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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 14832

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Dr. Sara Travaglione

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Guest Editor

Department of Cardiovascular, Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità, 00161 Rome, Italy
Interests: bacterial protein toxins; Rho GTPases; actin cytoskeleton; mitochondria; cellular microbiology; cancer; toxins as therapeutics

Dr. Alessia Fabbri

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Guest Editor

Special Issue Information

Dear Colleagues,

The human body is inhabited by a complex community of at least 100 trillion microbial cells, including bacteria, eukaryotes, viruses, and archaeon collectively referred to as microbiota, which interact with one another and with the host, influencing human well-being. Protein toxins are among the main virulence factors produced by pathogenic bacteria and favor their colonization and diffusion in the host, disturbing the host's balance, thus causing disease. Toxins can manipulate crucial host cellular processes, such as protein synthesis, cytoskeletal organization, intracellular signaling pathways, and vesicle trafficking. Thanks to their highly specific enzymatic activity on molecular targets, some bacterial toxins have represented useful tools for molecular biology studies and, in recent years, have been considered for medical applications. In fact, an increasing number of bacterial toxins are employed as new therapeutics or are regarded as possible innovative drugs, especially in the field of anticancer therapies. On the other hand, however, growing evidence suggest that bacterial chronic infections may significantly contribute to carcinogenesis in some district and the pro-carcinogenic potential of chronic exposure to toxin-producing pathogenic bacteria is emerging as a new frontier in studies focused on the infectious causes of cancer. The pro-carcinogenic activity stems, as a side effect, from direct damage to the DNA, with consequent instability of the genome, or from perturbation of cell signaling pathways that influence resistance to cell death and proliferative signaling, resulting in cell transformation.

This special issue will be focused on bacterial toxins and cancer either considering the anti-cancer activity of toxins or their involvement in cancer onset and progression.

Dr. Sara Travaglione
Dr. Alessia Fabbri
Guest Editors

Manuscript Submission Information

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Keywords

bacterial toxins
dysbiosis
inflammation
microbiota
DNA damage
carcinogenesis
cell signaling
cell death
cell proliferation
immune system

Published Papers (7 papers)

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Editorial

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5 pages, 202 KiB

Open AccessEditorial

Special Issue “Bacterial Toxins and Cancer”

by Sara Travaglione, Francesca Carlini, Zaira Maroccia and Alessia Fabbri

Int. J. Mol. Sci. 2024, 25(4), 2128; https://doi.org/10.3390/ijms25042128 - 09 Feb 2024

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Abstract

Infection is a major contributor to the development of cancer, with more than 15% of new cancer diagnoses estimated to be caused by infection [...] Full article

(This article belongs to the Special Issue Bacterial Toxins and Cancer)

Research

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17 pages, 2002 KiB

Open AccessArticle

Feasibility of Co-Targeting HER3 and EpCAM Using Seribantumab and DARPin–Toxin Fusion in a Pancreatic Cancer Xenograft Model

by Tianqi Xu, Alexey Schulga, Elena Konovalova, Sara S. Rinne, Hongchao Zhang, Olga Vorontsova, Anna Orlova, Sergey M. Deyev, Vladimir Tolmachev and Anzhelika Vorobyeva

Int. J. Mol. Sci. 2023, 24(3), 2838; https://doi.org/10.3390/ijms24032838 - 02 Feb 2023

Cited by 3 | Viewed by 2163

Abstract

Pancreatic cancer (PC) is one of the most aggressive malignancies. A combination of targeted therapies could increase the therapeutic efficacy in tumors with heterogeneous target expression. Overexpression of the human epidermal growth factor receptor type 3 (HER3) and the epithelial cell adhesion molecule (EpCAM) in up to 40% and 30% of PCs, respectively, is associated with poor prognosis and highlights the relevance of these targets. Designed ankyrin repeat protein (DARPin) Ec1 fused with the low immunogenic bacterial toxin LoPE provides specific and potent cytotoxicity against EpCAM-expressing cancer cells. Here, we investigated whether the co-targeting of HER3 using the monoclonal antibody seribantumab (MM-121) and of EpCAM using Ec1–LoPE would improve the therapeutic efficacy in comparison to the individual agents. Radiolabeled ^99mTc(CO)₃-Ec1–LoPE showed specific binding with rapid internalization in EpCAM-expressing PC cells. MM-121 did not interfere with the binding of Ec1–LoPE to EpCAM. Evaluation of cytotoxicity indicated synergism between Ec1–LoPE and MM-121 in vitro. An experimental therapy study using Ec1–LoPE and MM-121 in mice bearing EpCAM- and HER3-expressing BxPC3 xenografts demonstrated the feasibility of the therapy. Further development of the co-targeting approach using HER3 and EpCAM could therefore be justified. Full article

