represents a significant global public health concern. It is currently the 10th most commonly diagnosed cancer worldwide, with an estimated 573,000 new cases and 213,000 deaths annually [1, 2]. The disease disproportionately affects populations in more developed regions. BC is further characterized by its high recurrence rate and the need for lifelong surveillance, including invasive procedures such as cystoscopy. These factors, along with its chronic nature, contribute to a substantial economic burden and adversely affect patients’ quality of life [3].
Among established risk factors, tobacco smoking remains the most significant modifiable contributor to BC. People who smoke are reported to have a two to fourfold increased risk of developing BC compared to individuals who do not smoke [4–6]. Furthermore, smoking can induce chronic inflammation in bladder tissue, where persistent inflammation may result in continuous tissue damage and abnormal cell proliferation, further elevating cancer risk [7, 8].
Given the extensive and growing body of literature on the relationship between smoking and bladder cancer, bibliometric analysis provides a powerful quantitative method for synthesizing and visualizing this research field. Bibliometrics applies statistical and mathematical tools to analyze patterns in scholarly output, identify influential authors and institutions, uncover collaboration networks, and trace the evolution of research topics and thematic shifts within a field [9]. This approach has been increasingly employed in biomedical research to map intellectual landscapes, evaluate research productivity, and guide future inquiry [10]. By providing a structured overview of global scientific activity, bibliometric studies can help identify knowledge gaps, research hotspots, and emerging directions relevant to both academia and public health policy.
Therefore, the present study aims to conduct a comprehensive bibliometric analysis of the global research output on smoking and bladder cancer, focusing on publications indexed in the Web of Science Core Collection from 1999 to 2023. Specifically, this study seeks to: (1) delineate publication trends and identify the most influential journals, authors, institutions, and countries; (2) map the intellectual structure and collaborative networks within this field; (3) identify major research themes, hotspots, and evolving conceptual frameworks, particularly concerning pathogenesis and public health implications; and (4) provide insights that may inform future research priorities and contribute to the evidence base for prevention strategies and clinical management related to smoking-associated bladder cancer.
Methods
Data source and search strategy
This study aimed to conduct a bibliometric analysis of literature concerning smoking and bladder cancer published between January 1, 1999, and December 31, 2023. Data were retrieved from the Web of Science Core Collection (WoSCC) database (Clarivate Analytics), which is widely regarded as a comprehensive data source for bibliometric research. The literature search was conducted on June 1, 2023.
To ensure the comprehensiveness and precision of the search, the following search query was utilized: TS = (bladder) NEAR/1 (cancer* OR tumor* OR tumour* OR oncology OR neoplasm* OR carcinoma*) AND (smok* OR tobacco* OR cigarette* OR nicotine*). While this search strategy incorporated broader terms such as tobacco* and nicotine* to ensure comprehensive coverage, the primary focus of this bibliometric analysis was on combustible cigarette smoking, given its established role as the principal risk factor for bladder cancer. An initial assessment of the retrieved literature confirmed that the vast majority of relevant publications pertained to smoking.
Inclusion criteria and literature screening
The initial search of the Web of Science Core Collection yielded 3,065 publications. To identify the most relevant literature for this bibliometric analysis, the following inclusion criteria were applied: (1) Document types were restricted to original research articles and reviews. (2) Studies directly addressed the relationship between smoking (with the primary focus on combustible cigarette smoking as defined in inclusion criteria and literature screening) and bladder cancer. This encompassed a comprehensive range of research, including studies on pathogenesis (e.g., molecular mechanisms, genetic predispositions, toxicological effects) as well as studies pertinent to public health and epidemiology (e.g., cohort studies, case–control studies, cross-sectional studies, meta-analyses, and research on risk assessment, prevention strategies, or public health impact). (3) Publications were in the English language.
The literature screening process was systematically conducted by two researchers independently (Yang Wang and Hancheng Zhou) to ensure reliability and minimize potential selection bias. First, all retrieved records were imported into Citespace for automated and manual duplicate removal. Subsequently, the titles and abstracts of the remaining unique records were rigorously screened by the two researchers based on the predefined inclusion and exclusion criteria. Any discrepancies or uncertainties regarding an article’s eligibility were resolved through in-depth discussion between the two researchers, if consensus could not be reached, by consulting a third senior researcher (Zhicheng Tang). Finally, the full texts of all potentially eligible articles were retrieved and thoroughly assessed for final inclusion. This systematic process resulted in a final dataset of 2,802 publications (comprising 2475 original articles and 347 reviews deemed suitable for the subsequent bibliometric analysis. The entire literature screening and selection process is illustrated in Fig. 1.
Fig. 1.
