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28 November 2022

Bidirectional Functional Effects of Staphylococcus on Carcinogenesis

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1
Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
2
Department of Immunology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
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Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Tianjin Medical University, Qixiangtai Road No. 22, Heping District, Tianjin 300070, China
4
Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Qixiangtai Road No. 22, Heping District, Tianjin 300070, China
Microorganisms2022, 10(12), 2353;https://doi.org/10.3390/microorganisms10122353
This article belongs to the Special Issue Characterisation and Molecular Analysis of Staphylococcal Species: Their Impact on Colonization and Infection
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Abstract

As a Gram-positive cocci existing in nature, Staphylococcus has a variety of species, such as Staphylococcus aureus and Staphylococcus epidermidis, etc. Growing evidence reveals that Staphylococcus is closely related to the occurrence and development of various cancers. On the one hand, cancer patients are more likely to suffer from bacterial infection and antibiotic-resistant strain infection compared to healthy controls. On the other hand, there exists an association between staphylococcal infection and carcinogenesis. Staphylococcus often plays a pathogenic role and evades the host immune system through surface adhesion molecules, α-hemolysin, PVL (Panton-Valentine leukocidin), SEs (staphylococcal enterotoxins), SpA (staphylococcal protein A), TSST-1 (Toxic shock syndrom toxin-1) and other factors. Staphylococcal nucleases (SNases) are extracellular nucleases that serve as genomic markers for Staphylococcus aureus. Interestingly, a human homologue of SNases, SND1 (staphylococcal nuclease and Tudor domain-containing 1), has been recognized as an oncoprotein. This review is the first to summarize the reported basic and clinical evidence on staphylococci and neoplasms. Investigations on the correlation between Staphylococcus and the occurrence, development, diagnosis and treatment of breast, skin, oral, colon and other cancers, are made from the perspectives of various virulence factors and SND1.

1. Introduction

Staphylococcus is a group of Gram-positive cocci that contains many different species, such as Staphylococcus aureus (S. aureus), Staphylococcus epidermidis (S. epidermidis), Staphylococcus saprophytics (S. saprophytics) [1,2,3,4]. As the most common pathogenic bacteria, S. aureus with different sequence types (STs) or spa types can cause inflammatory reactions in humans and animals [1,4,5]. The S. aureus-induced community and hospital-acquired infections may lead to adverse effects on the treatment and prognosis of patients [4]. With the widespread use of antibiotics in clinical practice, S. aureus has gradually become more drug-resistant, and the detection rate of methicillin-resistant Staphylococcus aureus (MRSA) also shows an upward trend [6]. Interestingly, Staphylococcus lugdunensis (S. lugdunensis) can secrete a polypeptide antibiotic called lugdunin to effectively restrain reproduction of and infection with MRSA [7]. As one of the main microorganisms on the skin’s surface, S. epidermidis plays an important role in the epidermal defense system of the body [8]. At present, more and more evidence supports the functional correlation between Staphylococcus and tumors, which is discussed in this review.
Staphylococcus in the host can play the role of inducing pathogenicity and escape from the host immune system through a variety of virulence factors, such as surface adhesion molecules, exotoxins and exoenzymes [9,10]. Various cell wall protein-anchored surface proteins, such as fibronectin-binding protein A/B (FnBPA/B), contribute to the adherence of Staphylococcus to host cells, which is the key to the staphylococcal pathogenesis [10,11,12,13]. As poreforming bacterial toxins, alpha-hemolysin and Panton-Valentine leukocidin (PVL) are considered to be the main virulence factors of severe infection caused by S. aureus infection [4,9,14]. A series of staphylococcal superantigens (SAg) produced by S. aureus can effectively activate the proliferation of T and B cells without any processing by antigen-presenting cells [9,15,16]. SpA (staphylococcal protein A) is one of the most important cell wall proteins in S. aureus, and has B cell superantigen activity [9]. SEs (staphylococcal enterotoxins) and TSST-1 (toxic shock syndrom toxin-1) function as potent inducers of cytotoxic T lymphocyte activity and cytokine production [15,16]. SEs include the Staphylococcus aureus enterotoxin A/B/C (SEA/B/C), and SEC is further divided into three subtypes (C1/2/3) [17,18]. TSST-1 can lead to toxic shock syndrome, and even multiple organ failure [19].
Extracellular nuclease is a secreted virulence factor and genetic marker for S. aureus. There exist two types of extracellular nuclease, staphylococcal nucleases (SNases) and thermonucleases (TNases) [20,21,22]. SND1 (staphylococcal nuclease and Tudor domain-containing 1) is the human homologue of Staphylococcus aureus nuclease, and can work as a member of RNA-induced silencing complex (RISC) that takes part in the cleavage of mRNA [23,24,25]. It is currently believed that human SND1 consists of four repeating staphylococcal nuclease-like (SN-like) domains [SN(1–4)] at the N terminus, and a SN5a-Tudor-SN5b (TSN) domain at the C terminus [25,26,27]. SND1 is a multifunctional protein that plays an important role in gene transcription regulation, pre-mRNA splicing, cell cycle, RNA metabolism and other biological processes [25,26,28,29,30,31,32,33]. Furthermore, a growing body of evidence reveals that SND1 with a recognizable nuclease domain is a kind of oncoprotein closely related to the occurrence and development of tumors, and which involves the potential nuclease activity [25,34,35,36,37].
In this study, we first conducted a retrieval from the Pubmed database using the search term: “(((((((((((Staphylococcus) or (Staphylococcus aureus)) or (Staphylococcus epidermidis)) OR (Staphylococcus saprophytics)) or (S. aureus)) or (S. epidermidis)) or (S. saprophytics)) or (Staphylococcus lugdunensis)) or (S. lugdunensis)) or (SND1)) or (staphylococcal nuclease)) AND ((((((carcinogenesis) or (cancer)) OR (cancers)) or (tumor)) or (tumors)) or (tumorigenesis))”. Then, the obtained literature was screened by reading the abstracts or full texts. Finally, we selected a total of 78 articles containing the scientific data between the presence of Staphylococcus and the occurrence, development, and treatment of different types of cancer. Table 1 summarizes the relevant clinical reports and basic experimental evidence, in terms of surface adhesion molecules, α-hemolysin, PVL, SEs, TSST-1, SpA, and SND1.
Table 1. Summary of evidence on Staphylococcus and carcinogenesis.

2. Staphylococcus and Cancer-Related Clinical Reports

After the systematic literature research, a series of publications were retrieved regarding Staphylococcus and different clinical tumor diseases. For instance, when compared with negative controls, cancer patients tend to develop staphylococcal infections, and suffer from MRSA, which also greatly reduces the survival rate of patients with malignant tumors [40,61,86,91,109,113,116,117]. A 3-year retrospective study from a comprehensive cancer center reported that S. lugdunensis causes infection much less often than other coagulase-negative staphylococci species [81]. On the other hand, S. aureus is frequently detected in the oral cavity of most patients with malignant tumors undergoing chemotherapy and/or radiotherapy [47,58,86,87]. Maślak, E. et al. also observed the changes of Staphylococcus in the urine sample of prostate cancer patients treated with radiotherapy [112]. A study of an S. aureus bacteremia (SAB) case in a national database (n = 12,918) and a random population cohort (n = 117,465) analyzed the risk of primary cancer and discovered that SAB cases appeared more frequently in multiple myeloma, leukemia, sarcoma, cervical, liver, pancreatic, and urinary tract cancer, compared with a control group [100].
Microbiome sequencing and functional analysis for tumor and non-tumor patients will help to explore the correlation between staphylococcal system disorders and tumorigenesis prevention or treatment. Herein, we have gathered the scientific data on the functional relationship between staphylococci and several types of cancers.

2.1. Breast Cancer

Emerging evidence supports the links of Staphylococcus with breast diseases, especially breast cancer [99,118]. There are many clinical cases of breast cancer with MRSA [44]. Staphylococcus exhibits distinct distribution characteristics in different pathological tissues or states. For example, a relative abundance of Staphylococcus was detected in the breast tissues of women with breast cancer [78,82,97,98]. For instance, as the second most dominant bacterium, Staphylococcus (6.4% ± 9.4%) was prevalent in 22 out of 23 breast tissue samples of cases within black or white non-Hispanic cohorts of breast cancer [97]. Additionally, S. aureus and S. epidermidis are the common bacteria that cause infections around breast implants in cancer patients [72]. However, there are also reports with inconsistent conclusions. Breast microbiome profile data showed that the presence of Staphylococcus is negligible in the tissue of breast cancer [107], but An, J. et al. reported that the blood sample of healthy controls had a greater diversity of Staphylococcus than breast cancer patients [111].

2.2. Skin Cancer

In contrast to healthy skin, the presence of S. aureus DNA was strongly associated with squamous cell carcinoma [52]. Madhusudhan, N. et al. further reported that excessive S. aureus is significantly associated with an increased expression of human β-defensin-2 (HBD-2) in tumor samples from patients with cutaneous squamous cell carcinoma [93]. Cutaneous colonization of S. aureus is reportedly associated with the incidence of cutaneous T-cell lymphoma [69,119]. In response to adverse external stimuli, the expression microbiome of the body may become disorganized, such potentially suffering from a reduced level of the anti-tumor S. epidermidis population or a higher abundance of pathogenic S. aureus, which is associated with a high susceptibility to skin cancer [88,120,121]. When tumor patients are given specific clinical treatments, such as radiotherapy, chemotherapy, and probiotics, disorders of the skin microbiome are often observed [120,121].

2.3. Bladder Cancer

The altered abundance of Staphylococcus was detected in the tumor mucosa or urine samples of bladder cancer patients. For instance, Staphylococcus (cluster 2) was enriched in the microbial composition of tumor mucosa samples for bladder cancer [108]. Urine microbiota analysis of male bladder cancer patients in China indicated that various functional pathways were enriched in the cancer group, including S. aureus infection [85]. An abundance of Staphylococcus was significantly higher in urine samples of bladder cancer patients compared to benign prostatic hyperplasia controls [114].

2.4. Colon Cancer

In 2007, Noguchi, N. et al. first reported that tannin-producing S. ludunensis was more frequent in the swab samples of fecal and rectal for the advanced colon cancer group compared with the adenoma or normal group [48]. Furthermore, the genetic background investigation of the forty S. lugdunensis isolates from 288 rectal swabs indicated the links between the specific group D clone of S. lugdunensis and colon cancer [89].

2.5. Oral Cancer

Compared with healthy individuals, Staphylococcus was significantly more abundant in the oral squamous cell carcinomas group [110]. In 2004, Fujiki H. et al. found that tobacco tar-resistant S. aureus exists in the oral cavity of some individuals and has carcinogenic potential [42]. In addition, a study of 186 patients with oral squamous cell carcinoma reported a predominance of Gram-positive bacteria, including S. aureus and S. epidermidis, in the mouth of patients treated with chemotherapy and chemoradiotherapy [58].

2.6. Others

Apart from working to induce the discussed cancers, there are links between Staphylococcus and lung cancer, glioblastoma, and lymphoma. Fourdrain, A. et al. reported that the S. aureus carried in the nasal cavity before lung cancer surgery is related to an increased risk of health care-associated infection [94]. Similarly, S. epidermidis can also be detected in tissue samples taken from lung cancer patients during surgery [57]. In some glioblastoma multiforme cases, intracranial abscess complications caused by S. aureus have been observed [51]. Interestingly, some glioblastoma patients with staphylococcal intracranial infection after craniotomy displayed a relatively longer survival time [105]. However, the results are conflicting in breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). It was reported that there was a high abundance of Staphylococcus in both breast implant-associated anaplastic and contralateral breast controls [90], but Hu H. et al. reported a lower abundance of Staphylococcus in the BIA-ALCL samples compared to that in the nontumor capsule specimens [79].

3. Staphylococcal Nuclease and Cancer

The presence or absence of S. aureus in samples can be determined by their diagnostic marker, staphylococcal nucleases [122]. Nucleases have long been recognized as potential biomarkers of cancer [36], however, no direct correlation between staphylococcal nucleases and cancer has been reported. The staphylococcal nuclease is a small globular protein containing 149 amino acid residues, and has been utilized to study the protein folding process [123]. As the staphylococcal nuclease purifies from a recombinant E. coli strain, micrococcal nuclease (Mnase) was applied in the chromatin immunoprecipitation assay or single-cell micrococcal nuclease sequencing of tumor samples [124,125]. SND1 is a conformed oncoprotein [25,34,35], which is the human homologue of SNases and contains four staphylococcal nuclease-like domains [23,24].

3.1. Structural Characteristics

Human SND1 protein (NP_055205.2; A0A140VK49_HUMAN), coded by the SND1 gene localized on chromosome 7q32.1 [34,126,127], consists of 910 amino acids. In 1997, Callebaut I. et al. first utilized the hydrophobic cluster analysis (HCA) method to initially resolve the structure of human SND1 protein and found that SND1 consists of four repetitive N-terminal SN and C-terminal Tudor domains [128]. In 2007, we first resolved the crystal structure of the TSN domain in human SND1 protein and found that TSN contains four α-helices, nine β-folds, and 14 linkage loops, in which the β (1~2) fold is involved in the composition of SN5a (679–703) [26]. Most of the α1-helices and β (3~6) fold to form a typical β-barrel Tudor (704–793) domain, and the β (7–9)-fold and α (2–4) helix are involved in the composition of SN5b (794–895) [26]. In 2008, Li, C. L. further reported that the SN3, SN4, Tudor and SN5 domains of human SND1 protein aggregate together to form a crescent-like structure [27]. The recessed basic surface formed by SN3 and SN4 serves as a binding site for citrate ions at the RNase active site, which can specifically bind with and degrade highly edited IU- and UI-containing double-stranded microRNA precursors [27]. Thus, staphylococcal nuclease-like domains of SND1 can bind to proteins and nucleic acids. This may involve a synergistic interaction between multiple SN structures.

3.2. Staphylococcal Nuclease Activity

The staphylococcal nuclease (SN) is a type of Ca2+-dependent enzyme that hydrolyzes the 5′-phosphodiester bond of single/double-stranded DNA and RNA [129,130]. It was initially thought that the SN domains of SND1 proteins lack key catalytic residues, like those of staphylococcal nucleases [24,128]. It was speculated that SND1 might have only nucleic acid binding ability, but no nuclease activities.
Nevertheless, emerging evidence suggests that the SND1 protein in multiple species can bind nucleic acids [27,131,132,133,134,135,136] and exhibits some nuclease activity [23,27,131,137,138,139,140,141,142,143,144]. For instance, Hannon et al. first discovered that the SND1 is a candidate of RISC and shows the nuclease activity in mammalian, Drosophila, and Caenorhabditis elegans, despite lacing a classical active site sequence [23,137]. In Plasmodium falciparum, the SND1 protein can degrade the RNA and single-stranded DNA, displaying Ca2+-dependent nuclease activity [131]. The nuclease activity of the SND1 protein was also detected in the species of Tick, Penaeus monodon, and Toxoplasma gondii [140,142,143,144]. In addition, the SND1 protein has some degradation ability for pri-miRNA/dsRNA and specific types of miRNAs after RNA editing which is supported by the crystal structure evidence [27]. SND1 protein degrades highly edited A to I pri-miR-142 [138]. Additionally, SND1 also specifically binds and degrades I-dsRNAs enriched in IU base pairs, without interacting with IU base pair-free dsRNAs [139].

3.3. SND1 and Cancer

The potential nuclease activity of the SN domain within SND1 may be closely linked to the oncogenic role of the SND1 protein [25,34,35,36,37]. SND1 plays a vital role in regulating several aspects of RNA metabolism through its nuclease activity. For instance, the binding of SND1 to the 3′UTR of PTPN23 (protein tyrosine phosphatase nonreceptor type 23) mRNA in human hepatocellular carcinoma (HCC) promotes its RNA degradation [37]. As a conventional staphylococcal nuclease inhibitor, pdTp (3′,5′-deoxythymidine bisphosphate) was reported to suppress the nuclease activity of SND1 [131,137]. In HCC cells, the remarkably enriched RISC activity of SND1 depends on the nuclease activity of highly expressed SND1, which can be affected by pdTp [56]. For the subcutaneous or in situ mouse models of HCC, the treatment of pdTp injection hinders the tumorigenesis of mice by affecting the nuclease activity of SND1 [84]. Scholarship generally concludes that the inhibition of SND1 nuclease activity by pdTp could be an effective intervention or therapeutic strategy for hepatocellular carcinoma.

