Prerpints.org logo
Preprint
Review

The Influence of Microbiome on Urological Malignancies: A Systematic Review

Altmetrics

Downloads

97

Views

42

Comments

0

A peer-reviewed article of this preprint also exists.

supplementary.docx (57.59KB )

Submitted:

15 September 2023

Posted:

18 September 2023

You are already at the latest version

Alerts
Abstract
The microbiome, once considered peripheral, is emerging as a relevant player in the intricate web of factors contributing to cancer development and progression. These often overlooked microorganisms, in the context of urological malignancies, have been investigated primarily focusing on the gut microbiome, while exploration of urogenital microorganisms remains limited. In light of this, our systematic review delves into the complex role of these understudied actors in various neoplastic conditions, including prostate, bladder, kidney, penile, and testicular cancers. Our analysis found a total of 37 studies, with prostate cancer-12, bladder cancer-20, kidney cancer-4, penile/testicular cancer-1, which reveals distinct associations specific to each condition, hinting at potential therapeutic avenues and future biomarker discoveries. It becomes evident that further research is imperative to unravel the complexities of this domain and provide a more comprehensive understanding.
Keywords: 
Subject: Medicine and Pharmacology  -   Urology and Nephrology

1. Introduction

Defining the term “microbiome” is complex due to the intricate relationships within microbial communities and their host organisms. Over time, numerous definitions have emerged, with some focusing on the community of microorganisms, others emphasizing their collective genomes, or others yet looking at the broader ecological context including biotic and abiotic conditions. Despite the varying definitions, it is essential to view the microbiome as a dynamic ecosystem, highlighting the interconnections among microorganisms and their environment [1]. Extensive exploration of the role of the microbiome in cancer evolution has demonstrated that while the microbiome can affect cancer cells themselves, it can also modulate the cancer immunosurveillance [2].
Cancer has an immense impact on international health and lifespan. An extensive analysis of cancer prevalence and mortality data from GLOBOCAN, encompassing 185 nations and 36 distinct types of cancer, estimated that in 2020, there were approximately 19.3 million cases of cancer and nearly 10 million deaths worldwide due to the disease. Alarming projections indicate that the worldwide toll of cancer is anticipated to rise to 28.4 million incidences by the year 2040 [3].
Worldwide in 2018, approximately 2.2 million cancer diagnoses were linked to infections. Moreover, it is believed that nearly one-fifth of all human cancers could possibly result from infectious pathogens [4].
The human microbiome, an expansive network of often overlooked organisms, plays a crucial role in our health and wellbeing. Individual differences in these microbiomes result in a distinctive, ever-changing microbial fingerprint [5]. These microbes have demonstrated various functions, including metabolism, local and systemic inflammation, and immunity. Many studies have pinpointed discrepancies in microbial fingerprints between healthy individuals and patients with urological malignancies. Such microbiomes have been found to host microbes that might contribute to the development of disease and provide insights about a person’s health and response to specific drugs, such as immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs).

2. Materials and Methods

On March 28th, 2023, we conducted a comprehensive literature search of Ovid MEDLINE using the following keywords: “microbiota” AND “prostate cancer,” “microbiota” AND “bladder cancer,” “microbiota” AND “renal cancer,” “microbiota” AND “testicular cancer,” and “microbiota” AND “penis cancer.” The aim of the search was to identify relevant clinical microbiome studies associated with noninfectious malignant urological conditions that were published between 2013 and 2023.
The inclusion criteria for the purposes of this review included: all studies had to (i) be solely focused on assessing the relationships between the urine microbiome and non-infectious neoplastic urologic diseases; (ii) use human clinical samples; (iii) perform 16S ribosomal RNA (rRNA) gene sequencing thorough PCR, or next generation sequencing (NGS); and (v) be written in English.
This systematic review strictly adhered to the PRISMA framework (Figure 1). Initially, after removing duplicate entries, a thorough evaluation of search results was carried out independently by three reviewers (BP, JGP, and MCS), who screened titles and abstracts for relevance. Following this, the chosen set of studies underwent a second screening process based on the full-text articles. Exclusions were made for review articles, editorials, comments, systematic reviews, or conference abstracts lacking complete data. Additionally, studies involving gut microbiome, animal subjects, or in vitro experiments were also excluded. Since this study only utilized publicly available unidentified data from known publications, institutional review board approval or patient consent were not required.
In case of any disagreements during the review process, a third member (HS) was consulted, and a consensus was diligently reached. In total, our analysis identified 37 studies that met the specified criteria and aligned seamlessly with the focus of our research. These studies were meticulously categorized into four distinct groups: prostate cancer-12, bladder cancer-20, kidney cancer-4, and penis/testicular cancer-1, ensuring a structured approach to our findings.