Flow chart illustrating the literature extraction process from the database
Data extraction and cleaning
For the 2,802 included publications, full records including titles, authors, affiliations, author keywords, abstracts, publication years, journal names, and cited references were downloaded from WoSCC in plain text format. Before formal analysis, data cleaning was performed. This involved: Standardizing variations in country names; Reviewing and merging highly similar keywords (e.g., singular/plural forms, common synonyms related to core concepts) to improve the accuracy of keyword-based analyses; For key entities like highly productive institutions or authors, names were checked for consistency and merged where variants were identified (e.g., “Univ Calif” vs “University of California System”).
Data management
The cleaned dataset comprising the bibliographic information of the 2,802 selected publications was organized and managed using Microsoft Excel 2019 (Microsoft Corp., Redmond, WA, USA) for initial descriptive statistics and subsequently formatted for import into specialized bibliometric software.
Bibliometric analysis and visualization
The bibliometric analysis utilized data visualization and network analysis tools, specifically VOSviewer and CiteSpace, to identify publication trends, collaboration networks and research impact. To create network visualizations and explore potential relationships within the dataset, two bibliometric mapping software tools were employed. CiteSpace (version 6.2.4) facilitated visual analyses focused on institutional affiliations, journal distributions and notable citation bursts. Concurrently, VOSviewer (version 1.6.19) was used to develop visualization networks for countries, authors/co-cited authors, journals and keywords. In the network visualizations generated by VOSviewer, nodes represent the analyzed items (e.g., countries, authors, keywords), with node size typically proportional to metrics such as publication count, occurrence frequency, or total link strength. Lines (or edges) between nodes signify relationships, such as co-authorship or keyword co-occurrence, with line thickness often indicating the strength of these associations (e.g., more co-authored papers or higher co-occurrence frequency). VOSviewer’s clustering algorithm assigns colors to nodes, grouping closely related items into clusters. In keyword co-occurrence maps, these clusters generally represent distinct research themes or subtopics, while in co-authorship maps, they can indicate collaborative research communities. Consequently, keyword co-occurrence networks are interpreted as visual maps of a research field's thematic structure, where dense clusters of interconnected keywords highlight major research hotspots and inter-topic relationships. Similarly, co-authorship networks (for authors, institutions, or countries) depict the collaborative landscape, aiding in the identification of influential actors, collaborative groups, isolated entities, and key bridging elements within the network.
Quality control
Several quality control measures were implemented throughout the research process. The search strategy was iteratively developed and tested. Two researchers independently performed literature screening and data extraction for key parameters, with disagreements resolved by a third researcher. A random sample of 5% of the included publications was cross-verified against the WoSCC database to ensure the accuracy of the downloaded bibliographic data. The selection of analytical parameters within VOSviewer and CiteSpace was based on established bibliometric practices and preliminary testing to ensure meaningful outputs.
Results
Annual publication analysis
From 1999 to 2023, the annual publication volume concerning smoking and bladder cancer showed a consistent upward trend, reflecting growing research interest in the topic. In the early 2000 s, publication numbers were relatively low, but a gradual increase was observed starting around 2004. A marked surge occurred post-2010, with a significant peak in 2013, demonstrating heightened academic interest. In the 2020 s, publication levels remained high, highlighting ongoing research and attention to the topic (Fig. 2).
Fig. 2.
The growth trend of the number of publications and citations from 1999 to 2023. The left vertical axis represents the annual publication count, while the right vertical axis indicates the annual citation frequency
Annual citation analysis
The citation trend mirrored the annual publication trend, displaying a year-by-year increase. In the initial years (1999–2005), citations were limited, likely due to the nascent state of research in this field and its lack of widespread recognition at that time. As the number of publications increased, so did the citations, culminating in a peak in 2022. Post-2015, citation numbers rose dramatically, illustrating the growing academic influence and application of research findings in this field. By 2023, the citation count had reached a new high, indicating broad acceptance and utility of the research outcomes (Fig. 2).
National collaboration analysis
The analysis of international collaboration, based on Fig. 3 and Table 1, highlighted the publication volume and cooperation relationships between key research countries. The United States had the highest publication output, with 1,143 papers, demonstrating its leading role in the field. China followed with 551 papers, showcasing its substantial research capabilities. Germany, Italy, and the United Kingdom also made notable contributions, with publication volumes of 268, 254, and 245, respectively. Citations and H-index data showed that the United States led with 58,526 citations, an H-index of 113, and an average of 51.2 citations per paper. China followed with 15,386 citations and an H-index of 57, averaging 27.92 citations per paper. Germany exhibited an H-index of 64 with 15,863 citations, averaging 29.19 citations per paper. Italy and the United Kingdom also showed considerable academic influence, with average citation counts of 56.06 and 65.96 per paper, respectively. The collaboration relationships visualized in the figure indicate that the USA frequently collaborated with countries such as China, Germany, Japan and Italy, underscoring its central role in international cooperation. Similarly, China maintained strong collaborations with several nations, including the USA, Germany and Japan, reflecting its active role in global research networks. European nations, particularly Germany, Italy and others, were also shown to have strong collaborative ties.
