Umeå University's logo

umu.sePublikasjoner
Endre søk
Link to record
Permanent link

Direct link
Bergonzini, Anna
Publikasjoner (10 av 10) Visa alla publikasjoner
Pateras, I. S., Igea, A., Nikas, I. P., Leventakou, D., Koufopoulos, N. I., Ieronimaki, A. I., . . . Panayiotides, I. G. (2024). Diagnostic challenges during inflammation and cancer: current biomarkers and future perspectives in navigating through the minefield of reactive versus dysplastic and cancerous lesions in the digestive system. International Journal of Molecular Sciences, 25(2), Article ID 1251.
Åpne denne publikasjonen i ny fane eller vindu >>Diagnostic challenges during inflammation and cancer: current biomarkers and future perspectives in navigating through the minefield of reactive versus dysplastic and cancerous lesions in the digestive system
Vise andre…
2024 (engelsk)Inngår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, nr 2, artikkel-id 1251Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.

sted, utgiver, år, opplag, sider
MDPI, 2024
Emneord
artificial intelligence, biomarkers, cancer, digital pathology, dysplasia, immunohistochemistry, inflammation, molecular biology, pathology, reactive atypia, tissue response
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-220457 (URN)10.3390/ijms25021251 (DOI)38279253 (PubMedID)2-s2.0-85183424720 (Scopus ID)
Forskningsfinansiär
Swedish Cancer Society, 23 2814 PjThe Kempe Foundations, 2021 JCK-3110
Tilgjengelig fra: 2024-02-05 Laget: 2024-02-05 Sist oppdatert: 2024-02-05bibliografisk kontrollert
Bergonzini, A. (2023). Effects of bacterial genotoxins on immune modulation, chronic inflammation and cancer development. (Doctoral dissertation). Umeå: Umeå University
Åpne denne publikasjonen i ny fane eller vindu >>Effects of bacterial genotoxins on immune modulation, chronic inflammation and cancer development
2023 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Alternativ tittel[sv]
Effekter av bakteriella genotoxiner på immunmodulering, kronisk inflammation och cancerutveckling
Abstract [en]

The intestinal microbiome of Inflammatory Bowel Disease and colorectal cancer patients is enriched in genotoxin-producing bacteria, which cause DNA damage in the host cells.

Genotoxins have recently been identified as a novel family of effectors produced by pathogenic and commensal bacteria. At present, only three types of bacterial genotoxins have been identified: colibactin, produced by some Escherichia coli strains; cytolethal distending toxins, produced by several Gram-negative pathogens; and the typhoid toxin, produced by Salmonella enterica serovar Typhi.

Exposure to high toxin doses activates the classical DNA damage response, which consequently blocks proliferation and eventually induces death in mammalian cells. However, exposure to low toxin doses has shown to promote classical signs of carcinogenesis in vitro, such as cell survival and acquisition of genomic instability. Despite an extensive characterization of their mode of action in vitro, we have a poor understanding of genotoxins´ role in chronic infection and, considering the genotoxic potential, of their carcinogenic capacity. To investigate further the role played by the genotoxins, we focused specifically on Salmonella Typhi, since it is the only genotoxin-producing bacterium that induces a chronic infection associated with increased risk of tumor development in humans. 

The results presented in this thesis show that these unusual bacterial effectors are not classical toxins, but rather act as immunomodulators, highlighting a complex and tissue-specific crosstalk between two highly conserved stress responses: the immune response and the DNA damage response. 

Our data indicate that the impact of genotoxin-producing bacteria on the modulation of the host mucosal response is still poorly characterized and suggest that the host-microbe interaction and the tissue microenvironment are the key players in determining the outcome of the infection and the toxin carcinogenic potential. 

sted, utgiver, år, opplag, sider
Umeå: Umeå University, 2023. s. 93
HSV kategori
Forskningsprogram
immunologi
Identifikatorer
urn:nbn:se:umu:diva-203905 (URN)978-91-7855-971-8 (ISBN)978-91-7855-972-5 (ISBN)
Disputas
2023-02-24, Major Groove, Department of Molecular Biology, University hospital area, building 6L., Umeå, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2023-02-03 Laget: 2023-01-23 Sist oppdatert: 2023-01-25bibliografisk kontrollert
Lopez Chiloeches, M., Bergonzini, A., Martin, O. C. B., Bergstein, N., Erttmann, S. F., Aung, K. M., . . . Frisan, T. (2023). Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes. Frontiers in Immunology, 14, Article ID 1270449.
Åpne denne publikasjonen i ny fane eller vindu >>Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes
Vise andre…
2023 (engelsk)Inngår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, artikkel-id 1270449Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Introduction: Typhoid toxin-expressing Salmonella enterica causes DNA damage in the intestinal mucosa in vivo, activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain.