3. Discussion

3.1. Prostate Cancer

Prostate cancer (PCa), resulting in over 250,000 deaths worldwide annually, represents the prevailing form of nonskin malignancy and stands as the 6th foremost contributor to cancer-related fatalities in men, thereby engendering significant apprehension within the realm of public health [6,7]. Recent insights have increasingly implicated chronic inflammation as a crucial factor in the pathogenesis of PCa [8]. Given the well-established role of microorganisms in provoking prostatic inflammation, the question of whether a correlation exists between the microbiome and PCa has emerged [8,9].
The gastrointestinal microbiome stands as one of the extensively investigated human microbiomes within the academic medical sphere. Numerous studies have delved into its potential correlation with PCa pathogenesis, treatment response, and prognosis [10,11,12]. However, recent attention has shifted towards other microbiotas, such as the urinary microbiome, as the prostate-urine loop has exhibited promising outcomes. For instance, Alanee et al. reported that individuals diagnosed with PCa exhibiting similar bacterial communities that clustered separately from those without cancer [13]. Additionally, it was observed that patients with PCa exhibited a significantly lower urinary alpha-diversity in comparison to individuals without malignancy. Notably, patients with Gleason 7 displayed a distinct urinary microbiome profile when contrasted with men who did not have tumor. Conversely, fecal samples did not demonstrate any clustering or significant disparity in alpha-diversity or Gleason staging concerning benign or malignant prostate biopsies [13].
Similarly, in a case-control study comparing men with benign and malignant prostate biopsies, noteworthy findings emerged. The study revealed that biopsies containing a higher degree of cancer exhibited a distinct urinary cluster of bacteria, including Streptococcus anginosus, Anaerococcus lactolyticus, Anaerococcus obesiensis, Actinobaculum schaalii, Varibaculum cambriense, and Propionimicrobium lymphophilum [14]. Nonetheless, no significant differences were found in the urinary alpha- or beta-diversity between the cases and controls. Furthermore, there was no disparity detected in the relative abundance of Propionibacterium acnes, a species previously associated with PCa [9,14].
Interestingly, a study that evaluated urine samples after digital rectal exam and prostatic secretions after prostatectomy found five genera of strict anaerobes (Fenollaria, Peptoniphilus, Anaerococcus, Porphyromonas, and Fusobacterium) that could serve as a urinary biomarker due to its association with PCa aggressiveness and biochemical recurrence [6], highlighting the great potential that the urinary microbiome could play in PCa diagnosis, staging and even prognosis.
While bacteria are the most frequently detected germ in the human microbiome, investigations in the context of PCa have unveiled the presence of viruses, fungi, and even protozoa. For example, Xu et al. discovered that in the plasma microbiome of men with PCa, the beta-diversity of the circulating fungal microbiome exhibited notable distinctions when compared to age- and race-matched healthy controls [15]. Moreover, their findings highlighted a significant enrichment of class Sordariomycetes among PCa patients with advanced pathological grades (pT3 or pT4) [15]. Banerjee et al. also reported a distinguished fungal microbiome when comparing prostate specimens of patients with benign prostatic hyperplasia (BPH) and PCa, founding that the majority of the fungal signatures in PCa arose from the division Ascomycota (61%) [16]. Remarkably, the researchers also observed distinct viral compositions among the groups under investigation. However, what proved to be particularly intriguing was their ability to identify the integration of viral and microbial DNA into human chromosomes [16]. The study revealed a significant number of genomic integration sites, with HPV18 exhibiting the highest count, followed by KSHV and HPV2. It is worth noting that these viruses have been previously linked to tumorigenesis [16].
A study conducted with a similar objective, comparing the microbiome in biopsies from men diagnosed with BPH and PCa, revealed a high prevalence of tumorigenic viruses, such as HVP and HBV, in the PCa specimens. Furthermore, a robust association was established between the presence of these viruses and the elevated abundance of two distinct bacterial species, Cupriavidus taiwanensis and Methylobacterium organophilum, within diseased prostate lesions [7]. The notable prevalence of these tumorigenic viruses raises the question of whether there is an association between sexually transmitted infections and the inflammatory environment that contributes to prostate carcinogenesis. Miyake et al. elegantly answered this question by screening surgical and biopsy specimens from 45 patients with PCa (cases) and 33 patient with BPH (controls) against a panel of sexually transmitted infection-related organisms [17]. They found that among the tested organisms, Mycoplasma genitalium was significantly more prevalent in the PCa group and was associated with the extensiveness of the diseases. Nonetheless, it is important to note that no significant association was found between Mycoplasma genitalium and the grade of intraprostatic inflammation [17].
Another intriguing aspect that envelops PCa and the microbiome pertains to whether the observed variations in incidence across races and geographical locations correspond to disparities in the microbiome composition. A study comparing fresh prostate biopsies from age-matched Africans and Australians reported that the overall bacterial composition was similar between groups, with the most abundant genera being Escherichia, Propionibacterium, and Pseudomonas [18]. A significantly higher bacterial richness was observed in the African group, suggesting that bacterially-driven oncogenic transformation within the prostate microenvironment may contribute to the aggressive disease presentation commonly observed in Africans [18].
Interestingly, a parallel study conducted in a Chinese population revealed comparable findings, with Escherichia, Propionibacterium, and Pseudomonas emerging as the most abundant genera within the prostate [19]. Furthermore, they reported no discernible differences in alpha-diversity or relative abundances between the tumor and adjacent benign prostate tissue. Consequently, no definitive association could be established between the microbiome and Gleason stage or PSA level [19]. Likewise, a study examining prostate cancer tumor, peri-tumor, and non-tumor tissues in white Caucasian, nondiabetic, nonobese PCa patients yielded analogous results [20]. These findings underscore the need for further investigations to elucidate the intricate interplay between the microbiome, prostate cancer, race, and geographical location. Additional studies are necessary to consolidate and strengthen the existing body of evidence.
As previously stated, PCa showcases a distinctive microbial signature within the urine, plasma, and prostate microbiotas. Even, PCa has demonstrated variations in terms of alpha-diversity, beta-diversity, and species composition when compared to other genitourinary malignancies, such as bladder and kidney cancer [21]. The unique microbiome alterations associated with it have also been implicated in metagenomic and metabolic changes, that have even been linked with modifications in inflammatory responses [22]. It is important to acknowledge the inherent challenges in generalizing results due to the considerable inter- and intra-variability of the microbiome. However, the observed associations between PCa and the microbiome serve as compelling impetus to further advance research in this field. By doing so, we may eventually harness the potential of the microbiome as a diagnostic, prognostic, and therapeutic tool.