Fig. 3.
Analysis of global research trends and collaborations. A The total link strength of publications in different countries/regions. B Visualization graph of collaborations between countries/regions. The sizes of the bubbles bearing the names of countries correspond to the respective quantities of publications, while the color of the bubbles represents the total link strength (TLS)
Table 1.
Top 10 productive countries/regions for cigarette research on bladder cancer development
| Rank | Country/regions | Count | Total citations | H-index | Average citation per paper |
|---|---|---|---|---|---|
| 1 | USA | 1143 | 58,526 | 113 | 51.2 |
| 2 | China | 551 | 15,386 | 57 | 27.92 |
| 3 | Germany | 268 | 15,863 | 64 | 29.19 |
| 4 | Italy | 254 | 14,240 | 60 | 56.06 |
| 5 | United Kingdom | 245 | 16,161 | 63 | 65.96 |
| 6 | France | 207 | 14,357 | 58 | 69.36 |
| 7 | Spain | 191 | 11,025 | 55 | 57.72 |
| 8 | Netherlands | 170 | 11,727 | 50 | 68.98 |
| 9 | Japan | 154 | 6424 | 43 | 41.71 |
| 10 | Canada | 148 | 8839 | 46 | 59.72 |
Institutional collaboration and contributions
Figure 4 and Table 2 revealed major research institutions and their collaboration networks in the area of smoking and bladder cancer research. Among these, the National Institutes of Health (NIH) in the USA emerged as one of the most active institutions, publishing 194 papers with high centrality (0.11) in the international collaboration network. The NIH National Cancer Institute (NCI) also made significant contributions, with 166 publications and notable collaboration efforts with multiple international research institutions.The University of Texas System produced 154 publications and demonstrated a broad collaboration network. The International Agency for Research on Cancer (IARC) in France, Harvard University in the USA and the World Health Organization (WHO) in Switzerland also played pivotal roles. WHO’s centrality (0.12) highlighted its significant influence in the international collaboration network. The analysis of collaboration frequency and centrality suggested that institutions with frequent collaborations, such as WHO and the University of California System, also possessed high centrality, thus indicating their importance within the global research network. Regional collaboration was prominent among institutions in the USA, such as NIH, NCI and the University of Texas System, which maintained close ties with international organizations, including IARC and WHO. Similarly, institutions like IARC in France and WHO in Switzerland played key roles in international collaborations, maintaining strong ties with multiple countries. These findings emphasize that major research institutions, particularly those with high centrality, are central to international cooperation, driving progress in this field.
Fig. 4.
Inter-institutional collaboration network. This visualization depicts the network of institutional collaboration. Each node represents an institution, with the size of the node indicating the volume of publications by that institution. The lines connecting the institutions reflect their collaborative relationships
Table 2.
Top 10 institutes in the publications for cigarette research on bladder cancer development
| Rank | Institutions | Countries/regions | Count | Centrality |
|---|---|---|---|---|
| 1 | National institutes of Health | USA | 194 | 0.11 |
| 2 | NIH National Cancer Institute | USA | 166 | 0.05 |
| 3 | University of Texas System | USA | 154 | 0.08 |
| 4 | International Agency for Research on Cancer | France | 107 | 0.03 |
| 5 | Harvard University | USA | 104 | 0.04 |
| 6 | World Health Organization | Swiss | 100 | 0.12 |
| 7 | University of California System | USA | 93 | 0.21 |
| 8 | UTMD Anderson Cancer Center | USA | 88 | 0.11 |
| 9 | Helmholtz Association | Germany | 69 | 0.01 |
| 10 | German Cancer Research Center | Germany | 65 | 0.00 |
Journal analysis
The journal co-citation network (Fig. 5) further revealed that these top-publishing journals also form the core intellectual base of the field, frequently being cited together and thus shaping the foundational knowledge. Using data from Fig. 5 and Table 3, the analysis of journals with the highest publication volumes on smoking and bladder cancer highlighted their impact on the research field. Key journals included Cancer Epidemiology Biomarkers & Prevention (USA) with an impact factor of 3.8, International Journal of Cancer (Switzerland) with an impact factor of 6.4, and Urologic Oncology: Seminars and Original Investigations (USA) with an impact factor of 2.7. These journals demonstrated significant influence in cancer research, featuring numerous high-quality studies that contributed to advancing understanding in smoking and bladder cancer. Other notable journals such as Journal of Urology and European Urology also played critical roles by publishing key research and maintaining high impact factors and citation counts.
Fig. 5.
Journal collaboration network. Each node in this network diagram represents a scientific journal, with the size of the node proportional to the number of publications attributed to that journal. The lines connecting the nodes illustrate the collaborative relationships between the journals
Table 3.
