Microbial mysteries: Staphylococcus aureus and the enigma of carcinogenesis.

Staphylococcus aureus, a common human pathogen, has long been the focus of scientific investigation due to its association with various infections. However, recent research has unveiled a tantalizing enigma surrounding this bacterium and its potential involvement in carcinogenesis. Chronic S. aureus infections have been linked to an elevated risk of certain cancers, including skin cancer and oral cancer. This review explores the current state of knowledge regarding this connection, examining epidemiological evidence, pathogenic mechanisms, and biological interactions that suggest a correlation. Although initial studies point to a possible link, the precise mechanisms through which S. aureus may contribute to cancer development remain elusive. Emerging evidence suggests that the chronic inflammation induced by persistent S. aureus infections may create a tumor-promoting environment. This inflammation can lead to DNA damage, disrupt cellular signaling pathways, and generate an immunosuppressive microenvironment conducive to cancer progression. Additionally, S. aureus produces a variety of toxins and metabolites that can directly interact with host cells, potentially inducing oncogenic transformations. Despite these insights, significant gaps remain in our understanding of the exact biological processes involved. This review emphasizes the urgent need for more comprehensive research to clarify these microbiological mysteries. Understanding the role of S. aureus in cancer development could lead to novel strategies for cancer prevention and treatment, potentially transforming therapeutic approaches.

A bibliometric analysis of global research on microbial immune microenvironment in melanoma from 2012 to 2022.

BACKGROUND: Melanoma is an aggressive malignancy primarily impacting the skin, mucous membranes, and pigment epithelium. The tumor microbial microenvironment encompasses both the microorganisms inhabiting the tumor vicinity and the environmental factors influencing their interactions. Emerging evidence highlights the pivotal role of the microbial immune microenvironment in melanoma. METHODS: We conducted an extensive review of scholarly works published from 2012 to 2022, utilizing The Web of Science Core Collection. Subsequently, we employed analytical tools such as VOSviewer, CiteSpace, and the R programming language to scrutinize prevailing research patterns within this domain. RESULTS: A sum of 513 articles were pinpointed, with notable input coming from the United States and China. Harvard University stood out as the top-contributing institution, while the journal Science received the most citations. Current research within this sphere chiefly focuses on two principal domains: the gut microbiota and the PD-L1 pathway concerning melanoma treatment. CONCLUSION: The study offers an extensive analysis and overview of the worldwide research landscape concerning the immune microenvironment with a focus on microbes in melanoma. It underscores the promising prospects for harnessing the microbial immune microenvironment's potential in melanoma. These findings furnish valuable insights and guidance for advancing scientific inquiry and refining clinical approaches within this dynamic field.

Genetic causal relationship between gut microbiota and basal cell carcinoma: A two-sample mendelian randomization study.

OBJECTIVE: Research has previously established connections between the intestinal microbiome and the progression of some cancers. However, there is a noticeable gap in the literature in regard to using Mendelian randomisation (MR) to delve into potential causal relationships between the gut microbiota (GM) and basal cell carcinoma (BCC). Therefore, the purpose of our study was to use MR to explore the causal relationship between four kinds of GM (Bacteroides, Streptococcus, Proteobacteria and Lachnospiraceae) and BCC. METHODS: We used genome-wide association study (GWAS) data and MR to explore the causal relationship between four kinds of GM and BCC. This study primarily employed the random effect inverse variance weighted (IVW) model for analysis, as complemented by additional methods including the simple mode, weighted median, weighted mode and MR‒Egger methods. We used heterogeneity and horizontal multiplicity to judge the reliability of each analysis. MR-PRESSO was mainly used to detect and correct outliers. RESULTS: The random-effects IVW results showed that Bacteroides (OR = 0.936, 95% CI = 0.787-1.113, p = 0.455), Streptococcus (OR = 0.974, 95% CI = 0.875-1.083, p = 0.629), Proteobacteria (OR = 1.113, 95% CI = 0.977-1.267, p = 0.106) and Lachnospiraceae (OR = 1.027, 95% CI = 0.899-1.173, p = 0.688) had no genetic causal relationship with BCC. All analyses revealed no horizontal pleiotropy, heterogeneity or outliers. CONCLUSION: We found that Bacteroides, Streptococcus, Proteobacteria and Lachnospiraceae do not increase the incidence of BCC at the genetic level, which provides new insight for the study of GM and BCC.