3.2. Bladder Cancer

In 2020, there were a total of 573,278 new urothelial bladder carcinoma cases and 212,536 deaths positioning it as the 10th most common form of cancer diagnosed globally [23]. The bladder was previously thought to be a sterile environment, but emerging research has revealed the presence of a distinct microbial community, known as the bladder microbiome [24].
Several studies have reported dysbiotic changes in the bladder microbiome of bladder cancer individuals. These changes are characterized by a decrease in microbial diversity and alterations in the abundance of specific bacterial taxa. It was found that patients with bladder cancer had lower alpha-diversity than non-cancer patients controls [25,26,27]. Ma et al. stated that smoking is one of the main factors affecting the urinary tract microbial composition on a beta diversity analysis. Describing the top five species in smokers were Bacteroidetes, Bacteroides, Bacteroidales, Clostridia, and Clostridiales [28]. In addition to the identification of specific biomarkers in the bladder, the microbiome may have diagnostic and prognostic implications for bladder cancer. Studies have shown the potential of microbial signatures as non-invasive biomarkers for early detection and monitoring of bladder cancer. It is well known that infections caused by Schistosoma haematobium, a species of parasitic blood flukes are associated with the development of squamous cell carcinoma of the bladder due to chronic inflammation [29]. Schistosomiasis progression has also been associated with other organisms like Fusobacterium, Sphingobacterium, Bacterioides, and Enterococcus, known as mediators of inflammatory and immunologic reactions [30].
Although the genitourinary microbiome has a possible role in bladder cancer progression, it also has a role in treatment. The Bacillus Calmette–Guerin (BCG) vaccine, known to prevent disseminated tuberculosis, has been used as the standard first-line therapy for high-grade NMBIC [24]. This vaccine is identified as a Mycobacterium, an Actinomycete that activates the immune system as well as reacting to the tumor cells, causing apoptosis, necrosis, and oxidative stress [31]. A study showed a significantly higher abundance of Actinobacteria in non-neoplastic bladder mucosa samples than in tumor tissues. Supporting the hypothesis that microbiota rich in Actinomycetes are related to the lower incidence of bladder cancer in women and, therefore, may have a preventive effect against this type of cancer [32].
Comparative analysis of the bladder microbiome between cancer patients and control has also provided important insight into how diverse the bacterial species are and how they are related to the progression of cancer. In a study done in the Czech Republic, collecting and comparing urine samples of 34 men with bladder cancer and 29 control patients, describing bladder cancer patients at the phylum level, Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes were the most predominant [25]. Mansour et al. described a median abundance of Cyanobacteria, Staphylococcus, and Corynebacterium as well as the previously mentioned microbial groups. Similar findings were noted in two studies from Spain and United States of America, Parra-Grande et al. and Zeng et al., respectively [32,33]. Likewise, some studies reported a high abundance of the following phylum: Bacteroides, Faecalibacterium, Bacilliales, Clostridium, and Actinobacteria, and at genus level: Streptococcus, Lactobacillus, and Prevotella [26,34,35,36]. Interestingly, there is an association between the increased abundance of Fusobacterium and reduced levels of Lactobacillus with bladder cancer [29]. Bučević et al. state that Fusobacterium nucleatum may be a pro-tumorigenic pathogen based on their findings in 11 out of 42 patients [34].
Compositionally, Perdezoli et al. found the urinary microbiome was dominated by the members of the three major bacterial phyla: Proteobacteria, Firmicutes, and Bacteroidetes, which accounted for 80% in males and 90% in females of all identified taxa [37]. Highlighting the order Opitutales and subordinate family Opitutaceae, together with the isolated class Acidobacteria in men; and the genus Klebsiella in females, with the family Enterobacteriaceae. Another finding was the higher abundance of the genus Burkholderia in both male and female tissues strongly suggesting an association with bladder cancer [37].
The microbiome composition presented significant differences according to the tumor tissue and its grade. Comparing MIBC and NMIBC, both groups presented Firmicutes, Proteobacteria, Actinobacteria, and Fusobacterium as the main phylum level [34,38]. Hussein et al. studied 42 patients with bladder cancer (MBIC 14 and NMIBC 29) finding that Haemophilus and Veillonella were significantly more abundant in the urine of MIBC patients, while Cupriavidus was present in NMIBC patients; when subclassified by sex, they found: Actinobacteria predominantly in men and Bacteriodetes in females [39]. Another study with 899 patients from China, found that Eubacterium CAG-581, Bacteroides sp 43-47FAA, and Flavobacteriales were predominant in the NMIBC group, reflecting a strong association with decreased survival rate and comparing NMIBC patients who responded to BCG and those who did not, Serratia and Brochothrix, Negativicoccus, Escherichia-Shigella, and Pseudomonas were significantly more abundant in the respondent group [39,40].
It has also been described that microbiota may upregulate PD-L1 expression in epithelial tumors promoting an immune escape [41]. Chen et al. stated that the rates of recurrence and progression of NMIB are higher in PD-L1 positive patients rather than in PD-L1 negative patients. They found that PD-L1 positive patients with NMIBC had abundant Leptotrichia which is closely related to Fusobacterium, previously described as a pro-tumorigenic pathogen. On the other hand, Prevotella was abundant in PD-L1 negative patients with NMIBC [42].
Further research is needed to elucidate the complex relationship between the bladder microbiome and bladder cancer. Longitudinal studies, functional characterization of microbial communities, and investigation of host-microbe interactions will contribute to a deeper understanding of the role of the bladder microbiome in disease development and treatment.