Top 10 Journals in the publications for cigarette research on bladder cancer development
| Rank | Journal title | Countries | Count | IF (2023) | JCR | Total citations |
|---|---|---|---|---|---|---|
| 1 | Cancer epidemiology biomarkers & prevention | USA | 102 | 3.8 | Q2 | 6592 |
| 2 | International journal of cancer | Switzerland | 102 | 6.4 | Q1 | 5004 |
| 3 | Urologic oncology-seminars and original investigations | USA | 66 | 2.7 | Q2 | 1003 |
| 4 | Journal of urology | United States | 65 | 6.6 | Q1 | 2646 |
| 5 | Cancer causes & control | Netherlands | 64 | 2.3 | Q4 | 2666 |
| 6 | Carcinogenesis | England | 59 | 4.7 | Q2 | 4105 |
| 7 | Plos one | USA | 56 | 3.7 | Q2 | 1309 |
| 8 | European urology | Netherlands | 46 | 23.4 | Q1 | 8559 |
| 9 | Bju international | England | 45 | 4.5 | Q1 | 1863 |
| 10 | Urology | USA | 44 | 2.1 | Q3 | 1225 |
Author analysis
Figure 6A, B and Table 4 identified key contributing authors in the field of smoking and bladder cancer research Fig. 6A depicts the co-authorship network among the most prolific authors, while Fig. 6B could illustrate a ranking of authors by total citations within the dataset. Prominent authors included Nathaniel Rothman, who published 44 papers with a total of 1,909 citations, and Debra T. Silverman, who contributed 43 papers with 2,620 citations (Fig. 6A). Other significant contributors included Shahrokh F. Shariat, Nuria Malats, and Margaret R. Karagas, all of whom produced highly cited research that was influential in the academic community (Fig. 6B). Collaboration among these authors was frequent and widespread, indicating the importance of cooperative research in driving advancements. International collaboration was a key feature, enhancing both the breadth and depth of research.
Fig. 6.
Analysis of authors and co-cited authors. A Visualization map of author analysis. B Visualization map of co-cited author analysis. Each node represents an author or co-cited author, with node size indicating their citation count or document volume. Lines between authors represent collaborative relationships
Table 4.
The top 10 authors and the top 10 co-cited authors for cigarette research on bladder cancer development
| Rank | Author | Count | Total citations | Co-cited author |
Total citations |
|---|---|---|---|---|---|
| 1 | Rothman Nathaniel | 44 | 1909 | Zeegers Mpa | 522 |
| 2 | Silverman Debra T | 43 | 2620 | Vineis P | 518 |
| 3 | Shariat Shahrokh F | 41 | 2660 | Jemal A | 421 |
| 4 | Malats Nuria | 35 | 2088 | Hein DW | 328 |
| 5 | Karagas Margaret R | 34 | 1182 | Silverman DT | 325 |
| 6 | Kogevinas Manolis | 33 | 2002 | Michaud DS | 298 |
| 7 | Zeegers Maurice P | 33 | 1120 | Freedman ND | 291 |
| 8 | Lotan Yair | 30 | 4373 | Garcia-closas M | 271 |
| 9 | Wu Xifeng | 28 | 994 | Rink M | 249 |
| 10 | Zhang Zhengdong | 27 | 620 | Parkin DM | 237 |
Keyword analysis
Keyword analysis provided crucial insights into the thematic structure and evolution of research on smoking and bladder cancer from 1999 to 2023. For the keyword co-occurrence network visualized in Fig. 7A, a minimum occurrence threshold of 5 times was applied for each keyword to be included in the analysis. The resulting network analysis identified 10 distinct thematic clusters, indicating the research foci within this domain genetics and molecular epidemiology: Foundational Research on Etiology and Risk. This, the largest cluster, was dominated by foundational keywords such as “bladder cancer”, “smoking”, “risk factor”, “epidemiology”, “carcinogenesis” and “case–control study”. These terms were consistently frequent throughout the study period, underscoring the sustained focus on establishing and understanding the fundamental link between smoking and bladder cancer incidence. Early keywords within this cluster also included “environment”, “air pollution”, “occupation”, and “alcohol drinking”, reflecting initial broader epidemiological investigations into bladder cancer risk factors, before a more concentrated focus on smoking emerged prominently.
Fig. 7.