Non-Melanoma Skin Cancer: news from microbiota research.

Recently, research has been deeply focusing on the role of the microbiota in numerous diseases, either affecting the skin or other organs. What it is well established is that its dysregulation promotes several cutaneous disorders (i.e. psoriasis and atopic dermatitis). To date, little is known about its composition, mediators and role in the genesis, progression and response to therapy of Non-Melanoma Skin Cancer (NMSC). Starting from a bibliographic study, we classified the selected articles into four sections: i) normal skin microbiota; ii) in vitro study models; iii) microbiota and NMSC and iv) probiotics, antibiotics and NMSC. What has emerged is how skin microflora changes, mainly represented by increases of Staphylococcus aureus, Streptococcus pyogenes and Pseudomonas aeruginosa strains, modifications in the mutual quantity of ß-Human papillomavirus genotypes, of Epstein Barr Virus and Malassezia or candidiasis, may contribute to the induction of a state of chronic self-maintaining inflammation, leading to cancer. In this context, the role of S. aureus and that of specific antimicrobial peptides look to be prominent. Moreover, although antibiotics may contribute to carcinogenesis, due to their ability to influence the microbiota balance, specific probiotics, such as Lacticaseibacillus rhamnosus GG, Lactobacillus johnsonii NCC 533 and Bifidobacteria spp., may be protective.

The microbial flora of clinically infected cutaneous metastases: a retrospective study.

Symptomatic cutaneous metastases are associated with discharge, malodour, pruritus and pain, all of which may negatively impact quality of life and cutaneous health. We conducted a retrospective chart review of patients referred to the Dermatology Service at Memorial Sloan Kettering Cancer Center between August 2006 and June 2015, and characterized the microbial flora and antimicrobial management of cutaneous metastases in 64 patients. We detected pathogenic and/or opportunistic bacteria in 50% of skin lesions. The most commonly isolated organisms were Staphylococcus aureus and Pseudomonas aeruginosa. Patients treated with oral antibiotics, alone or in combination with topical agents, had a statistically significant better improvement in infectious symptoms than those treated without oral antibiotics. Our findings suggest that the normal skin microbial flora is disrupted in patients with symptomatic skin metastases. Oral antibiotics may provide benefit when used as first-line therapy for infected skin lesions in patients with symptomatic cutaneous metastases.

The skin microbiome and immune system: Potential target for chemoprevention?

There has been increasing interest in understanding the role of the human microbiome in skin diseases. Microbiome studies are being utilized in skin cancer research in numerous ways. Commensal bacteria are being studied as a potential tool to judge the biggest environmental risk of skin cancer, ultraviolet (UV) radiation. Owing to the recognized link of skin microbes in the process of inflammation, there have been theories linking commensal bacteria to skin cancer. Viral metagenomics has also provided insight into virus linked forms of skin cancers. Speculations can be drawn for skin microbiome that in a manner similar to gut microbiome, they can be involved in chemoprevention of skin cancer. Nonetheless, there are definitely huge gaps in our knowledge of the relationship of microbiome and skin cancers, especially in relation to chemoprevention. The utilization of microbiome in skin cancer research seems to be a promising field and may help yield novel skin cancer prevention and treatment options. This review focuses on recent utilization of the microbiome in skin cancer research, and it explores the potential of utilizing the microbiome in prevention, earlier diagnosis, and treatment of skin cancers.

Cutaneous head and neck melanoma (CHNM): A population-based study of the prognostic impact of tumor location.

BACKGROUND: Most studies of cutaneous head and neck melanomas (CHNM) have reported poorer survival in CHNM compared with other sites, especially on the scalp/neck. OBJECTIVE: We sought to compare patient and tumor characteristics between CHNM and cutaneous trunk and extremity melanomas and between CHNM locations (face/ear vs scalp/neck, anterior vs posterior), and to study prognostic factors in patients with CHNM. METHODS: We studied all CHNM (n = 1074) from 8120 cases of cutaneous melanomas diagnosed in Norway in 2008 to 2012. RESULTS: Compared with cutaneous trunk and extremity melanomas, CHNM were more frequently found in men, more often nodular and lentigo maligna cutaneous melanomas, and diagnosed at higher T stage (P ≤ .01). CHNM located on posterior sites were diagnosed at significantly higher T stage, and were significantly more often diagnosed with ulceration and at more advanced stage compared with CHNM located on anterior sites (P < .001). T stage and clinical stage were the only significant prognostic factors for melanoma-specific and overall death in the multivariable analysis (P < .001). LIMITATIONS: Low number of cases and the relatively high frequency of missing values are limitations. CONCLUSION: More advanced CHNM were diagnosed on posterior compared with anterior locations, but location was not a significant prognostic factor for cutaneous melanoma-specific or overall death in the multivariable models.