4. Staphylococcus and Cancer Treatment

Clinical evidence indicates a correlation between the occurrence, development, and treatment of cancer and Staphylococcus [145]. In many cases, the predisposition to tumors is accompanied and facilitated by infection with specific staphylococci. Hattar, K. et al. reported that lipoteichoic acid, an inflammatory mediator from S. aureus, promotes the proliferation of lung cancer cell lines (A549 and H226) in vitro [83]. S. aureus infection was found to promote the lung metastasis of breast cancer cells through the formation of neutrophil extracellular traps [101]. Hence, some tumor-related interventions can be conducted, partly based on the pathogenesis of Staphylococcus. For instance, it may be possible to evade drug resistance in Staphylococcus and tumors by regulating intracellular reactive oxygen species [146].
Interestingly, there is continuous evidence that specific staphylococci have inhibitory effects on the proliferation, migration, and other biological behaviors of specific tumors [54,66]. For example, after intratumoral injection of S. aureus into the mouse model of orthotopic glioma, delayed glioma growth was observed, which may involve the anti-tumor effect of activated microglia [92].

4.1. Surface Adhesion Molecules

As a typical class of adhesion proteins from S. aureus, fibronectin-binding protein A/B (FnBPA/B) is associated with the adhesion and costimulatory signals of T lymphocytes [11,12]. The mice which were vaccinated with a recombinant Lactococcus lactis stain with cell surface-anchored FnBPA against S. aureus were better protected from the human papilloma virus (HPV)-induced cancer [76]. Aframomum melegueta extracts the display anti-adhesive abilities of S. aureus to lung carcinoma A549 cell line [106]. The extracellular adhesion protein (Eap) of S. aureus inhibited the bone metastasis of breast cancer cell line MDA-MB-231 [46]. In addition, some staphylococci were reported to adhere to bladder cancer cells. Szabados, F. et al. observed the internalization of S. saprophyticus ATCC 15305 into human urinary bladder carcinoma cell line 5637 in microscopy [49]. The treatment of metabolic glycoengineering with N-azidoacetyl-glucosamine (GlcNAz) leads to the reduced adherence of S. aureus to human T24 bladder carcinoma cells [64].

4.2. α-hemolysin

The α-hemolysin has certain anti-cancer effects and can also enhance the apoptosis of tumor cells induced by specific chemotherapy drugs [50,68,102]. For instance, a low toxic concentration of α-hemolysin can cause cell apoptosis through the mitochondrial pathway and improve the sensitivity of malignant pleural mesothelioma cells to cisplatin chemotherapy [50]. Additionally, researchers have tried to develop different bacterial delivery systems of α-hemolysin for the targeted killing of colorectal or breast cancer cells using Escherichia coli without the virulence factors [68,102].

4.3. Panton-Valentine leukocidin

As the S component of Panton-Valentine leukocidin, LukS-PV can induce mitochondria-mediated apoptosis and G0/G1 cell cycle arrest in human acute myeloid leukemia (AML) cell line (THP-1) [65], and effectively inhibit the tumorigenesis of HL-60 AML cells in severe combined immunodeficiency (SCID) mice [70]. This indicates that LukS-PV may be a multi-target drug candidate for the prevention and treatment of AML. For non-small-cell lung cancer (NSCLC) cells, LukS-PV promotes the apoptosis and cycle arrest of A549 and H460 cells through the P38/ERK MAPK signaling pathway [95]. For liver cancer, LukS-PV inhibits the migration of hepatocellular carcinoma cells by down-regulating histone deacetylase 6 (HDAC6) and increasing α-tubulin acetylation [115], and induces the apoptosis of HepG2 cells by regulating key proteins and metabolic pathways [96].