Keyword visualization and analysis. A Network visualization of keywords using VOSviewer, where node sizes increase with keyword frequency. B The 25 most frequently cited keywords by CiteSpace. The term “strength” refers to the connection intensity between two nodes, as determined by the software
Figure 7B presents the top 25 keywords with the highest occurrence frequency, along with their Average Publication Year (APY), providing a temporal perspective on impactful research topics. Foundational keywords such as “DNA repair” (APY ≈ 2009.83) demonstrated earlier emergence as core topics. In contrast, keywords like “genome-wide association study” (GWAS) (APY ≈ 2011.41), “smoking cessation” (APY ≈ 2011.44), and “neoadjuvant chemotherapy” (APY ≈ 2009.84, note: if this APY is relatively early for a “recent” topic, ensure consistency or re-evaluate its categorization, or it means early pivotal work) have become highly prominent more recently. This temporal distribution highlights a shift from foundational mechanistic and epidemiological understanding towards incorporating advanced genetic association studies and a stronger focus on interventional strategies like smoking cessation and optimizing treatment modalities.
Discussion
General information
This bibliometric analysis has provided a comprehensive, quantitative overview of the global research landscape concerning smoking and bladder cancer from 1999 to 2023. Our findings systematically map publication trends, identify key contributors and collaborative networks, and delineate the evolving thematic structure of this critical research domain. The observed consistent upward trend in both publications and citations (Fig. 2) underscores the sustained and intensifying global research efforts dedicated to understanding the multifaceted impact of smoking on bladder cancer, spanning from fundamental pathogenic mechanisms to clinical management and public health interventions. This discussion will now delve into the implications of our key bibliometric findings, contextualizing them within the existing body of knowledge and highlighting potential avenues for future research.
The impact of smoking on bladder cancer has gained considerable attention in recent years, becoming a major focus of global research efforts. Studies indicate that smoking is a significant risk factor for bladder cancer, with around 50% to 65% of newly diagnosed cases directly associated with smoking. Despite a decline in global smoking rates, the incidence and mortality of bladder cancer have remained relatively stable over the last few decades, potentially due to changes in the concentration and type of carcinogens inhaled by individuals who smokes [11]. Our bibliometric analysis systematically uncovers the current research status and development trends regarding the impact of smoking on bladder cancer, underscoring the need for continued research and provide a scientific foundation for bladder cancer prevention and treatment efforts.
In our bibliometric analysis, the number of research publications on smoking and bladder cancer increased steadily from 2000 to 2023, with a significant rise in research interest over the past decade. This trend indicates sustained focus and active engagement in this field. Our analysis of collaboration networks showed that the United States and China are the leading contributors in this field, with strong collaborations between research institutions and scholars from both countries. Key research institutions include the National Cancer Institute (NCI) in the United States and the Peking University Health Science Center in China, which form important academic networks. Besides, highly cited literature predominantly focuses on the molecular mechanisms of smoking-induced bladder cancer, epidemiological investigations and clinical interventions. These influential studies have significantly shaped the field.
The growth in research output was notably driven by leading countries such as the United States and China, which also demonstrated high H-indices and citation impact (Fig. 3, Table 1). Our analysis of institutional collaborations (Fig. 4, Table 2) further highlighted globally influential entities like the NIH, NCI, and IARC, whose high centrality suggests pivotal roles in fostering international research partnerships. These robust collaborative networks are essential for addressing a complex global health issue like smoking-associated bladder cancer, enabling large-scale epidemiological studies and the dissemination of best practices. The prominence of authors such as Nathaniel Rothman, identified through high productivity and co-citation patterns in our analysis (Fig. 6, Table 4), aligns with their recognized, field-shaping contributions. For instance, Rothman's influential work, frequently appearing among highly cited documents within our dataset, has significantly advanced the understanding of how occupational/environmental carcinogens, genetic susceptibility, and smoking interact in bladder cancer development [12], a theme also reflected in our keyword analysis. Through genome-wide association studies (GWAS), new genetic loci linked to bladder cancer risk were identified, which provided a deeper understanding of how genetic susceptibility and exposure to carcinogens interact in bladder cancer development.
The mechanisms by which smoking contributes to bladder cancer are multifaceted and include harmful chemicals produced by tobacco, such as polycyclic aromatic hydrocarbons (PAHs), nitrosamines and aromatic amines. For example, PAHs are metabolized by cytochrome P450 enzymes, like CYP1A1, into epoxides that react with DNA to form stable adducts, leading to G → T transversion mutations [13]. Nitrosamines, including NNK and NNN, form highly reactive methylation intermediates that bind with DNA, causing base mismatches and DNA strand breaks, ultimately leading to mutations [14, 15]. Aromatic amines such as 4-aminobiphenyl undergo metabolic activation by enzymes like NAT2 and CYP1A2, forming covalent adducts with DNA and leading to damage and mutations [16, 17]. These reactions contribute to the formation of DNA adducts, resulting in gene mutations and chromosomal aberrations [18].