Safe and effective deodorization of malodorous fungating tumors using topical metronidazole 0.75 % gel (GK567): a multicenter, open-label, phase III study (RDT.07.SRE.27013).

PURPOSE: Malignant fungating tumors are neoplastic tumors associated with skin ulcers, which are susceptible to microbial colonization. Bacterial infection and proliferation may lead to malodor causing distress to patients. Metronidazole-an effective agent against anaerobes-may contribute to deodorization and improvement in quality of life (QOL). This study investigated the efficacy and safety of topical metronidazole 0.75 % gel for alleviation of malodor in anaerobically infected fungating neoplastic tumors. METHODS: This was a multicenter, open-label, non-controlled, phase III study including subjects aged 20 years or older with cutaneous fungating tumors releasing malodor (minimum score of 2 (mildly offensive smell) on a scale from 0 (no smell) to 4 (extremely offensive smell) based on investigator's assessment). Subjects applied metronidazole 0.75 % gel once or twice daily at the investigator's discretion for 14 days. Success was defined as an odor score of 0 or 1 at day 14, as assessed by the investigator. Patient satisfaction was assessed using a satisfaction questionnaire. Adverse events (AEs) that occurred after application of metronidazole 0.75 % gel were also reported. RESULTS: A total of 21 subjects at a median age of 65.0 years were enrolled. The success rate of deodorization at day 14 was 95.2 % (20/21 subjects). The patient satisfaction assessment showed that 71.4 % (15/21) of subjects were markedly or moderately improved. The treatment was well tolerated with only two AE cases of skin neoplasm bleeding (one mild and one moderate). CONCLUSIONS: Metronidazole 0.75 % gel is an effective and safe treatment for deodorization of malodorous fungating tumors.

The role of the cutaneous microbiome in skin cancer: lessons learned from the gut.

The human microbiome has recently gained prominence as a major factor in health and disease. Here we review the literature regarding the microbiome and cancer and suggest how the microbiome may be manipulated for improved health outcomes. The gut microbiome has been relatively well studied, and the mechanisms of how it may increase or decrease the risk of certain cancers may apply to the skin microbiome. Additionally, the gut microbiome may directly impact the risk of cancer in the skin and other organs by promoting systemic inflammation. The skin microbiome itself is as diverse as the gut microbiome, but research has just begun to unravel its influence on the host. Like the gut microbiome, it affects the risk for several diseases, including cancer. By using healthpromoting strains from the microbiome in oral or topical probiotics, it may be possible to reduce the risk of skin cancer and perhaps even increase the likelihood of successful treatment.

Electrochemotherapy as a novel treatment for primary cutaneous marginal zone B-cell lymphomas.

In the present study, we describe the use of electrochemotherapy as alternative therapy for primary cutaneous marginal zone B-cell lymphomas in patients unsuitable for surgery or radiotherapy. Our experience refers to three patients with primary cutaneous marginal zone B-cell lymphomas related to Borrelia burgdorferi infection, treated with specific antimicrobial therapy and electrochemotherapy.

Genetic causal relationship between gut microbiota and cutaneous melanoma: a two-sample Mendelian randomization study.