4.4. Staphylococcal Superantigens

Currently, there are many S. aureus superantigens, such as SEA, SEB, SEC, TSST1, and SpA, which can exert anti-tumor effects by inducing immune cell death, tumor cell apoptosis and other mechanisms [147,148,149]. Several tumor-specific superantigens for cancer treatment are under development [39,150,151].

4.4.1. Staphylococcus Aureus Enterotoxin A

Enhanced SEA expression in tumor cells with poor immunogenicity increases immunogenicity as a vaccine [53]. In addition, SEA can be utilized in the design of fission superantigen fusion proteins for cancer immunotherapy [41,62,147,151]. For instance, Dohlsten M. et al. designed a C242Fab-SEA fusion protein to target SEA-reactive T cells against MHC-class II negative human colon cancer cells at nanomolar concentrations in vitro [41]. Additionally, an oncolytic adenovirus (PPE3-SEA) was reported to inhibit the growth of mice bladder cancer MB49 cells [62].

4.4.2. Staphylococcus Aureus Enterotoxin B

Like SEA, SEB has significant anti-tumor effects by activating T cells in tumor-bearing mice [38]. Akbari, A. et al. reported that SEB effectively down-regulated the expression of SMAD family members by 2/3 and reduced the proliferation of human primary glioblastoma cell line U87 [80]. Several publications reported the links between SEB and bladder cancer. SEB can activate T lymphocytes and inhibit bladder tumor cell growth in vitro and in vivo [152]. The anti-angiogenic effect of SEB was also observed in an experiment using a rat model of nonmuscle invasive bladder cancer [59]. SEB-stimulated peripheral blood mononuclear cells can lead to the apoptosis of transitional cell carcinoma cells [43]. Similarly, the corresponding modifications of SEB serve as efficient instruments of cancer therapy [60,147]. For instance, Gu L. et al. designed the SEB-H32Q/K173E mutant, which retains the properties of SAg, enhances the host immune response to tumor disease, and reduces the associated thermotoxicity [60].

4.4.3. Staphylococcus Aureus Enterotoxin C

Highly agglutinative staphylococcin (HAS), a mixture of S. aureus culture filtrate, plays a certain immunomodulatory role through the active SEC component in the clinical treatment of breast cancer, colon cancer, bladder cancer and other cancers [74,75,153]. As a result, HAS may reduce the side effects of radiotherapy or chemotherapy in specific tumors to a certain extent and improve the survival prognosis of patients [74,153]. In China, SEC2 and a series of mutants have commonly been used as antitumor immunotherapy agents [67,154,155].

4.4.4. Toxic Shock Syndrom Toxin-1

Superantigen TSST-1 was reported to stimulate T-cell activation and enhance the cytotoxic effect of T cells on colorectal cancer LoVo cells [63]. Jiang Y. Q. et al. reported that the fusion of protein TSST-1 with a 12-mer peptide was able to inhibit the hepatocellular carcinoma cell growth by activating T lymphocytes [45]. Additionally, LINC00847 lncRNA may serve as a therapeutic target of the staphylococcal enterotoxin TST gene in renal cell carcinoma [104].

4.4.5. Staphylococcal Protein A

As one of the most essential S. aureus cell wall proteins, SpA can be utilized in the clinical treatment of cancer [156]. Based on the cross-linking between SpA and the Fc region of an immunoglobulin, the immunoprecipitation assay of tumor-related protein molecular interactions can be performed, or the delivery system of anti-cancer antibodies or drugs can be prepared [157,158]. For instance, an alkyl vinyl sulfone/protein A-based immunostimulating complex was established to deliver the cancer drugs to trastuzumab-resistant HER2 (human epidermal growth factor receptor 2)-overexpressing breast HCC1954 cells [73].