Through GWAS, Rothman and others identified genetic loci that confer increased risk of bladder cancer in individuals who smokes. Key loci include ERCC2, which encodes a protein involved in nucleotide excision repair; the D312N variant of ERCC2 reduces its repair efficiency, increasing susceptibility to bladder cancer [19]. The NBN gene, which encodes the NBS1 protein involved in repairing double-strand DNA breaks, has a variant (E185Q) that significantly reduces repair efficiency and increases bladder cancer risk in individuals who smokes [20]. Similarly, the XPC gene, responsible for DNA damage recognition and repair, has a variant (A499V) that reduces repair efficiency in individuals who smokes [21]. Genetic polymorphisms such as the slow acetylator phenotype of NAT2 and the null variant of GSTM1 also heighten bladder cancer risk due to inefficient metabolism of aromatic amines, resulting in increased DNA damage [22].
Chronic inflammation also plays a major role in smoking-induced bladder cancer. Smoking-induced inflammation in bladder tissue causes cellular damage and increased cell proliferation, contributing to carcinogenesis. Reactive oxygen species (ROS) and other intermediates released during inflammation further damage DNA, leading to mutations and chromosomal aberrations [23]. Smoking generates numerous free radicals, such as hydroxyl radicals, that attack DNA, causing oxidative base modifications like 8-oxoguanine formation, which increases mutation rates [24]. Oxidative stress impairs the cellular antioxidant defense system, leading to increased ROS levels and further DNA damage, ultimately resulting in genetic instability [23].
Preventive measures against smoking
Our bibliometric analysis also captured a significant and growing research focus on preventive measures and public health interventions, as evidenced by the increasing prominence and connectivity of keywords like “smoking cessation” (APY ≈ 2011.44, Fig. 7B) and the development of a distinct'Public Health and Prevention'keyword cluster (Fig. 7A).
This reflects a strong translational research current. Strategies targeting smoking behavior itself are extensively studied within this theme, including pharmacological aids like nicotine replacement therapy, varenicline, and bupropion [25]. Behavioral approaches, including cognitive-behavioral therapy and counseling, have also proven effective [26]. Comprehensive public smoking bans, increased taxation and public awareness campaigns targeting vulnerable groups, such as adolescents, are important public health measures to curb smoking rates [27–29].
Preventive measures against pathogenesis
Beyond primary prevention through smoking cessation, the analyzed literature also delves into secondary preventive measures aimed at mitigating carcinogenic pathways, particularly for individuals struggling to quit or during the cessation process. Although specific compounds might not always emerge as high-frequency individual keywords in a broad bibliometric map, the mechanistic themes identified earlier (e.g., related to CYP450 enzymes, oxidative stress) provide the foundation for these targeted prevention studies. Examples found within these broader thematic clusters include research on inhibiting PAH metabolism using CYP1A1 inhibitors like apigenin [30]. Antioxidants like vitamins C and E help neutralize ROS, reducing oxidative stress [31]. Similarly, inhibitors of CYP2A6 and CYP2A13, such as methoxsalen, can block nitrosamine activation, while PARP inhibitors, like Olaparib, enhance DNA repair capacity by promoting homologous recombination repair [32, 33]. For aromatic amine pathways, caffeine has been shown to inhibit CYP1A2 activity, thereby reducing the formation of harmful metabolites [34]. Moreover, antioxidants like EGCG from green tea and anti-inflammatory agents like curcumin can help counteract the oxidative and inflammatory damage caused by carcinogen metabolism [35].
Preventive measures against specific genetic mutations also show promise. For instance, histone deacetylase (HDAC) inhibitors like Vorinostat have been shown to enhance ERCC2 function, thereby improving DNA repair capacity [36, 37]. Small molecules such as M3814 and resveratrol have also been investigated for their ability to enhance NBN and XPC functions, respectively, providing a basis for reducing cancer susceptibility through genetic modulation [38–40]. To prevent the risks associated with NAT2 and CYP1A2 mutations, caffeine and sodium thiosulfate can be employed to inhibit the activity of CYP1A2, thereby reducing the N-hydroxylation of 4-aminobiphenyl (4-ABP). This results in decreased formation of harmful active intermediates and subsequently lowers the risk of DNA adduct formation, thereby offering protection against bladder cancer development [12].
Counteracting DNA oxidation and inflammation involves the use of compounds such as EGCG and curcumin, which have shown promising effects in reducing oxidative stress and inflammation, both of which contribute significantly to cancer development. EGCG, derived from green tea, acts by donating hydrogen atoms through its phenolic hydroxyl groups to neutralize free radicals, thereby protecting DNA from oxidative damage. On the other hand, curcumin, an active component of turmeric, plays a key role in inhibiting the NF-κB signaling pathway, which leads to a reduction in the release of inflammatory mediators such as TNF-α and IL-6. This suppression of inflammatory pathways ultimately helps to mitigate DNA damage resulting from chronic inflammation and oxidative stress [41]. Looking forward, future research should focus on further elucidating the molecular mechanisms by which smoking induces bladder cancer, particularly in relation to DNA damage repair pathways and gene-environment interactions. Additionally, investigating the long-term effects of smoking cessation on bladder cancer prognosis, strengthening epidemiological studies across diverse populations, and applying advanced molecular biology techniques for early detection and prevention strategies are critical research directions.