(This article belongs to the Special Issue Bacterial Toxins and Cancer)

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15 pages, 2099 KiB

Open AccessArticle

Expanding the Therapeutic Window of EGFR-Targeted PE24 Immunotoxin for EGFR-Overexpressing Cancers by Tailoring the EGFR Binding Affinity

by Sei-Yong Jun, Dae-Seong Kim and Yong-Sung Kim

Int. J. Mol. Sci. 2022, 23(24), 15820; https://doi.org/10.3390/ijms232415820 - 13 Dec 2022

Cited by 4 | Viewed by 1689

Abstract

Immunotoxins (ITs), which are toxin-fused tumor antigen-specific antibody chimeric proteins, have been developed to selectively kill targeted cancer cells. The epidermal growth factor receptor (EGFR) is an attractive target for the development of anti-EGFR ITs against solid tumors due to its overexpression on the cell surface of various solid tumors. However, the low basal level expression of EGFR in normal tissue cells can cause undesirable on-target/off-tumor toxicity and reduce the therapeutic window of anti-EGFR ITs. Here, based on an anti-EGFR monobody with cross-reactivity to both human and murine EGFR, we developed a strategy to tailor the anti-EGFR affinity of the monobody-based ITs carrying a 24-kDa fragment of Pseudomonas exotoxin A (PE24), termed ER-PE24, to distinguish tumors that overexpress EGFR from normal tissues. Five variants of ER-PE24 were generated with different EGFR affinities (K_D ≈ 0.24 nM to 104 nM), showing comparable binding activity for both human and murine EGFR. ER/0.2-PE24 with the highest affinity (K_D ≈ 0.24 nM) exhibited a narrow therapeutic window of 19 pM to 93 pM, whereas ER/21-PE24 with an intermediate affinity (K_D ≈ 21 nM) showed a much broader therapeutic window of 73 pM to 1.5 nM in in vitro cytotoxic assays using tumor model cell lines. In EGFR-overexpressing tumor xenograft mouse models, the maximum tolerated dose (MTD) of intravenous injection of ER/21-PE24 was found to be 0.4 mg/kg, which was fourfold higher than the MTD (0.1 mg/kg) of ER/0.2-PE24. Our study provides a strategy for the development of IT targeting tumor overexpressed antigens with basal expression in broad normal tissues by tailoring tumor antigen affinities. Full article

(This article belongs to the Special Issue Bacterial Toxins and Cancer)

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14 pages, 2746 KiB

Open AccessArticle

Macrophage-Mediated Melanoma Reduction after HP-NAP Treatment in a Zebrafish Xenograft Model

by Gaia Codolo, Nicola Facchinello, Nicole Papa, Ambra Bertocco, Sara Coletta, Clara Benna, Luigi Dall’Olmo, Simone Mocellin, Natascia Tiso and Marina de Bernard

Int. J. Mol. Sci. 2022, 23(3), 1644; https://doi.org/10.3390/ijms23031644 - 31 Jan 2022

Cited by 8 | Viewed by 3658

Abstract

The Helicobacter pylori Neutrophil Activating Protein (HP-NAP) is endowed with immunomodulatory properties that make it a potential candidate for anticancer therapeutic applications. By activating cytotoxic Th1 responses, HP-NAP inhibits the growth of bladder cancer and enhances the anti-tumor activity of oncolytic viruses in the treatment of metastatic breast cancer and neuroendocrine tumors. The possibility that HP-NAP exerts its anti-tumor effect also by modulating the activity of innate immune cells has not yet been explored. Taking advantage of the zebrafish model, we examined the therapeutic efficacy of HP-NAP against metastatic human melanoma, limiting the observational window to 9 days post-fertilization, well before the maturation of the adaptive immunity. Human melanoma cells were xenotransplanted into zebrafish embryos and tracked in the presence or absence of HP-NAP. The behavior and phenotype of macrophages and the impact of their drug-induced depletion were analyzed exploiting macrophage-expressed transgenes. HP-NAP administration efficiently inhibited tumor growth and metastasis and this was accompanied by strong recruitment of macrophages with a pro-inflammatory profile at the tumor site. The depletion of macrophages almost completely abrogated the ability of HP-NAP to counteract tumor growth. Our findings highlight the pivotal role of activated macrophages in counteracting melanoma growth and support the notion that HP-NAP might become a new biological therapeutic agent for the treatment of metastatic melanomas. Full article

(This article belongs to the Special Issue Bacterial Toxins and Cancer)