Currently, numerous studies suggest a potential association between the gut microbiota and the progression of melanoma. Hence, our objective was to examine the genetic impact of the gut microbiota on melanoma through the utilization of the Mendelian randomization (MR) approach. This research employed Bacteroides, Streptococcus, Proteobacteria, and Lachnospiraceae as exposure variables and cutaneous melanoma (CM) as the outcome in a two-sample MR analysis. In this MR research, the primary analytical approach was the random-effects inverse-variance weighting (IVW) model. Complementary methods included weighted median, MR Egger, and basic and weighted models. We assessed both heterogeneity and horizontal pleiotropy in our study, scrutinizing whether the analysis results were affected by any individual SNP. The random-effects IVW outcomes indicated that Streptococcus, Bacteroides, Lachnospiraceae and Proteobacteria had no causal relationship with CM, with odds ratios of 1.001 [95% confidence interval (CI) = 0.998-1.004, P  = 0.444], 0.999 (95% CI = 0.996-1.002, P  = 0.692), 1.001 (95% CI = 0.998-1.003, P  = 0.306), and 0.999 (95% CI = 0.997-1.002, P  = 0.998), respectively. No analyses exhibited heterogeneity, horizontal pleiotropy, or deviations. Our research determined that Bacteroides, Streptococcus, Proteobacteria, and Lachnospiraceae do not induce CM at the genetic level. However, we cannot dismiss the possibility that these four gut microbiotas might influence CM through other mechanisms.

From Molecules to Microbes: Tracing Cutaneous T-Cell Lymphoma Pathogenesis through Malignant Inflammation.

The etiology of CTCL is a subject of extensive investigation. Researchers have explored links between CTCL and environmental chemical exposures, such as aromatic hydrocarbons (eg, pesticides and benzene), as well as infectious factors, including various viruses (eg, human T-lymphotropic virus [HTLV]-I and HTLV-II) and bacteria (eg, Staphylococcus aureus). There has been growing emphasis on the role of malignant inflammation in CTCL development. In this review, we synthesize studies of environmental and infectious exposures, along with research on the aryl hydrocarbon receptor and the involvement of pathogens in disease etiology, providing insight into the pathogenesis of CTCL.

The skin microbiome stratifies patients with cutaneous T cell lymphoma and determines event-free survival.

Mycosis fungoides (MF) is the most common entity of Cutaneous T cell lymphomas (CTCL) and is characterized by the presence of clonal malignant T cells in the skin. The role of the skin microbiome for MF development and progression are currently poorly understood. Using shotgun metagenomic profiling, real-time qPCR, and T cell receptor sequencing, we compared lesional and nonlesional skin of 20 MF patients with early and advanced MF. Additionally, we isolated Staphylococcus aureus and other bacteria from MF skin for functional profiling and to study the S. aureus virulence factor spa. We identified a subgroup of MF patients with substantial dysbiosis on MF lesions and concomitant outgrowth of S. aureus on plaque-staged lesions, while the other MF patients had a balanced microbiome on lesional skin. Dysbiosis and S. aureus outgrowth were accompanied by ectopic levels of cutaneous antimicrobial peptides (AMPs), including adaptation of the plaque-derived S. aureus strain. Furthermore, the plaque-derived S. aureus strain showed a reduced susceptibility towards antibiotics and an upregulation of the virulence factor spa, which may activate the NF-κB pathway. Remarkably, patients with dysbiosis on MF lesions had a restricted T cell receptor repertoire and significantly lower event-free survival. Our study highlights the potential for microbiome-modulating treatments targeting S. aureus to prevent MF progression.

The Tumor Microbiome as a Predictor of Outcomes in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.

Emerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and its potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICI). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA sequencing (RNA-seq) was conducted on the formalin-fixed, paraffin-embedded and fresh frozen tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival >24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic} tool. The age of the 71 patients with metastatic melanoma ranged from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy-responsive versus nonresponsive tumors. Responders showed significant enrichment of bacteriophages in the phylum Uroviricota, and nonresponders showed enrichment of several bacteria, including Campylobacter jejuni. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs. SIGNIFICANCE: We analyzed the tumor microbiome and interactions with genes and pathways in metastatic melanoma treated with immunotherapy and identified several microbes associated with immunotherapy response and immune-related gene expression signatures. Machine learning models that combined microbe abundances and gene expression outperformed models using either dataset alone in predicting immunotherapy responses.

Characterization of the skin microbiome in normal and cutaneous squamous cell carcinoma affected cats and dogs.