4.5. Others

Other substances of Staphylococcus are found to have certain tumor-suppressive effects. First, a protein purified from Staphylococcus hominis strain MANF2 was found to have the ability to reduce the viability of colon cancer cell line (HT-29) and lung cancer cell line (A549) when associated with fermented food [103]. Second, the chemotaxis inhibitory protein of S. aureus can inhibit the mitochondrial peptide-induced migration of U87 glioblastoma cells [71]. Third, the peptidoglycan of infectious S. aureus can actively trigger the Toll-like receptor 2 to promote the invasiveness and adhesiveness of MDA-MB-231 cells in vitro [55]. Fifth, the S. epidermidis strain MO34 inhibited the melanoma growth by producing 6-n-hydroxyaminopurine [88,159]. Sixth, cytoplasmic fractions of Enterococcus faecalis and Staphylococcus hominis, isolated from human breast milk, can inhibit the proliferation of MCF-7 cells [77]. Lastly, S. aureus-derived extracellular vesicles enhance the efficacy of tamoxifen therapy in breast cancer cells (MCF7 and BT474) [111].

5. Conclusions

The treatment of clinical cancer patients is often complicated with Staphylococcus infection, and different tumor treatments are often accompanied by a change in the Staphylococcus spectrum. Other types of staphylococci have distinct and even opposite effects on the occurrence and development of specific tumors. Herein, we provided a bidirectional functional effect model of Staphylococcus on carcinogenesis, as shown in Figure 1.
Figure 1. Bidirectional functional effects of Staphylococcus on carcinogenesis. Staphylococcus has the bidirectional effects on carcinogenesis in various types of cancers, such as skin cancer, lung cancer, bladder cancer, colon cancer, liver cancer, lymphoma, breast cancer, glioblastoma, and oral cancer. On the one hand, the changes of staphylococcal flora in some tissues of the body, such as oral cavity, skin or urinary system, was linked to the predisposition to cancer or detected in cancer cases undergoing chemotherapy and/or radiotherapy. MRSA is often associated with a reduced survival rate of patients with malignant tumors. SNases work as the extracellular nucleases of S. aureus, and there exists a human homologue of SNases, SND1, which is closely related to the occurrence and development of different cancers. On the other hand, S. lugdunensis can secrete a lugdunin to curb the reproduction and infection of MRSA. S. aureus may play the role of tumor inhibition through the points of bacterial toxins (alpha-hemolysin, PVL or LurkS-PV), superantigens (SEA/B/C, TSST-1, SpA) of T/B cells, or adhesion molecules. Additionally, the inhibition of SND1 nuclease activity by pdTp may be an effective intervention or therapeutic strategy for liver cancer. This figure was drawn by Figdraw.
To treat cancer patients with bacterial infections, it is important to suppress their complications, starting with the pathogenic mechanism of specific Staphylococcus. Targeting the structures, secreted products, or artificial modifications of various virulence factors may result in great success when treating tumors. The accurate and efficient application of specific staphylococcal anti-tumor components also depends on basic experimental evidence, as well as the ongoing improvement of the system for the separation, purification, and presentation of active components.
In this review, we, for the first time, summarize the clinical reports, cellular and animal experimental evidence regarding the association between Staphylococcus and the diagnosis and treatment of tumors. Additionally, we systematically investigated the functional links between staphylococci and the occurrence, development, diagnosis, and treatment of breast, skin, oral, colon, and other types of cancers, in terms of surface adhesion molecules, α-hemolysin, PVL, SEs, TSST-1, SpA, and SND1, which provides novel insight into the functional relationship between bacterial infections and tumors.

Author Contributions

Conceptualisation: J.Y., Y.R., X.G.; data curation: X.Y., Y.W., E.S.; writing—original draft preparation: Y.W., X.G., Y.R.; writing—review and editing: E.S., J.Y.; project administration: J.Y.; funding acquisition: J.Y., X.G. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by grants from Tianjin Natural Science Foundation (20JCYBJC00470 to X.J.); National Nature Science Foundation of China (32271201, 32070724 to J.Y.); Scientific Research Project of Tianjin Education Commission (Natural Science) (2019KJ171 to Y.R.); Excellent Talent Project of Tianjin Medical University (to J.Y.).

Data Availability Statement

Availability of published literature and correspondence should be addressed to the corresponding author.

Conflicts of Interest

The author declares no conflict of interest.

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