3.3. Kidney Cancer

Kidney cancer is ranked as the 14th most prevalent neoplasia on a global scale, with an incidence rate of 4.5 cases per 100,000 individuals [3,43]. Renal cell carcinoma (RCC) most commonly encompasses the primary subtypes of clear cell (ccRCC), papillary, and chromophobe [44]. Generally, risk factors associated with this ailment include smoking, obesity, and hypertension [45]. While research on the impact of microbiomes on this condition remains limited, most studies focus on the gut microbiota [46,47,48,49,50,51,52,53,54,55]. It is widely recognized that gastrointestinal conditions influence the kidney, and investigating the gut microbiome offers advantages due to the relatively accessible nature of this microbiome compared to the kidney itself, facilitating sample collection and analysis. However, emerging studies on the kidney microbiome itself hold promise for providing further insights into kidney cancer and its associated conditions.
Three studies investigated retrospectively the role of the microbiome in RCC by examining mainly tumorous kidney tissue and adjacent normal tissue (ANT). These studies utilized 16S rRNA sequencing as a method to extract bacterial DNA. In a pilot study conducted by Heidler et al., five patients with renal cancer (including four with RCC and one with chromophobic cell carcinoma) who underwent radical nephrectomy were assessed [56]. A significant difference in microorganisms between the malignant and benign tissue, with the malignant tissue exhibiting more diversity. Another study by Wang et al., involving 24 RCC patients, also revealed a distinct composition of the bacterial community in RCC and normal tissues [57]. However, the authors found a decrease in species diversity within the RCC tissue. Both studies reached a consensus that Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria were the predominant phyla in both cancerous and non-cancerous renal tissues. Additionally, both studies identified the bacterial family Comamonadaceae as significantly more abundant in the control group [56,57].
Furthermore, Wang et al. highlighted the accuracy of prediction of RCC of certain microbiomes, in which high accuracy was found for the class Chloroplast and the order Streptophyta, while moderate accuracy for Deinococcus and Phyllobacterium [57]. These findings indicate potential for utilizing the microbiome as a reliable biomarker in various areas such as treatment response monitoring, early detection, and prognostic assessment. Additionally, the assessment of tumor grade in neoplasia revealed an interesting trend [57]. It was observed that there is a decreasing trend in microbiota richness as the tumor grade increases. Moreover, it was found that Rhodoplanes were significantly more abundant in grade I RCC samples compared to grade II samples. These findings provide valuable insights into potential utilization of microbiome as risk stratification tool.
Microbiome-mediated modulation may impact diverse cellular processes and metabolic activities, potentially influencing cancer development and progression. Wang et al. investigated this relationship between the microbiome and RCC to comprehend the immune response within the tumor microenvironment [57]. In malignant tissues, they identified alterations in pathways related to membrane transport, transcription, and cell growth and death, while in ANT tissues, the affected pathways were cell motility, signal transduction, metabolism, metabolism of cofactors and vitamins, energy metabolism, and the endocrine system. Further investigations into the specific mechanisms underlying these alterations could offer promising insights into novel therapeutic approaches targeting the microbiome to modulate immune responses and improve patient outcomes in kidney cancer.
Given the significant roles that various receptors play in the development, progression, and targeted treatment of RCC, it is imperative to comprehend the association between the microbiome and these pertinent receptors. Liss et al. conducted a study to investigate the interaction between the microbiome and PD-L1 receptor expression in relation to venous tumor thrombus (TT) in six patients with ccRCC [58]. The study involved analyzing three samples: tumor, ANT, and TT. The findings revealed a greater diversity of microbiota in the renal tumor tissue compared to ANT and TT. Specifically, they identified Micrococcus luteus, Fusobacterium nucleatum, Streptococcus agalactieae, and Corynebacterium diphtheriae in the tumor microbiome. Moreover, the authors discovered a correlation between the presence of aggregated oral microbiome within primary renal cancer tumors and its potential interaction with the tumor microenvironment. Patients with oral microbiome aggregation within the tumor exhibited higher expression of PD-L1 receptor within the TT. On the other hand, in a study conducted by Najm et al., the expression of the SUCNR1 receptor and its impact on ccRCC and papillary RCC were investigated using the cBioPortal platform [59,60,61,62,63]. The findings revealed that SUCNR1 receptor is associated with distinct microbiome signatures in each RCC subtype, leading to different disease-specific survival predictions. Specifically, in ccRCC, high SUCNR1 receptor expression along with the presence of Candidatus nitrosopelagicus and Indibacter bacteria correlated with better survival outcomes. Conversely, the presence of Anoxybacillus and Selenomonas bacteria, along with low SUCNR1 receptor expression, was associated with poor disease-specific survival in ccRCC. In papillary RCC, high SUCNR1 receptor expression correlated with the presence of Apibacter bacteria, which was linked to a worse prognosis. Notably, the study highlights the importance of understanding these microbiome profiles and their relationship with SUCNR1 receptor expression in guiding future targeted therapies for improved patient selection and outcomes.