Human cutaneous squamous cell carcinomas (SCCs) and actinic keratoses (AK) display microbial dysbiosis with an enrichment of staphylococcal species, which have been implicated in AK and SCC progression. SCCs are common in both felines and canines and are often diagnosed at late stages leading to high disease morbidity and mortality rates. Although recent studies support the involvement of the skin microbiome in AK and SCC progression in humans, there is no knowledge of this in companion animals. Here, we provide microbiome data for SCC in cats and dogs using culture-independent molecular profiling and show a significant decrease in microbial alpha diversity on SCC lesions compared to normal skin (P ≤ 0.05). Similar to human skin cancer, SCC samples had an elevated abundance of staphylococci relative to normal skin-50% (6/12) had >50% staphylococci, as did 16% (4/25) of perilesional samples. Analysis of Staphylococcus at the species level revealed an enrichment of the pathogenic species Staphylococcus felis in cat SCC samples, a higher prevalence of Staphylococcus pseudintermedius in dogs, and a higher abundance of Staphylococcus aureus compared to normal skin in both companion animals. Additionally, a comparison of previously published human SCC and perilesional samples against the present pet samples revealed that Staphylococcus was the most prevalent genera across human and companion animals for both sample types. Similarities between the microbial profile of human and cat/dog SCC lesions should facilitate future skin cancer research. IMPORTANCE: The progression of precancerous actinic keratosis lesions (AK) to cutaneous squamous cell carcinoma (SCC) is poorly understood in humans and companion animals, despite causing a significant burden of disease. Recent studies have revealed that the microbiota may play a significant role in disease progression. Staphylococcus aureus has been found in high abundance on AK and SCC lesions, where it secretes DNA-damaging toxins, which could potentiate tumorigenesis. Currently, a suitable animal model to investigate this relationship is lacking. Thus, we examined the microbiome of cutaneous SCC in pets, revealing similarities to humans, with increased staphylococci and reduced commensals on SCC lesions and peri-lesional skin compared to normal skin. Two genera that were in abundance in SCC samples have also been found in human oral SCC lesions. These findings suggest the potential suitability of pets as a model for studying microbiome-related skin cancer progression.

Modulation of the skin microbiome in cutaneous T-cell lymphoma delays tumour growth and increases survival in the murine EL4 model.

Cutaneous T-cell lymphomas (CTCL) are a group of lymphoproliferative disorders of skin-homing T cells causing chronic inflammation. These disorders cause impairment of the immune environment, which leads to severe infections and/or sepsis due to dysbiosis. In this study, we elucidated the host-microbial interaction in CTCL that occurs during the phototherapeutic treatment regime and determined whether modulation of the skin microbiota could beneficially affect the course of CTCL. EL4 T-cell lymphoma cells were intradermally grafted on the back of C57BL/6 mice. Animals were treated with conventional therapeutics such as psoralen + UVA (PUVA) or UVB in the presence or absence of topical antibiotic treatment (neomycin, bacitracin, and polymyxin B sulphate) as an adjuvant. Microbial colonisation of the skin was assessed to correlate with disease severity and tumour growth. Triple antibiotic treatment significantly delayed tumour occurrence (p = 0.026), which prolonged the survival of the mice (p = 0.033). Allocation to phototherapeutic agents PUVA, UVB, or none of these, along with antibiotic intervention, reduced the tumour growth significantly (p = 0.0327, p ≤ 0.0001, p ≤ 0.0001 respectively). The beta diversity indices calculated using the Bray-Curtis model showed that the microbial population significantly differed after antibiotic treatment (p = 0.001). Upon modulating the skin microbiome by antibiotic treatment, we saw an increase in commensal Clostridium species, e.g., Lachnospiraceae sp. (p = 0.0008), Ruminococcaceae sp. (p = 0.0001)., Blautia sp. (p = 0.007) and a significant reduction in facultative pathogens Corynebacterium sp. (p = 0.0009), Pelomonas sp. (p = 0.0306), Streptococcus sp. (p ≥ 0.0001), Pseudomonas sp. (p = 0.0358), and Cutibacterium sp. (p = 0.0237). Intriguingly, we observed a significant decrease in Staphylococcus aureus frequency (p = 0.0001) but an increase in the overall detection frequency of the Staphylococcus genus, indicating that antibiotic treatment helped regain the microbial balance and increased the number of non-pathogenic Staphylococcus populations. These study findings show that modulating microbiota by topical antibiotic treatment helps to restore microbial balance by diminishing the numbers of pathogenic microbes, which, in turn, reduces chronic inflammation, delays tumour growth, and increases survival rates in our CTCL model. These findings support the rationale to modulate the microbial milieu during the disease course of CTCL and indicate its therapeutic potential.