Limitations
This study has several limitations. Firstly, our reliance solely on the Web of Science Core Collection (WoSCC) may have excluded relevant publications found in other databases (e.g., Scopus, PubMed/MEDLINE), potentially impacting the overall comprehensiveness of the literature covered. Future studies could benefit from a multi-database approach. Secondly, publications towards the end of our study period (1999–2023) may have insufficient accumulated citations, potentially underrepresenting their emerging impact in citation-based analyses. Finally, inherent limitations of bibliometric analysis mean that quantitative metrics like publication volume and citation counts do not fully capture the nuanced scientific value, novelty, or specific impact of individual studies, which would necessitate qualitative content review.
Conclusion
In conclusion, this bibliometric analysis of 2,802 publications from 1999 to 2023 provides a quantitative and visual map of the research landscape on smoking and bladder cancer. It highlights sustained research growth, key global players and collaborative networks, and a thematic evolution from foundational etiological and mechanistic studies towards integrating advanced genetic insights and a stronger focus on prevention and smoking cessation.
Authors’ contributions
YW, HZ and ZT conceived the study. YH and HZ collected the data and wrote the manuscript. ZH, YH, HZ and JK revised and reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the National Natural Science Foundation of China (82203720, 82203188, 82002682, 81972731, 81773026, 81972383), the Guangzhou Municipal Basic Research Program Jointly Funded by City, University, and Enterprise Special Project (2024A03J0907) and the Natural Science Foundation of Guangdong Province (2024A1515013201).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This study did not involve any experiments on humans or animals, and thus, ethical approval was not required.
Consent for publications
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yang Wang, Hancheng Zhou and Zhicheng Tang contributed equally to this work and share first authorship.
Hui Zhuo, Yi Huang and Jianqiu Kong contributed equally to this work and share corresponding authorship.
References
- 1.van Hoogstraten LMC, Vrieling A, van der Heijden AG, Kogevinas M, Richters A, Kiemeney LA. Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice. Nat Rev Clin Oncol. 2023;20(5):287–304. [DOI] [PubMed] [Google Scholar]
- 2.Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. [DOI] [PubMed] [Google Scholar]
- 3.Leal J, Luengo-Fernandez R, Sullivan R, Witjes JA. Economic Burden of Bladder Cancer Across the European Union. Eur Urol. 2016;69(3):438–47. [DOI] [PubMed] [Google Scholar]
- 4.Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306(7):737–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, Kassouf W, Kiemeney LA, La Vecchia C, Shariat S, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234–41. [DOI] [PubMed] [Google Scholar]
- 6.Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, Hernández V, Kaasinen E, Palou J, Rouprêt M, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017;71(3):447–61. [DOI] [PubMed] [Google Scholar]
- 7.Bjurlin MA, Matulewicz RS, Roberts TR, Dearing BA, Schatz D, Sherman S, Gordon T, Shahawy OE. Carcinogen Biomarkers in the Urine of Electronic Cigarette Users and Implications for the Development of Bladder Cancer: A Systematic Review. Eur Urol. 2021;4(5):766–83. [DOI] [PubMed] [Google Scholar]
- 8.Feng L, Huang G, Peng L, Liang R, Deng D, Zhang S, Li G, Wu S. Comparison of bladder carcinogenesis biomarkers in the urine of traditional cigarette users and e-cigarette users. Front Public Health. 2024;12:1385628. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ninkov A, Frank JR, Maggio LA. Bibliometrics: Methods for studying academic publishing. Perspect Med Educ. 2022;11(3):173–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Wang X, Li X, Dong T, Yu W, Jia Z, Hou Y, Yang J, Liu Y. Global biomarker trends in triple-negative breast cancer research: a bibliometric analysis. Int J Surg. 2024;110(12):7962–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. [DOI] [PubMed] [Google Scholar]
- 12.Koutros S, Kiemeney LA, Pal Choudhury P, Milne RL, de Lopez Maturana E, Ye Y, Joseph V, Florez-Vargas O, Dyrskjøt L, Figueroa J, et al. Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights. Eur Urol. 2023;84(1):127–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Ding J-q, Wang X-m. Chander S, Li J-s: Identification of QTL for maize resistance to common smut by using recombinant inbred lines developed from the Chinese hybrid Yuyu22. J Appl Genet. 2008;49(2):147–54. [DOI] [PubMed] [Google Scholar]
- 14.Xue J, Yang S, Seng S. Mechanisms of Cancer Induction by Tobacco-Specific NNK and NNN. Cancers (Basel). 2014;6(2):1138–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Guo Z, Smith TJ, Ishizaki H, Yang CS. Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cytochrome P450IIB1 in a reconstituted system. Carcinogenesis. 1991;12(12):2277–82. [DOI] [PubMed] [Google Scholar]
- 16.Guo Z, Smith TJ, Thomas PE, Yang CS. Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by inducible and constitutive cytochrome P450 enzymes in rats. Arch Biochem Biophys. 1992;298(1):279–86. [DOI] [PubMed] [Google Scholar]
- 17.Hecht SS. Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol. 1998;11(6):559–603. [DOI] [PubMed] [Google Scholar]
- 18.Tomimatsu N, Mukherjee B, Catherine Hardebeck M, Ilcheva M, Vanessa Camacho C, Louise Harris J, Porteus M, Llorente B, Khanna KK, Burma S. Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nat Commun. 2014;5(1):3561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X, Figueroa JD, Real FX, Van Den Berg D, Matullo G, Baris D, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42(11):978–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lu M, Lu J, Yang X, Yang M, Tan H, Yun B, Shi L. Association between the NBS1 E185Q polymorphism and cancer risk: a meta-analysis. BMC Cancer. 2009;9:124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Stern MC, Lin J, Figueroa JD, Kelsey KT, Kiltie AE, Yuan JM, Matullo G, Fletcher T, Benhamou S, Taylor JA, et al. Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international consortium of bladder cancer. Cancer Res. 2009;69(17):6857–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.García-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, Tardón A, Serra C, Carrato A, García-Closas R, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet. 2005;366(9486):649–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Valavanidis A, Vlachogianni T, Fiotakis K, Loridas S. Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms. Int J Environ Res Public Health. 2013;10(9):3886–907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Chiorcea-Paquim AM: 8-oxoguanine and 8-oxodeoxyguanosine Biomarkers of Oxidative DNA Damage: A Review on HPLC-ECD Determination. Molecules 2022;1;27(5):1620 [DOI] [PMC free article] [PubMed]
- 25.Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2012;4:Cd006103. [DOI] [PubMed] [Google Scholar]
- 26.Japuntich SJ, Lee LO, Pineles SL, Gregor K, Joos CM, Patton SC, Krishnan-Sarin S, Rasmusson AM. Contingency management and cognitive behavioral therapy for trauma-exposed smokers with and without posttraumatic stress disorder. Addict Behav. 2019;90:136–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Tan CE, Glantz SA. Association between smoke-free legislation and hospitalizations for cardiac, cerebrovascular, and respiratory diseases: a meta-analysis. Circulation. 2012;126(18):2177–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Chaloupka FJ, Yurekli A, Fong GT. Tobacco taxes as a tobacco control strategy. Tob Control. 2012;21(2):172–80. [DOI] [PubMed] [Google Scholar]
- 29.Wakefield MA, Loken B, Hornik RC. Use of mass media campaigns to change health behaviour. Lancet. 2010;376(9748):1261–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Williams PA, Cosme J, Sridhar V, Johnson EF, McRee DE. Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. Mol Cell. 2000;5(1):121–31. [DOI] [PubMed] [Google Scholar]
- 31.Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med. 2011;51(5):1000–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Yano JK, Hsu M-H, Griffin KJ, Stout CD, Johnson EF. Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat Struct Mol Biol. 2005;12(9):822–3. [DOI] [PubMed] [Google Scholar]
- 33.Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N Engl J Med. 2012;366(15):1382–92. [DOI] [PubMed] [Google Scholar]
- 34.Zhou SF, Wang B, Yang LP, Liu JP. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev. 2010;42(2):268–354. [DOI] [PubMed] [Google Scholar]
- 35.Yang CS, Wang H, Li GX, Yang Z, Guan F, Jin H. Cancer prevention by tea: Evidence from laboratory studies. Pharmacol Res. 2011;64(2):113–22. [DOI] [PubMed] [Google Scholar]
- 36.Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006;5(1):37–50. [DOI] [PubMed] [Google Scholar]
- 37.Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5(9):769–84. [DOI] [PubMed] [Google Scholar]
- 38.Khan O, La Thangue NB. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol. 2012;90(1):85–94. [DOI] [PubMed] [Google Scholar]
- 39.Gordhandas SB, Manning-Geist B, Henson C, Iyer G, Gardner GJ, Sonoda Y, Moore KN, Aghajanian C, Chui MH, Grisham RN: Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer. Sci Rep 2022;19;12(1):974 [DOI] [PMC free article] [PubMed]
- 40.Liu Y, Han X, Yuan J, Geng T, Chen S, Hu X, Cui IH, Cui H. Biallelic insertion of a transcriptional terminator via the CRISPR/Cas9 system efficiently silences expression of protein-coding and non-coding RNA genes. J Biol Chem. 2017;292(14):5624–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41(1):40–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.