3.4. Penile Cancer

When it comes to the male genital organ and microbiome context, the existing literature focuses on circumcision and/or sexually transmitted diseases [64,65,66]. There is a notable absence of studies exploring the connection between the penile microbiome and penile cancer. Investigating the penile microbiome and its potential impact on penile cancer could provide valuable insights and benefits.

3.5. Testicular Cancer

Testicular cancer, although rare with a global incidence rate of 0.4%, is the most common malignancy in young men [3,67]. Previous studies have explored microbiome of seminal plasma and testicular tissue in benign conditions, revealing the presence of Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria as the most commonly found phyla [68,69]. However, only one study has specifically investigated microbiomes in the context of testicular cancer. Mørup et al. used small RNA sequencing to analyze seminal plasma samples from patients with testicular germ cell tumors (TGCT) and germ cell neoplasia in situ (GCNIS) [70]. Overall, the most prevalent microbiomes in the study were Alteromonas mediterranea, Falconid herpesvirus 1, and Stigmatella aurantiaca. When assessing association with TGCT/GCNIS or GCNIS-only, the authors identified Acaryochloris marina, Halovirus HGTV-1, Thermaerobacter marianensis, Thioalkalivibrio sp. K90mix, Burkholderia sp. YI23, and Desulfurivibrio alkaliphilus as the most common microorganisms. Conversely, Streptomyces phage VWB was significantly associated with subjects without malignancy. Moreover, after a comparison between seminoma and non-seminoma patients, no significant differences were observed in terms of microbiome composition.
The use of seminal plasma in testicular cancer research offers several advantages. It is a non-invasive and accessible sampling method, often collected as part of routine fertility testing or semen analysis. By analyzing the seminal plasma microbiome, valuable insights into the local microenvironment of the male reproductive system are provided. This approach holds potential for diagnostic value, as it may help identify biomarkers or specific microbial signatures associated with the disease. Such findings could contribute to the development of non-invasive screening methods and improved diagnostic tools. However, further studies are necessary to compare the microbiomes of malignant and benign testicular tissue and to investigate the relationship between the testicular and seminal plasma microbiomes. Additionally, exploring the microbiome of seminal vesicles could provide additional insights into the microbiome dynamics in this field.

4. Future Directions

Scientific understanding within the sphere of the urogenital microbiome and its association with malignant urological conditions is currently in an evolving phase, with limited concrete clinical insights to date. While the forefront of microbiome research has predominantly centered on the gut microbiome, it is reasonable to anticipate that similar valuable discoveries will emerge within the urogenital microbiome domain. Advancements in methodologies for assessing and gathering urogenital microbiome data are imperative to unlock this potential and pave the way for future insights. There is potential for microbiome-focused interventions to offer hope for presently unexplained medical conditions. Conducting long-term studies to track changes in the urinary microbiome over time can offer valuable insights into the development and resolution of diseases, leading to substantial advancements in clinical practice.

5. Conclusions

The microbiome in urological oncology offers a glimpse into a future where personalized medicine harnesses the power of microbiota as diagnostic tools, prognostic indicators, and even therapeutic targets. However, it is clear that we are only scratching the surface, and future investigations are essential to unlock the full potential of the urogenital microbiome in transforming the landscape of urological oncology. With continued research and advancements in methodologies, we stand poised to uncover new insights, enhance patient care, and ultimately improve outcomes for those affected by malignancies.