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Review

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33 pages, 4978 KiB

Open AccessReview

AB Toxins as High-Affinity Ligands for Cell Targeting in Cancer Therapy

by Ana Márquez-López and Mónica L. Fanarraga

Int. J. Mol. Sci. 2023, 24(13), 11227; https://doi.org/10.3390/ijms241311227 - 07 Jul 2023

Cited by 1 | Viewed by 1951

Abstract

Conventional targeted therapies for the treatment of cancer have limitations, including the development of acquired resistance. However, novel alternatives have emerged in the form of targeted therapies based on AB toxins. These biotoxins are a diverse group of highly poisonous molecules that show a nanomolar affinity for their target cell receptors, making them an invaluable source of ligands for biomedical applications. Bacterial AB toxins, in particular, are modular proteins that can be genetically engineered to develop high-affinity therapeutic compounds. These toxins consist of two distinct domains: a catalytically active domain and an innocuous domain that acts as a ligand, directing the catalytic domain to the target cells. Interestingly, many tumor cells show receptors on the surface that are recognized by AB toxins, making these high-affinity proteins promising tools for developing new methods for targeting anticancer therapies. Here we describe the structure and mechanisms of action of Diphtheria (Dtx), Anthrax (Atx), Shiga (Stx), and Cholera (Ctx) toxins, and review the potential uses of AB toxins in cancer therapy. We also discuss the main advances in this field, some successful results, and, finally, the possible development of innovative and precise applications in oncology based on engineered recombinant AB toxins. Full article

(This article belongs to the Special Issue Bacterial Toxins and Cancer)

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23 pages, 1812 KiB

Open AccessReview

Clostridioides difficile Toxin B Induced Senescence: A New Pathologic Player for Colorectal Cancer?

by Katia Fettucciari, Alessandro Fruganti, Fabrizio Stracci, Andrea Spaterna, Pierfrancesco Marconi and Gabrio Bassotti

Int. J. Mol. Sci. 2023, 24(9), 8155; https://doi.org/10.3390/ijms24098155 - 02 May 2023

Cited by 4 | Viewed by 2192

Abstract

Clostridioides difficile (C. difficile) is responsible for a high percentage of gastrointestinal infections and its pathological activity is due to toxins A and B. C. difficile infection (CDI) is increasing worldwide due to the unstoppable spread of C. difficile in the anthropized environment and the progressive human colonization. The ability of C. difficile toxin B to induce senescent cells and the direct correlation between CDI, irritable bowel syndrome (IBS), and inflammatory bowel diseases (IBD) could cause an accumulation of senescent cells with important functional consequences. Furthermore, these senescent cells characterized by long survival could push pre-neoplastic cells originating in the colon towards the complete neoplastic transformation in colorectal cancer (CRC) by the senescence-associated secretory phenotype (SASP). Pre-neoplastic cells could appear as a result of various pro-carcinogenic events, among which, are infections with bacteria that produce genotoxins that generate cells with high genetic instability. Therefore, subjects who develop IBS and/or IBD after CDI should be monitored, especially if they then have further CDI relapses, waiting for the availability of senolytic and anti-SASP therapies to resolve the pro-carcinogenic risk due to accumulation of senescent cells after CDI followed by IBS and/or IBD. Full article

(This article belongs to the Special Issue Bacterial Toxins and Cancer)

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19 pages, 1172 KiB

Open AccessReview

The Role of Cyclomodulins and Some Microbial Metabolites in Bacterial Microecology and Macroorganism Carcinogenesis

by Natalia N. Markelova, Elena F. Semenova, Olga N. Sineva and Vera S. Sadykova

Int. J. Mol. Sci. 2022, 23(19), 11706; https://doi.org/10.3390/ijms231911706 - 03 Oct 2022

Cited by 3 | Viewed by 1628

Abstract

A number of bacteria that colonize the human body produce toxins and effectors that cause changes in the eukaryotic cell cycle—cyclomodulins and low-molecular-weight compounds such as butyrate, lactic acid, and secondary bile acids. Cyclomodulins and metabolites are necessary for bacteria as adaptation factors—which are influenced by direct selection—to the ecological niches of the host. In the process of establishing two-way communication with the macroorganism, these compounds cause limited damage to the host, despite their ability to disrupt key processes in eukaryotic cells, which can lead to pathological changes. Possible negative consequences of cyclomodulin and metabolite actions include their potential role in carcinogenesis, in particular, with the ability to cause DNA damage, increase genome instability, and interfere with cancer-associated regulatory pathways. In this review, we aim to examine cyclomodulins and bacterial metabolites as important factors in bacterial survival and interaction with the host organism to show their heterogeneous effect on oncogenesis depending on the surrounding microenvironment, pathological conditions, and host genetic background. Full article

(This article belongs to the Special Issue Bacterial Toxins and Cancer)

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