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Journal of Cancer Prevention

Review

J Cancer Prev 2024; 29(4): 120-128

Published online December 30, 2024

https://doi.org/10.15430/JCP.24.010

© Korean Society of Cancer Prevention

Shiga Toxin: Emerging Producer Strains, Prophylactic Approaches, and Application in Cancer Therapy

Kiandokht Babolhavaeji1 , Amjad Ahmadi1,2 , Leili Shokoohizadeh3

1Department of Microbiology, School of Medicine, 2Student Research Committee, 3Infectious Disease Research Center, Avicenna Institute of Clinical Sciences, Avicenna Health Research Institute, Hamadan University of Medical Sciences, Hamadan, Iran

Correspondence to :
Leili Shokoohizadeh, E-mail: l.shokohizadeh@umsha.ac.ir, https://orcid.org/0000-0003-0136-3666

Received: June 9, 2024; Revised: October 18, 2024; Accepted: November 12, 2024

This is an Open Access article distrBifidobacterium longum, Irritable bowel syndrome, Rats, Probioticsibuted under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Shiga toxin-producing Escherichia coli is the most prevalent bacterial strain responsible for Shiga toxin-related infections. While Shiga toxin is inherently toxic, it has potential therapeutic applications as a component of anticancer drugs. Despite its association with infections and harmful effects on human health, Shiga toxin is being explored as a viable element in drug delivery systems targeting cancer cells. The findings indicate that the production of mutated bacteria containing Shiga toxin is an effective preventive strategy for immunization against these toxins. Furthermore, the B subunit of Shiga toxin shows promise for imaging cancer cells, opening new paths for therapeutic interventions.

Keywords: Shiga toxin, Escherichia coli, Cancer

INTRODUCTION

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Shiga toxins (Stxs) are type 2 ribosome-inactivating proteins primarily produced by Stx-producing Escherichia coli (STEC) and were first identified in Shigella dysenteriae [1,2]. They are classified into Stx1 and Stx2, with various subtypes, and their nomenclature has been inconsistent, causing confusion in identifying STEC strains [3]. A comparison of the nucleotide sequences of Stx from S. dysenteriae and STEC revealed that the genes encoding these toxins are almost identical [4]. Stx2 infections are more common than Stx1, and risk factors include dietary habits, environmental exposure, and socioeconomic status. The toxins are genetically phage-derived, and hybrid E. coli strains may increase pathogenicity [5]. Hybrid strains of E. coli have been described to be highly pathogenic. The development of these strains may be attributed to outbreaks when a mixture of different virulence genes is present in a single strain [6].

Stx infections can cause severe conditions like hemorrhagic colitis and hemolytic uremic syndrome (HUS), with symptom severity varying among individuals. Some gut microbiota can inhibit Stx production, suggesting probiotics may boost immune responses [7]. It has been shown that the commensal bacteria of the gut microbiota prevent Stx production by producing short-chain fatty acids such as acetic acid, lactic acid, and propionic acid, which can lower the intestinal tract pH. Furthermore, enhancing the levels of immunoglobulin A and promoting inflammatory responses against Stxs are associated with the presence of probiotic bacteria [8]. Additionally, high levels of Stxs’ receptor Gb3, found in cancer tissues, suggests its potential therapeutic applications in cancer treatment [5]. The present review summarizes studies describing the different characteristics of Stx and its producing strains with focus on Stx’s role in cancer prevention and treatment. In addition, especially this study will investigate Stx’s role in cancer prevention and treatment.

COMPARISON OF TOXICITY OF STX1 AND STX2

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In 1993, Tesh et al. [9] found that toxicity of Stx2a is considerably lower than that of Stx1a in mice when administered intravenously or intraperitoneally. Subsequent studies in primate models indicated that Stx1 caused more severe kidney histopathological damage compared to Stx2 [10]. However, epidemiological studies show that infections from STEC strains producing only Stx2a, or both Stx1a and Stx2a, are more likely to provoke life-threatening conditions such as HUS and thrombotic thrombocytopenic purpura than those from strains producing only Stx1a [11]. For example, intravenous doses of Stx2 induced HUS, while equivalent doses of Stx1 did not [12]. Additionally, Stx2a was found to be more potent than Stx1a in mice and had a significantly higher cytotoxicity to human renal microvascular endothelial cells. Notably, the presence of Stx1a in certain strains can reduce overall morbidity and Stx1a’s B subunit could decrease the toxicity of Stx2a in vivo [13]. The induction of stx1 expression does not cause bacterial lysis, with Stx1 mainly residing within bacterial cells, whereas stx2 gene transcription is closely linked to the phage lytic cycle and is more often associated with severe disease [14]. Studies have shown that Stx2a is more prevalent among HUS patients and commonly coexists with other STEC virulence factors [15]. Understanding the mechanisms underlying the greater potency of Stx2 is crucial for developing strategies to prevent E. coli O157:H7 infections from progressing to HUS. Stx2 also shows superior binding to Gb3 compared to Stx1 [16].