Author Contributions

Conceptualization, J.G.P., M.C.S, A.K, and H.N.S; methodology, J.G.P., M.C.S, B.P., A.K, and A.M.; investigation, J.G.P., M.C.S, B.P., and A.K ; writing—original draft preparation, J.G.P., M.C.S, B.P., A.K, A.M., B.N, S.P, C.R.R, M.L.G., D.J.P., R.M., and H.N.S.; writing—review and editing, J.G.P., M.C.S, B.P., A.K, A.M., B.N, S.P, C.R.R, M.L.G., D.J.P., R.M., and H.N.S.; supervision, A.K, A.M., B.N, S.P, C.R.R, M.L.G., D.J.P., R.M., and H.N.S.; project administration, M.C.S, A.K, and A.M.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lederberg, J.; McCray, A.T. Ome Sweet ’Omics-A Genealogical Treasury of Words. The Scientist 2001, vol.15, pp.8.
  2. Jain, T.; Sharma, P.; Are, A.C.; Vickers, S.M.; Dudeja, V. New Insights Into the Cancer–Microbiome–Immune Axis: Decrypting a Decade of Discoveries. Front. Immunol. 2021, vol. 12, pp. 622064. [CrossRef]
  3. Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J Clin 2021, vol. 71, pp. 209–249. [CrossRef]
  4. Howley, P.M. Gordon Wilson Lecture: Infectious Disease Causes of Cancer: Opportunities for Prevention and Treatment. Trans Am Clin Climatol Assoc 2015, vol. 126, pp. 117–132.
  5. Franzosa, E.A. et al. Identifying personal microbiomes using metagenomic codes. Proc. Natl. Acad. Sci. U.S.A. 2015, vol. 112. [CrossRef]
  6. Hurst, R. et al. Microbiomes of Urine and the Prostate Are Linked to Human Prostate Cancer Risk Groups. European Urology Oncology 2022, vol. 5, pp. 412–419. [CrossRef]
  7. Sarkar, P. et al. Differential Microbial Signature Associated With Benign Prostatic Hyperplasia and Prostate Cancer. Front. Cell. Infect. Microbiol. 2022, vol. 12, p. 894777. [CrossRef]
  8. Sfanos, K.S.; Yegnasubramanian, S.; Nelson, W.G.; De Marzo, A.M. The inflammatory microenvironment and microbiome in prostate cancer development. Nat Rev Urol 2018, vol. 15, pp. 11–24. [CrossRef]
  9. Cohen, R.J.; Shannon, B.A.; McNeal, J.E.; Shannon, T.; Garrett, K.L. Propionibacterium acnes associated with inflammation in radical prostatectomy specimens: a possible link to cancer evolution? Journal of Urology 2005, vol. 173, pp. 1969–1974. [CrossRef]
  10. Golombos, D.M. et al. The Role of Gut Microbiome in the Pathogenesis of Prostate Cancer: A Prospective, Pilot Study. Urology 2018, vol. 111, pp. 122–128. [CrossRef]
  11. Peiffer, L.B. et al. Composition of gastrointestinal microbiota in association with treatment response in individuals with metastatic castrate resistant prostate cancer progressing on enzalutamide and initiating treatment with anti-PD-1 (pembrolizumab). Neoplasia 2022, vol. 32, p. 100822. [CrossRef]
  12. Matsushita, M. et al. The gut microbiota associated with high-Gleason prostate cancer. Cancer Science 2021, vol. 112, pp. 3125–3135. [CrossRef]
  13. Alanee, S. et al. A prospective study to examine the association of the urinary and fecal microbiota with prostate cancer diagnosis after transrectal biopsy of the prostate using 16sRNA gene analysis. Prostate 2019, vol. 79, pp. 81–87. [CrossRef]
  14. Shrestha, E. et al. Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer. Journal of Urology 2018, vol. 199, pp. 161–171. [CrossRef]
  15. Wang, X.; Zhou, Z.; Turner, D.; Lilly, M.; Ou, T.; Jiang, W. Differential Circulating Fungal Microbiome in Prostate Cancer Patients Compared to Healthy Control Individuals. Journal of Immunology Research 2022, vol. 2022, pp. 1–7. [CrossRef]
  16. Banerjee, S. et al. Microbiome signatures in prostate cancer. Carcinogenesis 2019, vol. 40, pp. 749–764. [CrossRef]
  17. Miyake, M. et al. Mycoplasma genitalium Infection and Chronic Inflammation in Human Prostate Cancer: Detection Using Prostatectomy and Needle Biopsy Specimens. Cells 2019, vol. 8, p. 212. [CrossRef]
  18. Feng, Y. et al. Metagenomic analysis reveals a rich bacterial content in high-risk prostate tumors from African men. Prostate 2019, vol. 79, pp. 1731–1738. [CrossRef]
  19. Feng, Y. et al. Metagenomic and metatranscriptomic analysis of human prostate microbiota from patients with prostate cancer. BMC Genomics 2019, vol. 20, p. 146. [CrossRef]
  20. Cavarretta, I. et al. The Microbiome of the Prostate Tumor Microenvironment. European Urology 2017, vol. 72, pp. 625–631. [CrossRef]
  21. Ahn, H.K.; Kim, K.; Park, J.; Kim, K.H. Urinary microbiome profile in men with genitourinary malignancies. Investig Clin Urol 2022, vol. 63, p. 569. [CrossRef]
  22. Salachan, P. V.; Rasmussen, M.; Fredsøe, J.; Ulhøi, B.; Borre, M.; Sørensen, K. D. Microbiota of the prostate tumor environment investigated by whole-transcriptome profiling. Genome Med 2022, vol. 14, p. 9. [CrossRef]