Methods: In situ spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis.

Result: The presence of the typhoid toxin protected from colonic bacteria-induced inflammation, despite nuclear localization of p53, enhanced co-expression of type-I interferons (IfnbI) and the inflammasome sensor Aim2, both classic features of DNA-break-induced DDR activation. These effects were not observed in the livers of either infected group. Instead, in this tissue, the inflammatory response and DDR were associated with high oxidative stress-induced DNA damage.

Conclusions: Our work highlights the relevance of the tissue microenvironment in enabling the typhoid toxin to suppress the host inflammatory response in vivo.

sted, utgiver, år, opplag, sider
Frontiers Media S.A., 2023
Emneord
bacterial genotoxin, DNA damage response, inflammasome, inflammation, tissue specificity
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-220315 (URN)10.3389/fimmu.2023.1270449 (DOI)001150445700001 ()38274797 (PubMedID)2-s2.0-85183041210 (Scopus ID)
Forskningsfinansiär
Swedish Cancer Society, 20 0699 PjFSwedish Research Council, 2021-00960The Kempe Foundations, SMK-1962The Kempe Foundations, JCK-1826The Kempe Foundations, JCK-3110Cancerforskningsfonden i Norrland, AMP20-993Cancerforskningsfonden i Norrland, AMP 17-884
Tilgjengelig fra: 2024-02-13 Laget: 2024-02-13 Sist oppdatert: 2024-02-13bibliografisk kontrollert
Lopez Chiloeches, M., Bergonzini, A. & Frisan, T. (2021). Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators. Toxins, 13(6), Article ID 426.
Åpne denne publikasjonen i ny fane eller vindu >>Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators
2021 (engelsk)Inngår i: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 13, nr 6, artikkel-id 426Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

The idea that bacterial toxins are not only killers but also execute more sophisticated roles during bacteria-host interactions by acting as negotiators has been highlighted in the past decades. Depending on the toxin, its cellular target and mode of action, the final regulatory outcome can be different. In this review, we have focused on two families of bacterial toxins: genotoxins and pore-forming toxins, which have different modes of action but share the ability to modulate the host's immune responses, independently of their capacity to directly kill immune cells. We have addressed their immuno-suppressive effects with the perspective that these may help bacteria to avoid clearance by the host's immune response and, concomitantly, limit detrimental immunopathology. These are optimal conditions for the establishment of a persistent infection, eventually promoting asymptomatic carriers. This immunomodulatory effect can be achieved with different strategies such as suppression of pro-inflammatory cytokines, re-polarization of the immune response from a pro-inflammatory to a tolerogenic state, and bacterial fitness modulation to favour tissue colonization while preventing bacteraemia. An imbalance in each of those effects can lead to disease due to either uncontrolled bacterial proliferation/invasion, immunopathology, or both.

sted, utgiver, år, opplag, sider
MDPI, 2021
Emneord
bacterial genotoxins, pore-forming toxins, immunoregulation, cytokines, polarization immune response, innate and adaptive immunity
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-187370 (URN)10.3390/toxins13060426 (DOI)000665917200001 ()34204481 (PubMedID)2-s2.0-85109964915 (Scopus ID)
Forskningsfinansiär
Swedish Cancer Society, 2017/315, 20 0699 PjFSwedish Research Council, 2018-02521The Kempe Foundations, JCK-1826Cancerforskningsfonden i Norrland, AMP20- 993, AMP 17-884
Tilgjengelig fra: 2021-09-09 Laget: 2021-09-09 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Lagopati, N., Kotsinas, A., Veroutis, D., Evangelou, K., Papaspyropoulos, A., Arfanis, M., . . . Gorgoulis, V. G. (2021). Biological Effect of Silver-modified Nanostructured Titanium Dioxide in Cancer. Cancer Genomics & Proteomics, 18(3), 425-439
Åpne denne publikasjonen i ny fane eller vindu >>Biological Effect of Silver-modified Nanostructured Titanium Dioxide in Cancer
Vise andre…
2021 (engelsk)Inngår i: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 18, nr 3, s. 425-439Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

BACKGROUND/AIM: Nanomedicine is a promising scientific field that exploits the unique properties of innovative nanomaterials, providing alternative solutions in diagnostics, prevention and therapeutics. Titanium dioxide nanoparticles (TiO2 NPs) have a great spectrum of photocatalytic antibacterial and anticancer applications. The chemical modification of TiO2 optimizes its bioactive performance. The aim of this study was the development of silver modified NPs (Ag/TiO2 NPs) with anticancer potential.

MATERIALS AND METHODS: Ag/TiO2 NPs were prepared through the sol-gel method, were fully characterized and were tested on cultured breast cancer epithelial cells (MCF-7 and MDA-MB-231). The MTT colorimetric assay was used to estimate cellular viability. Western blot analysis of protein expression along with a DNA-laddering assay were employed for apoptosis detection.

RESULTS AND CONCLUSION: We show that photo-activated Ag/TiO2 NPs exhibited significant cytotoxicity on the highly malignant MDA-MB-231 cancer cells, inducing apoptosis, while MCF-7 cells that are characterized by low invasive properties were unaffected under the same conditions.

Emneord
anticancer properties, apoptosis, cytotoxicity, Nanomedicine, nanostructured titanium dioxide, photocatalysis, silver-modified titanium dioxide
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-184127 (URN)10.21873/cgp.20269 (DOI)000667611600005 ()33994365 (PubMedID)2-s2.0-85106628567 (Scopus ID)
Tilgjengelig fra: 2021-06-10 Laget: 2021-06-10 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Lopez Chiloeches, M., Bergonzini, A., Frisan, T. & Martin, O. C. .. (2021). Characterization of macrophage infiltration and polarization by double fluorescence immunostaining in mouse colonic mucosa. STAR Protocols, 2(4), Article ID 100833.
Åpne denne publikasjonen i ny fane eller vindu >>Characterization of macrophage infiltration and polarization by double fluorescence immunostaining in mouse colonic mucosa
2021 (engelsk)Inngår i: STAR Protocols, E-ISSN 2666-1667, Vol. 2, nr 4, artikkel-id 100833Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We recently characterized the association between DNA damage and immunoresponse in vivo in colonic mucosa of mice infected with a Salmonella Typhimurium strain expressing a genotoxin, known as typhoid toxin. In this protocol, we describe how to assess the extent and features of infiltrating macrophages by double immunofluorescence. Total macrophage population was determined using an F4/80 antibody, whereas the specific M2-like population was assessed using a CD206 antibody. For complete details on the use and execution of this protocol, please refer to Martin et al. (2021).

sted, utgiver, år, opplag, sider
Cell Press, 2021
Emneord
Cell-based assays, In situ hybridization, Microscopy
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-202969 (URN)10.1016/j.xpro.2021.100833 (DOI)2-s2.0-85122830767 (Scopus ID)
Forskningsfinansiär
Swedish Cancer Society, 20 0699 PjFSwedish Cancer Society, CAN 2017/315Swedish Research Council, 2018–02521Umeå UniversityThe Kempe Foundations, JCK-1826
Tilgjengelig fra: 2023-01-14 Laget: 2023-01-14 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Martin, O. C. .., Bergonzini, A., Lopez Chiloeches, M., Paparouna, E., Butter, D., Theodorou, S. D. .., . . . Frisan, T. (2021). Influence of the microenvironment on modulation of the host response by typhoid toxin. Cell Reports, 35(1), Article ID 108931.
Åpne denne publikasjonen i ny fane eller vindu >>Influence of the microenvironment on modulation of the host response by typhoid toxin
Vise andre…
2021 (engelsk)Inngår i: Cell Reports, E-ISSN 2211-1247, Vol. 35, nr 1, artikkel-id 108931Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram-negative bacteria, enriched in the microbiota of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We address the role of typhoid toxin in modulation of the host-microbial interaction in health and disease. Infection with a genotoxigenic Salmonella protects mice from intestinal inflammation. We show that the presence of an active genotoxin promotes DNA fragmentation and senescence in vivo, which is uncoupled from an inflammatory response and unexpectedly associated with induction of an anti-inflammatory environment. The anti-inflammatory response is lost when infection occurs in mice with acute colitis. These data highlight a complex context-dependent crosstalk between bacterial-genotoxin-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.

sted, utgiver, år, opplag, sider
Cell Press, 2021
Emneord
Ataxia-telangiectasia mutated (ATM), bacterial genotoxins, colitis, immune response, immunomodulation, microenviroment, senescence, typhoid toxin
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-182265 (URN)10.1016/j.celrep.2021.108931 (DOI)000637406700002 ()33826883 (PubMedID)2-s2.0-85103781998 (Scopus ID)
Tilgjengelig fra: 2021-04-20 Laget: 2021-04-20 Sist oppdatert: 2024-01-17bibliografisk kontrollert
Papalampros, A., Vailas, M., Ntostoglou, K., Chiloeches, m., Sakellariou, S., Chouliari, N. V., . . . Pateras, I. S. (2020). Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRP proportional to Expression. Cancers, 12(7), Article ID 1825.
Åpne denne publikasjonen i ny fane eller vindu >>Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRP proportional to Expression
Vise andre…
2020 (engelsk)Inngår i: Cancers, ISSN 2072-6694, Vol. 12, nr 7, artikkel-id 1825Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRP a axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.

HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-174629 (URN)10.3390/cancers12071825 (DOI)000557225400001 ()2-s2.0-85090734510 (Scopus ID)
Tilgjengelig fra: 2020-08-31 Laget: 2020-08-31 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Martin, O. C. B., Bergonzini, A., D'Amico, F., Chen, P., Shay, J. W., Dupuy, J., . . . Frisan, T. (2019). Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells. Cellular Microbiology, 21(12), Article ID e13099.
Åpne denne publikasjonen i ny fane eller vindu >>Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells
Vise andre…
2019 (engelsk)Inngår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 21, nr 12, artikkel-id e13099Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Several commensal and pathogenic Gram-negative bacteria produce DNA-damaging toxins that are considered bona fide carcinogenic agents. The microbiota of colorectal cancer (CRC) patients is enriched in genotoxin-producing bacteria, but their role in the pathogenesis of CRC is poorly understood. The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in the majority of sporadic CRCs. We investigated whether the loss of APC alters the response of colonic epithelial cells to infection by Salmonella enterica, the only genotoxin-producing bacterium associated with cancer in humans. Using 2D and organotypic 3D cultures, we found that APC deficiency was associated with sustained activation of the DNA damage response, reduced capacity to repair different types of damage, including DNA breaks and oxidative damage, and failure to induce cell cycle arrest. The reduced DNA repair capacity and inability to activate adequate checkpoint responses was associated with increased genomic instability in APC-deficient cells exposed to the genotoxic bacterium. Inhibition of the checkpoint response was dependent on activation of the phosphatidylinositol 3-kinase pathway. These findings highlight the synergistic effect of the loss of APC and infection with genotoxin-producing bacteria in promoting a microenvironment conducive to malignant transformation.

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2019
Emneord
APC, bacteria and cancer, bacterial genotoxin, DNA damage response, DNA repair, organotypic del, tumour-suppressor gene
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-167179 (URN)10.1111/cmi.13099 (DOI)000482652700001 ()31414579 (PubMedID)2-s2.0-85071087704 (Scopus ID)
Tilgjengelig fra: 2020-01-10 Laget: 2020-01-10 Sist oppdatert: 2023-01-23bibliografisk kontrollert
Bergonzini, A., Avila-Cariño, J., Lopez Chiloeches, M. & Frisan, T. The challenge of establishing immunocompetent human intestinal 3D models.
Åpne denne publikasjonen i ny fane eller vindu >>The challenge of establishing immunocompetent human intestinal 3D models
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Abstract [en]

Expression of typhoid toxin in Salmonella Typhimurium causes DNA damage, activating the DNA damage response (DDR), in absence of an inflammatory response in the colonic mucosa of infected mice. The anti-inflammatory effect is tissue specific and is not observed in the liver, suggesting that the local immune microenvironment modulates the DDR outcome.

To assess the role of the immune cells in the DDR outcome induced by the genotoxigenic Salmonella, we have initiated the development of an immunocompetent 3D colonic mucosal model based on a collagen matrix containing colonic fibroblasts and different subtypes of immune cells, overlayed with colonic epithelial cells.

Embedding of peripheral blood mononuclear cells in the collagen matrix did not influenced either the tissue integrity or the activation of the DDR, observed exclusively upon infection with the genotoxigenic strain. However, embedding of T cells, monocytes, or non-polarized macrophages altered the pattern of the DDR and the toxin specific effect was lost. Presence of macrophages was further associated with alteration of the epithelial layer integrity. This effect was infection-dependent, but not toxin specific.

Our data demonstrated that addition of immune cells to a 3D mucosal model altered the DDR induced by a genotoxigenic bacterium, highlighting the need to develop and optimize immunocompetent in vitro models.

Emneord
bacterial genotoxin, bacteria, DNA damage response, organotypic model, immune cells.
HSV kategori
Forskningsprogram
biologi; cellforskning; immunologi
Identifikatorer
urn:nbn:se:umu:diva-203903 (URN)
Tilgjengelig fra: 2023-01-23 Laget: 2023-01-23 Sist oppdatert: 2023-01-24
Organisasjoner