ESCHERICHIA COLI AS A PROMINENT BACTERIUM THAT PRODUCES SHIGA TOXIN

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Stxs are present in various STEC serotypes, including O26, O45, O55, O91, O103, O104, O111, O113, O121, O128, O145, O146, and O157 [17]. Notably, the serotype O157:H7 evolved from the non-STEC O55:H7 through the acquisition of two prophages that encode Stx [18]. Enterohaemorrhagic E. coli (EHEC), a subset of STEC, is associated with severe illnesses like bloody diarrhea and HUS [19]. EHEC strains also contain an additional eae gene found in the locus of enterocyte effacement (LEE) Pathogenicity Island, marking them as the “classical” subset of STEC [20]. While Stx and the LEE are significant virulence factors for classical EHEC, virulence levels among Stx-encoding E. coli strains are highly variable, and the LEE is not consistently present in all pathogenic strains [2].

HYBRID STRAINS AND NON-E. COLI BACTERIA THAT PRODUCE SHIGA TOXIN

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Hybrid pathotypes of E. coli are prevalent in outbreaks and consist of diverse strains that can share genetic Stx components with non-Stx-producing strains. These hybrid strains, including STEC/enterotoxigenic E. coli (ETEC) and STEC/uropathogenic E. coli, have been identified in both epidemic and non-epidemic contexts [21]. The Bai et al. [22] study identified clinical hybrids of STEC and ETEC. Notably, some hybrids, such as O15:H16, O187:H28, O100:H30, and O136:H12 serotypes, have also been isolated from individuals without any reported illness, indicating that healthy contacts can harbor these hybrids. This suggests a broader ecological presence of these serotypes beyond clinical settings [22]. Gati et al. [23] explored hybrid strains producing both diarrhea and urinary tract infections, suggesting a link to selective pressures within specific E. coli populations. Notably, hybrids like O104:H4, which emerged during the 2011 outbreak in Germany, exhibited a hybrid genome more similar to enteroaggregative E. coli than EHEC. Other serotypes, such as O137:H6, have also been identified as hybrids [24,25]. Stxs are also produced by non-E. coli bacteria, not just STEC strains. These toxins can be found in various bacterial genera through lysogenic phage transduction, leading to their insertion into bacterial genomes. For example, Campylobacter jejuni produces Shiga-like toxins at lower levels, which are antigenically different from those produced by STEC. Ultimately, the level of toxin production by non-STEC bacteria determines its classification as Stx [26-29]. Table 1 and 2 show different Stx types and subtypes in non-E. coli bacteria and virulence genes identified in STEC hybrid strains, respectively [30-53].

Table 1 . Stx gene(s)-positive non-Escherichia coli bacteria, type/subtype of stx harbored, stx carrier and origin

BacteriaStx type/
subtype		stx gene carrierOrigin of stx geneSourceReference
Shigella flexneri serotype 2aStx1ΦPOC-J13 phage-Clinical sample[30]
S. flexneri serotype YStx1ΦPOC-J13 phage-Clinical sample[31,32]
S. flexneri serotype 2Stx1a--Clinical sample[33]
Shigella dysenteriae serotype 1Stx1-Chromosome-[34,35]
S. dysenteriae serotype 4Stx1Phage-Clinical sample[31,32]
Shigella sonneiStx1PhageS. dysenteriae serotype 1Clinical sample[36]
S. sonneiStx1, Stx2aPhageE. coliClinical sample[37]
S. sonneiStx1ΦSs-VASD phage-Clinical sample[38]
ListeriaStx1a--Animal manure[39]
Aeromonas hydrophila F-0050Stx1, Stx2Extracellular DNA in outer membrane vesiclesSTEC O157:H7 CECT 4076Clinical sample[40]
A. hydrophilaShiga like toxin1PlasmidSTEC O157:H7Clinical sample[41]
Aeromonas caviaeShiga like toxin1PlasmidSTEC O157:H7Clinical sample[41]
AeromonasStx1, Stx2Phage-Clinical sample[42]
Salmonella entericaStx2f---[39]
Acinetobacter hemolyticusStx2Phage-Clinical sample[43]
Enterobacter cloacae M12X01451 strainStx1ePhage-Clinical sample[44]
E. cloacae strain 13047Stx1e, Stx1aPhageE. cloacae M12X01451,E. coli RM8530Designed in laboratory[18]
Citrobacter freundiiShiga like toxin2-STEC O157Clinical sample[45]
C. freundii RIT669Shiga like toxin--Turtles[46]
Citrobacter rodentium DBS770Stx2dPhage-Designed in laboratory[47]

Stx, Shiga toxin; -, not applicable.

Table 2 . Virulence genes in the STEC hybrid strains

Hybrid strainSerotypeCombined virulence geneReference
EPEC/EHEC-eaeAa + stx2b[48]
EPEC/EHEC-eaeA + bfpc + stx1,2[48]
EHEC/ETEC-stx2 + stad
stx1 + sta
stx1 + sta + lte		[48]
EAEC/EHEC/ETEC-eaggf + stx1 + sta[48]
EPEC/EHEC/ETEC-eaeA + stx1 + sta
eaeA + stx1,2 + lt + sta		[48]
STEC/ETEC strain SE572O187:H28stx2 + sta4,5[49]
STEC/ETEC strain SE573O15:H16stx2 + sta4[49]
STEC/ETEC strain SE574O136:H12stx2 + sta4,5[49]
STEC/ETEC strain SE575O100:H30stx2 + sta1[49]
STEC/ETEC strain MFDS1016416O100:H30stx2A + stx2B[50]
STEC/ETEC strain MFDS1015939O168:H8-[50]
STEC/ETEC strain MFDS1016233O8:H9-[50]
STEC/ETEC strain MFDS1016229O155:H21-[50]
STEC/ETEC strain MFDS1016200O141:H29-[50]
STEC/ETEC strain MFDS1016224O174:H2-[50]
STEC/ETEC strain MFDS1007784O2:H27-[50]
STEC/ETEC strain MFDS1009736O148:H7-[50]
STEC/ETEC strain MFDS1012367O2:H25-[50]
UPEC/STEC-hlyAg + cnfh + stx[51]
STEC/UPEC-hlyA + stx + EHEC-hlyAC*[51]
UPEC/STEC/EAEC-hlyA + stx + astAi[51]
EAEC/EHEC strain LB226692O104:H4stx2 + rfbO104j + fliCH4k[52]
STEC/ETEC strain FE95160O2:H25stx2A + stx2B + astA + sta1 + hlyA-D[53]
STEC/ETEC strain IH57218O2:H27stx1A + stx1B + sta1 + hlyA-D[53]
STEC/ETEC strain IH53473O101:H33stx1A + stx1B + hlyA-D[53]
STEC/UPECHM strain 2018C-3367O75:H7stx2b + fyuAl + vatm + yfcVn[18]
STEC/UPECHM strain 2013C-3244O1:K22:H4stx2b + fyuA + vat + yfcV[18]

STEC, Shiga toxin-producing Escherichia coli; EPEC, enteropathogenic Escherichia coli; stx, Shiga toxin; EHEC, enterohaemorrhagic Escherichia coli; ETEC, enterotoxigenic Escherichia coli; EAEC, enteroaggregative Escherichia coli; UPEC, uropathogenic Escherichia coli; -, not applicable. aEscherichia coli attaching and effacing, bShiga toxin, cbundle-forming pili, dheat-stable enterotoxin, eheat-labile enterotoxin, fentero adherent aggregative, ghemolysin,hcytotoxic necrotizing factor, iaggregative heat-stable toxin, jlipopolysaccharide, kflagellin, lferric yersiniabactin, mvacuolating autotransporter toxin, nfimbrial protein.

TREATMENT/PROPHYLAXIS APPROACHES

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Hybrid STEC strains primarily derived from E. coli typically do not produce Stxs and are associated with severe complications, such as bloody diarrhea and HUS. The serotype O157 is the most common in HUS cases, and a study indicated that pediatric patients under two are particularly affected [54]. High levels of Stx can trigger the SOS response in the host, leading to increased toxin production and worsened infections [55]. Research has explored antibiotics that inhibit transcription and translation to reduce Stx production in EHEC, suggesting potential treatments for Stx-related infections. Additionally, dietary factors, such as the level of butyrate and fiber intake, have been shown to influence Stx binding and uptake, affecting the severity of infections in mouse models. High-fiber diets were linked to increased STEC colonization and to worse health outcomes compared to low-fiber diets [56].

VACCINES FOR SHIGA TOXIN-RELATED INFECTIONS

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Research is exploring vaccines as alternatives to antibiotics for preventing Stx-related infections, as antibiotics can increase the risk of progressing to HUS. Vaccination against stx2d-producing Citrobacter rodentium has shown efficacy, and a conjugate vaccine protected mice against STEC O157:H7 and O91:H21 [55]. Cattle, asymptomatic carriers of STEC O157, are targeted for vaccination to reduce zoonotic transmission [57]. Studies demonstrated that adjuvant vaccines in cattle elicited strong immune responses, while vaccination of pigs reduced mortality from STEC [58]. Transcutaneous immunization with the Stx 1 B subunit (StxB1) in rabbits showed promise, improving weight gain and eliciting specific antibody responses [59]. Additionally, oral administration of a Vibrio cholerae strain produced neutralizing antibodies, and a mutant Salmonella strain expressing the StxB1 induced significant immune responses [48,60]. Overall, these findings encourage continued development of vaccines for STEC infections.

USING STX FOR CANCER THERAPY

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The Gb3 receptor for Stx is overexpressed in cancer tissues, suggesting a potential path for using Stx in combination with therapeutic compounds for cancer imaging and targeted therapy [61]. However, Farkas-Himsley et al. [62] have noted that increased Gb3 levels are not directly indicative of malignancy but rather serve as a marker of cellular growth. Elevated levels of Gb3 have been observed in various cancers, including B-cell lymphomas and certain solid tumors like, such as testicular, breast, and ovarian carcinomas. Consequently, several planned Stxs have been developed and are currently under evaluation as potential anticancer agents. Additionally, researchers are exploring the potential of the non-active binding subunit, StxB, as a delivery mechanism for the treatment or imaging of Gb3-positive tumors [63].The attachment of a molecule to StxB or StxA can change the original Stx’s chemical and physical properties, affecting its stability, immunogenicity, and biodistribution, which could influence off-target toxicity and efficacy [63]. Moreover, the small size of StxB may hinder its ability to bind to Gb3 when connected to larger molecules. Thus, ensuring stability and optimal pharmacokinetics is essential in developing engineered Stxs [64,65]. Key points regarding the application of Stxs in biomedical contexts, focusing on their therapeutic potential, challenges, and innovations in engineering for cancer treatment are summarized as follows: Stxs specifically target Gb3-positive cells and efficiently deliver toxins to the cytosol, surpassing endosomal degradation. Stxs are stable in extreme pH and protease presence, and can cross tissue barriers, enhancing biodistribution. Gb3 is overexpressed in various tumors (e.g., breast, ovarian, pancreatic, etc.), including metastatic cancers, suggesting a potential link to chemoresistance. Stxs may possess antineoplastic (anti-cancer) and anti-angiogenic properties, effectively inducing cancer cell apoptosis [62-70]. Shiga and Shiga-like toxins show promise for treating Gb3-expressing cancers due to their high specificity and ability to induce apoptosis. This apoptotic process involves increased levels of pro-apoptotic proteins and a reduction in anti-apoptotic ones. By selectively targeting specific signaling pathways, these toxins may minimize damage to normal tissues and serve as a foundation for developing targeted antitumor therapies [71].

PREFERENCE FOR MODIFIED STX TOXIN

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Intratumor injections of Stx have improved survival in mice with various cancers. Holotoxins have significant toxicity (e.g., damage to endothelial cells) and high immunogenicity, which limits their clinical applications [61]. Testing Stx in clinical trials is also constrained by its immunogenicity, primarily attributed to the A subunit [63,72,73]. Preference for modified toxins over holotoxins to reduce immunogenicity while preserving therapeutic effects are as follows:

The antibody-coupled A subunit for cancer treatment

Immunotoxins that are Linking link toxin subunits to antibodies (immunotoxins) enhances specificity and have been utilized in Food and Drug Administration-approved treatments, though few have been approved [63,73].

Engineered toxin bodies

Molecular templates have developed engineered toxin bodies (ETBs), where a modified Stx1 A subunit is fused to antibody fragments for targeted therapy (e.g., MT-3724 for diffuse large B-cell lymphoma). Early trials of MT-3724 show promising results with manageable side effects. In the second-generation ETBs the deimmunized StxA are employed and are showing potential in targeting other markers (e.g., HER2 with MT-5111). In the third-generation ETBs, further ETBs are engineered to deliver antigens for immune recognition, such as MT-6402, targeting PD-L1 and enhancing immune response against tumors [63,74-77]. Danielewicz et al. [78] created a novel noncanonical amino acid, azido lysine incorporated-StxB1 (STxAZK), which effectively recognizes and binds to the Gb3 receptor, as confirmed by flow cytometry. Gb3 was detected in human colorectal adenocarcinoma cell lines, particularly abundant in HT-29 cells, and present in lower amounts in LS-174 cells. Moreover, STxAZK was combined with the anti-cancer prodrug monomethyl auristatin E, resulting in a highly effective formulation capable of eliminating HT-29 cancer cells [78].

UNIQUE PROPERTIES OF STXB FOR CANCER THERAPY

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StxB retains significantly more binding sites on cancer cells compared to antibodies, making StxB a more effective vector for targeted delivery of cytotoxic drugs to Gb3-positive cancers. It can transport poorly soluble molecules and has been successfully coupled with various chemotherapy agents like doxorubicin, auristatin F, and SN38, demonstrating impressive potency against cancer cell lines, particularly with StxB-SN38 showing over 100 times stronger cytotoxicity than irinotecan [63]. StxB has also enhanced the efficacy of photosensitizers used in photodynamic therapy, showing improved delivery and effectiveness in targeting cells [79-83]. Recently, StxB has been shown to facilitated the delivery of engineered monobodies that inhibit oncogenic proteins, and studies indicate its potential for tumor suppression, although most research has been in vitro [84]. Additionally, StxB has potential in cancer immunotherapy as it can promote antigen presentation and T-cell responses, highlighting its versatility as a carrier in both drug delivery and vaccine development. Vaccination of mice with StxB conjugated to E7, a protein derived from HPV16, has demonstrated the ability to inhibit the growth of tumors that express E7 [63,85]. Therefore, StxB represents a promising and competitive candidate as a carrier protein for cancer vaccines. The StxB effectively targets antigens to dendritic cells (DC) in vivo, which enhances anti-tumor immunity [85]. By facilitating the delivery of these antigens, StxB promotes the activation of T-cells, leading to a stronger immune response against cancer cells. The findings suggest that StxB could serve as a valuable tool in cancer immunotherapy by improving antigen presentation and boosting the body’s ability to fight tumors [85].

Some in vivo studies, such as the N8A-StxB fusion showing tumor growth suppression in mice, suggest that further optimization of StxB conjugates is necessary for enhanced efficacy in clinical settings [86]. They concluded STxB is a potent and versatile carrier protein for immunization. Since STxB binds to the same glycolipid, Gb3, in both human and mouse DC, and this receptor’s distribution is consistent across species; the preclinical findings can likely be translated to human applications [85]. Table 3 summarizes the investigated anti-cancer or anti-tumor activities of Stx, highlighting its targets and mechanisms or effects [87-94].

Table 3 . Anti-cancer activities of Stx

TargetMechanismReference
Cancer cellsStx induces apoptosis through activation of caspase-3, leading to programmed cell death[87,88]
Endothelial cellsStx inhibits angiogenesis by binds to Gb3 receptors on endothelial and tumor cells[66]
Tumor microenvironmentStx can be used in antigen presentation studies, to induce protective cell mediated immunity to improve the clearance of certain tumors
Stx can deliver antigen directly to dendritic cells		[85]
Glycolipid receptorsStx binds to Gb3 receptors on cancer cells, resulting in cell death[90-92]
Cell cycle regulatorsStx induces G1 phase arrest in cancer cells, leading to inhibited proliferation[93]
Metastatic spreadStx may disrupt cellular adhesion and migration, potentially reducing metastasis[94]

Stx, Shiga toxin.

KEY CHALLENGE IN UTILIZING STXS AS ANTICANCER AGENTS

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A significant challenge in using Stxs as anticancer agents is the economic and environmental feasibility of their large-scale production, which is typically done in E. coli. However, these recombinant proteins often aggregate in inclusion bodies, limiting yield and requiring extensive processing, leading to further losses. Moreover, endotoxins produced during this process must be removed before human use. This subject contributed to the discontinuation of the clinical use of some approved immunotoxins [63,95].

CONCLUSION

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Stxs are prominent protein synthesis-inhibiting toxins produced by STEC and pose significant health risks. To combat infections caused by these toxins, innovative vaccine candidates are being developed, as conventional antibiotic treatment becomes less viable due to rising bacterial resistance. Stx shows potential for targeted cancer therapy by exploiting specific cellular receptors commonly overexpressed in tumors. Stxs have evolved to be highly effective carriers for delivering toxic proteins to cells by binding to specific surface receptors. They can be utilized as anticancer agents in both their native and engineered forms, with ETBs showing particular promise. Recent advancements in genetic engineering facilitate the creation of immunotoxins. Ongoing research is critical to further establish Stx the efficacy and safety profile of Stx across varied cancer types.

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