  23. Li, W.T. et al. The Bladder Microbiome Is Associated with Epithelial-Mesenchymal Transition in Muscle Invasive Urothelial Bladder Carcinoma. Cancers (Basel) 2021, vol. 13, p. 3649. [CrossRef]
  24. Whiteside, S.A.; Razvi, H.; Dave, S.; Reid, G.; Burton, J. P. The microbiome of the urinary tract—a role beyond infection. Nat Rev Urol 2015, vol. 12, pp. 81–90. [CrossRef]
  25. Hrbáček, J.; Tláskal, V.; Čermák, P.; Hanáček, V.; Zachoval, R. Bladder cancer is associated with decreased urinary microbiota diversity and alterations in microbial community composition. Urologic Oncology: Seminars and Original Investigations 2023, vol. 41, p. 107.e15-107.e22. [CrossRef]
  26. Mansour, B. et al. Bladder Tissue Microbiome Composition in Patients of Bladder Cancer or Benign Prostatic Hyperplasia and Related Human Beta Defensin Levels. Biomedicines 2022, vol. 10, p. 1758. [CrossRef]
  27. Chipollini, J. et al. Characterization of urinary microbiome in patients with bladder cancer: Results from a single-institution, feasibility study. Urologic Oncology: Seminars and Original Investigations 2020, vol. 38, pp. 615–621. [CrossRef]
  28. Ma, W. et al. Can Smoking Cause Differences in Urine Microbiome in Male Patients With Bladder Cancer? A Retrospective Study. Front Oncol 2021, vol. 11, p. 677605. [CrossRef]
  29. Marand, A.J.B. et al. Urinary Microbiome and its Correlation with Disorders of the Genitourinary System. Urology Journal 2021, no. Instant, p. 5976. [CrossRef]
  30. Adebayo, A.S. et al. The microbiome in urogenital schistosomiasis and induced bladder pathologies. PLoS Negl Trop Dis 2017, vol. 11, p. e0005826. [CrossRef]
  31. Yu, D.; Wu, C.; Ping, S.; Keng, C.; Shen, K. Bacille Calmette-Guerin can induce cellular apoptosis of urothelial cancer directly through toll-like receptor 7 activation. The Kaohsiung J of Med Scie 2015, vol. 31, pp. 391–397. [CrossRef]
  32. Parra-Grande, M. et al. Profiling the Bladder Microbiota in Patients With Bladder Cancer. Front Microbiol 2021, vol. 12, p. 718776. [CrossRef]
  33. Zeng, J. et al. Alterations in Urobiome in Patients With Bladder Cancer and Implications for Clinical Outcome: A Single-Institution Study. Front. Cell. Infect. Microbiol. 2020, vol. 10, p. 555508. [CrossRef]
  34. Bučević Popović, V.; Šitum, M.; Chow, C.-E. T.; Chan, L. S.; Roje, B.; Terzić, J. The urinary microbiome associated with bladder cancer. Sci Rep 2018, vol. 8, p. 12157. [CrossRef]
  35. Liu, F. et al. Dysbiosis signatures of the microbial profile in tissue from bladder cancer. Cancer Med 2019, vol. 8, pp. 6904–6914. [CrossRef]
  36. Bi, H. et al. Urinary microbiota – a potential biomarker and therapeutic target for bladder cancer. Journal of Medical Microbiology 2019, vol. 68, pp. 1471–1478. [CrossRef]
  37. Pederzoli, F. et al. Sex-specific Alterations in the Urinary and Tissue Microbiome in Therapy-naïve Urothelial Bladder Cancer Patients. European Urology Oncology 2020, vol. 3, pp. 784–788. [CrossRef]
  38. Wu, P. et al. Profiling the Urinary Microbiota in Male Patients With Bladder Cancer in China. Front. Cell. Infect. Microbiol. 2018, vol. 8, p. 167. [CrossRef]
  39. Hussein, A.A. et al. Investigating the association between the urinary microbiome and bladder cancer: An exploratory study. Urologic Oncology: Seminars and Original Investigations 2021, vol. 39, p. 370.e9-370.e19. [CrossRef]
  40. Zhang, Y.; Wang, W.; Zhou, H.; Cui, Y. Urinary Eubacterium sp. CAG:581 Promotes Non-Muscle Invasive Bladder Cancer (NMIBC) Development through the ECM1/MMP9 Pathway. Cancers (Basel) 2023, vol. 15, p. 809. [CrossRef]
  41. Fukumoto, K. et al. Clinical Role of Programmed Cell Death-1 Expression in Patients with Non-muscle-invasive Bladder Cancer Recurring After Initial Bacillus Calmette–Guérin Therapy. Ann Surg Oncol 2018, vol. 25, pp. 2484–2491. [CrossRef]
  42. Chen, C. et al. Urogenital Microbiota:Potentially Important Determinant of PD-L1 Expression in Male Patients with Non-muscle Invasive Bladder Cancer. BMC Microbiol 2022, vol. 22, p. 7. [CrossRef]
  43. Huang, J. et al. A Global Trend Analysis of Kidney Cancer Incidence and Mortality and Their Associations with Smoking, Alcohol Consumption, and Metabolic Syndrome. European Urology Focus 2022, vol. 8, pp. 200–209. [CrossRef]
  44. Moch, H.; Cubilla, A.L.; Humphrey, P.A.; Reuter, V.E.; Ulbright, T.M. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part A: Renal, Penile, and Testicular Tumours. European Urology 2016, vol. 70, pp. 93–105. [CrossRef]
  45. Chow, W.-H.; Dong, L.M.; Devesa, S.S. Epidemiology and risk factors for kidney cancer. Nat Rev Urol 2010, vol. 7, pp. 245–257. [CrossRef]
  46. Chen, Y. et al. Characteristics of Gut Microbiota in Patients With Clear Cell Renal Cell Carcinoma. Front. Microbiol. 2022, vol. 13, p. 913718. [CrossRef]
  47. Dai, G.; Chen, X.; He, Y. The Gut Microbiota Activates AhR Through the Tryptophan Metabolite Kyn to Mediate Renal Cell Carcinoma Metastasis. Front. Nutr. 2021, vol. 8, p. 712327. [CrossRef]
  48. Dizman, N. et al. Randomized trial assessing impact of probiotic supplementation on gut microbiome and clinical outcome from targeted therapy in metastatic renal cell carcinoma. Cancer Med. 2021, vol. 10, pp. 79–86. [CrossRef]
  49. Dizman, N. et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med 2022, vol. 28, pp. 704–712. [CrossRef]
  50. Ianiro, G. et al. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma. Nat Commun 2020, vol. 11, p. 4333. [CrossRef]
  51. Su, Z.; Lu, L.; Chen, F.; Chen, J.; Chen, X. Gut Microbiota and Sunitinib-Induced Diarrhea in Metastatic Renal Cell Carcinoma: A Pilot Study. CMAR 2021, vol. 13, pp. 8663–8672. [CrossRef]
  52. Derosa, L. et al. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients. European Urology 2020, vol. 78, pp. 195–206. [CrossRef]
  53. Hahn, A.W. et al. Targeting Bacteroides in Stool Microbiome and Response to Treatment With First-Line VEGF Tyrosine Kinase Inhibitors in Metastatic Renal-Cell Carcinoma. Clinical Genitourinary Cancer 2018, vol. 16, pp. 365–368. [CrossRef]
  54. Pal, S.K. et al. Stool Bacteriomic Profiling in Patients with Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor–Tyrosine Kinase Inhibitors. Clinical Cancer Research 2015, vol. 21, pp. 5286–5293. [CrossRef]
  55. Salgia, N.J. et al. Stool Microbiome Profiling of Patients with Metastatic Renal Cell Carcinoma Receiving Anti–PD-1 Immune Checkpoint Inhibitors. European Urology 2020, vol. 78, pp. 498–502. [CrossRef]
  56. Heidler, S.; Lusuardi, L.; Madersbacher, S.; Freibauer, C. The Microbiome in Benign Renal Tissue and in Renal Cell Carcinoma. Urol Int 2020, vol. 104, pp. 247–252. [CrossRef]
  57. Wang, J. et al. Uncovering the microbiota in renal cell carcinoma tissue using 16S rRNA gene sequencing. J Cancer Res Clin Oncol 2021, vol. 147, pp. 481–491. [CrossRef]
  58. Liss, M.A. et al. Microbiome within Primary Tumor Tissue from Renal Cell Carcinoma May Be Associated with PD-L1 Expression of the Venous Tumor Thrombus. Advances in Urology 2020, vol. 2020, pp. 1–6. [CrossRef]
  59. Najm, R.; Hachim, M.Y.; Kandasamy, R.K. Divulging a Pleiotropic Role of Succinate Receptor SUCNR1 in Renal Cell Carcinoma Microenvironment. Cancers (Basel) 2022, vol. 14, p. 6064. [CrossRef]
  60. Guo, Y.; Cho, S.W.; Saxena, D.; Li, X. Multifaceted Actions of Succinate as a Signaling Transmitter Vary with Its Cellular Locations. Endocrinol Metab 2020, vol. 35, p. 36. [CrossRef]
  61. Mills, E.; O’Neill, L.A.J. Succinate: a metabolic signal in inflammation. Trends in Cell Biology 2014, vol. 24, pp. 313–320. [CrossRef]
  62. Jiang, S.; Yan, W. Succinate in the cancer–immune cycle. Cancer Letters 2017, vol. 390, pp. 45–47. [CrossRef]
  63. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012, vol. 2, pp. 401–404. [CrossRef]
  64. Onywera, H. et al. The penile microbiota of Black South African men: relationship with human papillomavirus and HIV infection. BMC Microbiol 2020, vol. 20, p. 78. [CrossRef]
  65. Mishra, K. et al. Characterization of Changes in Penile Microbiome Following Pediatric Circumcision. Eur Urol Focus 2022, pp. S2405-4569(22)00290–5. [CrossRef]
  66. Waltmann, A.; Thomas, C.; Duncan, J.A. The role of the genital microbiota in the acquisition and pathogenesis of sexually transmitted infections. Curr Opin Infect Dis 2023, vol. 36, pp. 35–48. [CrossRef]
  67. Gurney, J.K. et al. International Trends in the Incidence of Testicular Cancer: Lessons from 35 Years and 41 Countries. European Urology 2019, vol. 76, pp. 615–623. [CrossRef]
  68. Farahani, L.; Tharakan, T.; Yap, T.; Ramsay, J.W.; Jayasena, C.N.; Minhas, S. The semen microbiome and its impact on sperm function and male fertility: A systematic review and meta-analysis. Andrology 2021, vol. 9, pp. 115–144. [CrossRef]
  69. Alfano, M. et al. Testicular microbiome in azoospermic men—first evidence of the impact of an altered microenvironment. Human Reproduction 2018, vol. 33, pp. 1212–1217. [CrossRef]
  70. Mørup, N; Main, A. M.; Jørgensen, N.; Daugaard, G.; Juul, A.; Almstrup, K. The seminal plasma microbiome of men with testicular germ cell tumours described by small RNA sequencing. Andrology 2023, vol. 11, pp. 756–769. [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated