112 results on '"Tanori, M."'
Search Results
2. Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum
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Tanori, M, Pasquali, E, Leonardi, S, Giardullo, P, Di Majo, V, Taccioli, G, Essers, J, Kanaar, R, Mullenders, L H, Atkinson, M J, Mancuso, M, Saran, A, and Pazzaglia, S
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- 2011
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3. Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo
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Mancuso, M, Pasquali, E, Leonardi, S, Rebessi, S, Tanori, M, Giardullo, P, Borra, F, Pazzaglia, S, Naus, C C, Di Majo, V, and Saran, A
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- 2011
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4. Two-hit model for progression of medulloblastoma preneoplasia in Patched heterozygous mice
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Pazzaglia, S, Tanori, M, Mancuso, M, Gessi, M, Pasquali, E, Leonardi, S, Oliva, M A, Rebessi, S, Di Majo, V, Covelli, V, Giangaspero, F, and Saran, A
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- 2006
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5. Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice
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Pazzaglia, S, Tanori, M, Mancuso, M, Rebessi, S, Leonardi, S, Di Majo, V, Covelli, V, Atkinson, M J, Hahn, H, and Saran, A
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- 2006
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6. Contribution of Genetic Background to the Radiation Risk for Cancer and Non-Cancer Diseases in Ptch1+/– Mice.
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De Stefano, I., Leonardi, S., Casciati, A., Pasquali, E., Giardullo, P., Antonelli, F., Novelli, F., Babini, G., Tanori, M., Tanno, B., Saran, A., Mancusoa, M., and Pazzaglia, S.
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BACKGROUND radiation ,DISEASE risk factors ,RADIATION tolerance ,DENTATE gyrus ,CRYSTALLINE lens ,RADIATION exposure - Abstract
Experimental mouse studies are important to gain a comprehensive, quantitative and mechanistic understanding of the biological factors that modify individual risk of radiation-induced health effects, including age at exposure, dose, dose rate, organ/tissue specificity and genetic factors. In this study, neonatal Ptch1
+/– mice bred on CD1 and C57Bl/6 background received whole-body irradiation at postnatal day 2. This time point represents a critical phase in the development of the eye lens, cerebellum and dentate gyrus (DG), when they are also particularly susceptible to radiation effects. Irradiation was performed with γ rays (60 Co) at doses of 0.5, 1 and 2 Gy, delivered at 0.3 Gy/min or 0.063 Gy/min. Wild-type and mutant mice were monitored for survival, lens opacity, medulloblastoma (MB) and neurogenesis defects. We identified an inverse genetic background-driven relationship between the radiosensitivity to induction of lens opacity and MB and that to neurogenesis deficit in Ptch1+/– mutants. In fact, high incidence of radiation-induced cataract and MB were observed in Ptch1+/– /CD1 mutants that instead showed no consequence of radiation exposure on neurogenesis. On the contrary, no induction of radiogenic cataract and MB was reported in Ptch1+/– /C57Bl/6 mice that were instead susceptible to induction of neurogenesis defects. Compared to Ptch1+/– /CD1, the cerebellum of Ptch1+/– /C57Bl/6 mice showed increased radiosensitivity to apoptosis, suggesting that differences in processing radiation-induced DNA damage may underlie the opposite strain-related radiosensitivity to cancer and non-cancer pathologies. Altogether, our results showed lack of dose-rate-related effects and marked influence of genetic background on the radiosensitivity of Ptch1+/– mice, supporting a major contribution of individual sensitivity to radiation risk in the population. [ABSTRACT FROM AUTHOR]- Published
- 2022
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7. miRNA-Signature of Irradiated Ptch1+/– Mouse Lens is Dependent on Genetic Background.
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Tanno, B., Babini, G., Leonardi, S., De Stefano, I., Merla, C., Novelli, F., Antonelli, F., Casciati, A., Tanori, M., Pasquali, E., Giardullo, P., Pazzaglia, S., and Mancuso, M.
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MICE ,IONIZING radiation ,EPITHELIAL-mesenchymal transition ,TOLL-like receptors ,NUCLEOTIDE sequencing - Abstract
One harmful long-term effect of ionizing radiation is cataract development. Recent studies have been focused on elucidating the mechanistic pathways involved in this pathogenesis. Since accumulating evidence has established a role of microRNAs in ocular diseases, including cataract, the goal of this work was to determine the microRNA signature of the mouse lens, at short time periods postirradiation, to understand the mechanisms related to radio-induced cataractogenesis. To evaluate the differences in the microRNA profiles, 10-week-old Patched1 heterozygous (Ptch1
+/– ) mice, bred onto two different genetic backgrounds (CD1 and C57Bl/6J), received whole-body 2 Gy γ-ray irradiation, and 24 h later lenses were collected. Next-generation sequencing and bioinformatics analysis revealed that genetic background markedly influenced the list of the deregulated microRNAs and the mainly predicted perturbed biological functions of 2 Gy irradiated Ptch1+/– mouse lenses. We identified a subset of microRNAs with a contra-regulated expression between strains, with a key role in regulating Toll-like receptor (TLR)-signaling pathways. Furthermore, a detailed analysis of miRNome data showed a completely different DNA damage response in mouse lenses 24 h postirradiation, mainly mediated by a marked upregulation of p53 signaling in Ptch1+/– /C57Bl/6J lenses that was not detected on a CD1 background. We propose a strict interplay between p53 and TLR signaling in Ptch1+/– /C57Bl/6J lenses shortly after irradiation that could explain both the resistance of this strain to developing lens opacities and the susceptibility of CD1 background to radiation-induced cataractogenesis through activation of epithelial-mesenchymal transition. [ABSTRACT FROM AUTHOR]- Published
- 2022
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8. Modulation of basal and squamous cell carcinoma by endogenous estrogen in mouse models of skin cancer
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Mancuso, M., Gallo, D., Leonardi, S., Pierdomenico, M., Pasquali, E., De Stefano, I., Rebessi, S., Tanori, M., Scambia, G., Di Majo, V., Covelli, V., Pazzaglia, S., and Saran, A.
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- 2009
9. Push–pull configuration of high-power MOSFETs for generation of nanosecond pulses for electropermeabilization of cells
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Davies, I. W., primary, Merla, C., additional, Casciati, A., additional, Tanori, M., additional, Zambotti, A., additional, Mancuso, M., additional, Bishop, J., additional, White, M., additional, Palego, C., additional, and Hancock, C. P., additional
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- 2019
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10. Cancer risk from low dose radiation in Ptch1/ mice with inactive DNA repair systems: Therapeutic implications for medulloblastoma
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Tanori, M., primary, Pannicelli, A., additional, Pasquali, E., additional, Casciati, A., additional, Antonelli, F., additional, Giardullo, P., additional, Leonardi, S., additional, Tanno, B., additional, De Stefano, I., additional, Saran, A., additional, Mancuso, M., additional, and Pazzaglia, S., additional
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- 2019
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11. Nitric oxide production in Caco-2 cells exposed to different inducers, inhibitors and natural toxins
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Vignoli, A.L, Srivastava, R.C, Stammati, A, Turco, L, Tanori, M, and Zucco, F
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- 2001
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12. The Patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract
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De Stefano I, Tanno B, Giardullo P, Leonardi S, Pasquali E, Antonelli F, Tanori M, Casciati A, Pazzaglia S, Saran A, Mancuso M., De Stefano, I, Tanno, B, Giardullo, P, Leonardi, S, Pasquali, E, Antonelli, F, Tanori, M, Casciati, A, Pazzaglia, S, Saran, A, and Mancuso, M.
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- 2015
13. Push-Pull Configuration of High Power MOSFETs for Generation of Nanosecond Pulses for Electropermeabilization of Isolated Cancer Stem Cells
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Davies, I.W., primary, Merla, C., additional, Tanori, M., additional, Zambotti, A., additional, Bishop, J., additional, Palego, C., additional, and Hancock, C. P., additional
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- 2018
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14. Developmental and oncogenic radiation effects bon neural stem cells and their differentiating progeny in mouse cerebellum
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Tanori M, Pasquali E, Leonardi S, Casciati A, Giardullo P, De Stefano I, Mancuso M, Pazzaglia S, Saran A., Tanori, M, Pasquali, E, Leonardi, S, Casciati, A, Giardullo, P, De Stefano, I, Mancuso, M, Pazzaglia, S, and Saran, A.
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- 2013
15. Oncogenic radiation abscopal effects in vivo: interrogating mouse skin
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Mancuso M, Leonardi S, Giardullo P, Pasquali E, Tanori M, De Stefano I, Casciati A, Pazzaglia S, Saran A., Mancuso, M, Leonardi, S, Giardullo, P, Pasquali, E, Tanori, M, De Stefano, I, Casciati, A, Pazzaglia, S, and Saran, A.
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- 2013
16. Dose and spatial effects in radiation bystander signaling in vivo: implications for tumorigenesis
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Mancuso M, Giardullo P, Pasquali E, Leonardi S, Tanori M, Di Majo V, Pazzaglia S, Saran A., Mancuso, M, Giardullo, P, Pasquali, E, Leonardi, S, Tanori, M, Di Majo, V, Pazzaglia, S, and Saran, A.
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- 2013
17. The estrogen receptor beta agonist diarylpropionitrile (DPN) inhibits medulloblastoma development via anti-proliferative and pro-apototic pathways
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Mancuso M, Leonardi S, Giardullo P, Pasquali E, Borra F, Stefano ID, Prisco MG, Tanori M, Scambia G, Majo VD, Pazzaglia S, Saran A, Gallo D., Mancuso, M, Leonardi, S, Giardullo, P, Pasquali, E, Borra, F, Stefano, Id, Prisco, Mg, Tanori, M, Scambia, G, Majo, Vd, Pazzaglia, S, Saran, A, and Gallo, D.
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- 2011
18. Medulloblastoma growth inhibition by the gene PC3 through dual action on cell cycle and differentiation of cerebellar precursors
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FARIOLI VECCHIOLI, S, Tanori, M, Micheli, L, Mancuso, M, Leonardi, L, Saran, A, Ciotti, Mt, Ferretti, Elisabetta, Gulino, Alberto, Pazzaglia, S, and Tirone, F.
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- 2007
19. Basal cell carcinoma and its development: Insights from radiation-induced tumors in Ptch1-deficient mice
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Mancuso, M., Pazzaglia, S., Tanori, M., Hahn, H., Merola, P., Rebessi, S., Atkinson, M.J., di Majo, V., Covelli, V., and Saran, A.
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integumentary system ,skin and connective tissue diseases - Abstract
Loss-of-function mutations in Patched (Ptch1) are implicated in constitutive activation of the Sonic hedgehog pathway in human basal cell carcinomas (BCCs), and inherited Ptch1 mutations underlie basal cell nevus syndrome in which a typical feature is multiple BCC occurring with greater incidence in portals of radiotherapy. Mice in which one copy of Ptch1 is inactivated show increased susceptibility to spontaneous tumor development and hypersensitivity to radiation-induced tumorigenesis, providing an ideal in vivo model to study the typical pathologies associated with basal cell nevus syndrome. We therefore examined BCC development in control and irradiated Ptch1neo67/+ mice. We show that unirradiated mice develop putative BCC precursor lesions, i.e., basaloid hyperproliferation areas arising from both follicular and interfollicular epithelium, and that these lesions progress to nodular and infiltrative BCCs only in irradiated mice. Data of BCC incidence, multiplicity, and latency support the notion of epidermal hyperproliferations, nodular and infiltrative BCC-like tumors representing different stages of tumor development. This is additionally supported by the pattern of p53 protein expression observed in BCC subtypes and by the finding of retention of the normal remaining Ptch1 allele in all nodular, circumscribed BCCs analyzed compared with its constant loss in infiltrative BCCs. Our data suggest chronological tumor progression from basaloid hyperproliferations to nodular and then infiltrative BCC occurring in a stepwise fashion through the accumulation of sequential genetic alterations.
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- 2004
20. The Radiation Bystander Effect and its Potential Implications for Human Health
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Mancuso, M., primary, Pasquali, E., additional, Giardullo, P., additional, Leonardi, S., additional, Tanori, M., additional, Di Majo, V., additional, Pazzaglia, S., additional, and Saran, A., additional
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- 2012
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21. Modulation of basal and squamous cell carcinoma by endogenous estrogen in mouse models of skin cancer
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Mancuso, M., primary, Gallo, D., additional, Leonardi, S., additional, Pierdomenico, M., additional, Pasquali, E., additional, De Stefano, I., additional, Rebessi, S., additional, Tanori, M., additional, Scambia, G., additional, Di Majo, V., additional, Covelli, V., additional, Pazzaglia, S., additional, and Saran, A., additional
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- 2008
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22. Effects of Exposure of NewbornPatched1Heterozygous Mice to GSM, 900 MHz
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Saran, A., primary, Pazzaglia, S., additional, Mancuso, M., additional, Rebessi, S., additional, Di Majo, V., additional, Tanori, M., additional, Lovisolo, G. A., additional, Pinto, R., additional, and Marino, C., additional
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- 2007
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23. Contribution of Genetic Background to the Radiation Risk for Cancer and Non-Cancer Diseases in Ptch1+/– Mice
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De Stefano, I., Leonardi, S., Casciati, A., Pasquali, E., Giardullo, P., Antonelli, F., Novelli, F., Babini, G., Tanori, M., Tanno, B., Saran, A., Mancusoa, M., and Pazzaglia, S.
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- 2021
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24. miRNA-Signature of Irradiated Ptch1+/– Mouse Lens is Dependent on Genetic Background
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Tanno, B., Babini, G., Leonardi, S., De Stefano, I., Merla, C., Novelli, F., Antonelli, F., Casciati, A., Tanori, M., Pasquali, E., Giardullo, P., Pazzaglia, S., and Mancuso, M.
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- 2021
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25. Effects of Exposure of Newborn Patched1 Heterozygous Mice to GSM, 900 MHz
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Saran, A., Pazzaglia, S., Mancuso, M., Rebessi, S., Di Majo, V., Tanori, M., Lovisolo, G. A., Pinto, R., and Marino, C.
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- 2007
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26. Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways
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Rossana Cuciniello, Francesco Di Meo, Maria Sulli, Olivia Costantina Demurtas, Mirella Tanori, Mariateresa Mancuso, Clizia Villano, Riccardo Aversano, Domenico Carputo, Alfonso Baldi, Gianfranco Diretto, Stefania Filosa, Stefania Crispi, Cuciniello, R., Di Meo, F., Sulli, M., Demurtas, O. C., Tanori, M., Mancuso, M., Villano, C., Aversano, R., Carputo, D., Baldi, A., Diretto, G., Filosa, S., and Crispi, S.
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MDM2 ,natural molecule ,gene expression ,cancer metabolism ,grape-seed extract ,apoptosis ,proanthocyanidins ,natural molecules ,General Medicine ,apoptosi - Abstract
Grapevine (Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.
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- 2023
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27. Cancer risk from low dose radiation in Ptch1/ mice with inactive DNA repair systems: Therapeutic implications for medulloblastoma
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I. De Stefano, Simona Leonardi, Paola Giardullo, Barbara Tanno, M. Mancuso, Simonetta Pazzaglia, Arianna Casciati, Francesca Antonelli, Anna Saran, Mirella Tanori, Alessandro Pannicelli, Emanuela Pasquali, Tanori, M., Pannicelli, A., Pasquali, E., Casciati, A., Antonelli, F., Giardullo, P., Leonardi, S., Tanno, B., De Stefano, I., Saran, A., Mancuso, M., and Pazzaglia, S.
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DNA End-Joining Repair ,Neoplasms, Radiation-Induced ,Cell cycle checkpoint ,DNA Repair ,Carcinogenesis ,DNA-Activated Protein Kinase ,DNA Helicase ,medicine.disease_cause ,Biochemistry ,Mice ,0302 clinical medicine ,Neoplasms ,Molecular Targeted Therapy ,Homologous Recombination ,DNA-PKcs ,NU7441 ,Rad54 ,Targeted therapies ,Tumorigenesis ,Animals ,Cell Line, Tumor ,Cerebellar Neoplasms ,DNA Damage ,DNA Helicases ,DNA-Binding Proteins ,Dose-Response Relationship, Radiation ,Humans ,Medulloblastoma ,Mutation ,Nuclear Proteins ,Patched-1 Receptor ,Risk ,X-Rays ,Carcinogenesi ,Nuclear Protein ,0303 health sciences ,Tumor ,Radiation ,DNA-PKc ,030220 oncology & carcinogenesis ,Human ,DNA repair ,DNA damage ,DNA-Binding Protein ,Biology ,Cell Line ,Dose-Response Relationship ,03 medical and health sciences ,medicine ,Molecular Biology ,030304 developmental biology ,Tumorigenesi ,Animal ,Cerebellar Neoplasm ,Cell Biology ,enzymes and coenzymes (carbohydrates) ,Radiation-Induced ,Apoptosis ,Cancer research ,Targeted therapie ,Homologous recombination - Abstract
DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1+/− mice. In the current study we provide a comprehensive link on the role of HR/NHEJ at low doses (0.042 and 0.25 Gy) from the early molecular changes through DNA damage processing, up to the late consequences of their inactivation on tumorigenesis. Our data indicate a prominent role for HR in genome stability, by preventing spontaneous and radiation-induced oncogenic damage in neural precursors of the cerebellum, the cell of origin of MB. Instead, loss of DNA-PKcs function increased DSBs and apoptosis in neural precursors of the developing cerebellum, leading to killing of tumor initiating cells, and suppression of MB tumorigenesis in DNA-PKcs-/-/Ptch1+/− mice. Pathway analysis demonstrates that DNA-PKcs genetic inactivation confers a remarkable radiation hypersensitivity, as even extremely low radiation doses may deregulate many DDR genes, also triggering p53 pathway activation and cell cycle arrest. Finally, by showing that DNA-PKcs inhibition by NU7441 radiosensitizes human MB cells, our in vitro findings suggest the inclusion of MB in the list of tumors beneficiating from the combination of radiotherapy and DNA-PKcs targeting, holding promise for clinical translation.
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- 2019
28. Human Medulloblastoma Cell Lines: Investigating on Cancer Stem Cell-Like Phenotype
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Caterina Merla, Barbara Tanno, Luca Persano, Arnaud Pothier, Mirella Tanori, Elena Rampazzo, Mariateresa Mancuso, Elena Porcù, Giampietro Viola, Arianna Casciati, Claire Dalmay, Paola Giardullo, Remi Manczak, Sofiane Saada, Fabrice Lalloué, Casciati, A., Tanori, M., Manczak, R., Saada, S., Tanno, B., Giardullo, P., Porcu, E., Rampazzo, E., Persano, L., Viola, G., Dalmay, C., Lalloue, F., Pothier, A., Merla, C., Mancuso, M., Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile (ENEA), RF-ELITE : RF-Electronique Imprimée pour les Télécommunications et l'Energie (XLIM-RFEI), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Contrôle de l’Activation Cellulaire, Progression Tumorale et Résistance thérapeutique (CAPTuR), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Guglielmo Marconi University [Roma], University of Padua–Ospedale Giustinianeo [Padua, Italy], Universita degli Studi di Padova, Department of Pediatrics, and Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA)
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0301 basic medicine ,CD133 ,D283Med ,cancer stem cell ,cross-over frequency ,dielectrophoresis ,stemness biomarkers ,Cancer Research ,Cancer stem cell ,Cross-over frequency ,Dielectrophoresis ,Stemness biomarkers ,Cellular differentiation ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Tumor initiation ,Biology ,Stem cell marker ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,[SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics ,Medulloblastoma ,Cancer ,Dielectrophoresi ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Phenotype ,3. Good health ,[SPI.ELEC]Engineering Sciences [physics]/Electromagnetism ,030104 developmental biology ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research - Abstract
International audience; (M.M.) † These authors contributed equally to this work. Abstract: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains significant and the long-term adverse effects in survivors are substantial. The fraction of cancer stem-like cells (CSCs) because of their self-renewal ability and multi-lineage differentiation potential is critical for tumor initiation, growth, and resistance to therapies. For the development of new CSC-targeted therapies, further in-depth studies are needed using enriched and stable MB-CSCs populations. This work, aimed at identifying the amount of CSCs in three available human cell lines (DAOY, D341, and D283), describes different approaches based on the expression of stemness markers. First, we explored potential differences in gene and protein expression patterns of specific stem cell markers. Then, in order to identify and discriminate undifferentiated from differentiated cells, MB cells were characterized using a physical characterization method based on a high-frequency dielectrophoresis approach. Finally, we compared their tumorigenic potential in vivo, through engrafting in nude mice. Concordantly, our findings identified the D283 human cell line as an ideal model of CSCs, providing important evidence on the use of a commercial human MB cell line for the development of new strategic CSC-targeting therapies.
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- 2020
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29. G-quadruplex ligand RHPS4 radiosensitizes glioblastoma xenograft in vivo through a differential targeting of bulky differentiated- and stem-cancer cells
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Mariateresa Mancuso, Mariachiara Buccarelli, Stefano Leone, Francesco Berardinelli, Roberto Pallini, Antonio Antoccia, Lucia Ricci-Vitiani, A. Di Masi, D. Muoio, Mirella Tanori, Berardinelli, F., Tanori, M., Muoio, D., Buccarelli, M., Di Masi, A., Leone, S., Ricci-Vitiani, L., Pallini, R., Mancuso, M., and Antoccia, A.
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0301 basic medicine ,Radiation-Sensitizing Agents ,Cancer Research ,Mice ,0302 clinical medicine ,RHPS4 ,Tumor ,Brain Neoplasms ,Chemistry ,Telomere ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Gene Expression Regulation, Neoplastic ,Telomeres ,Oncology ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Female ,Human ,Programmed cell death ,Cell Survival ,DNA repair ,DNA damage ,G4 ligands ,Glioma stem-like cells ,Radiosensitization ,Acridines ,Animals ,Cell Line, Tumor ,Cell Proliferation ,Checkpoint Kinase 1 ,Glioblastoma ,Humans ,Rad51 Recombinase ,Xenograft Model Antitumor Assays ,lcsh:RC254-282 ,Cell Line ,Brain Neoplasm ,03 medical and health sciences ,In vivo ,Radioresistance ,Acridine ,Radiation-Sensitizing Agent ,Neoplastic ,G4 ligand ,Animal ,Cell growth ,Research ,030104 developmental biology ,Gene Expression Regulation ,Apoptosis ,Cancer cell ,Cancer research ,Neoplastic Stem Cell ,Glioma stem-like cell - Abstract
Background Glioblastoma is the most aggressive and most lethal primary brain tumor in the adulthood. Current standard therapies are not curative and novel therapeutic options are urgently required. Present knowledge suggests that the continued glioblastoma growth and recurrence is determined by glioblastoma stem-like cells (GSCs), which display self-renewal, tumorigenic potential, and increased radio- and chemo-resistance. The G-quadruplex ligand RHPS4 displays in vitro radiosensitizing effect in GBM radioresistant cells through the targeting and dysfunctionalization of telomeres but RHPS4 and Ionizing Radiation (IR) combined treatment efficacy in vivo has not been explored so far. Methods RHPS4 and IR combined effects were tested in vivo in a heterotopic mice xenograft model and in vitro in stem-like cells derived from U251MG and from four GBM patients. Cell growth assays, cytogenetic analysis, immunoblotting, gene expression and cytofluorimetric analysis were performed in order to characterize the response of differentiated and stem-like cells to RHPS4 and IR in single and combined treatments. Results RHPS4 administration and IR exposure is very effective in blocking tumor growth in vivo up to 65 days. The tumor volume reduction and the long-term tumor control suggested the targeting of the stem cell compartment. Interestingly, RHPS4 treatment was able to strongly reduce cell proliferation in GSCs but, unexpectedly, did not synergize with IR. Lack of radiosensitization was supported by the GSCs telomeric-resistance observed as the total absence of telomere-involving chromosomal aberrations. Remarkably, RHPS4 treatment determined a strong reduction of CHK1 and RAD51 proteins and transcript levels suggesting that the inhibition of GSCs growth is determined by the impairment of the replication stress (RS) response and DNA repair. Conclusions We propose that the potent antiproliferative effect of RHPS4 in GSCs is not determined by telomeric dysfunction but is achieved by the induction of RS and by the concomitant depletion of CHK1 and RAD51, leading to DNA damage and cell death. These data open to novel therapeutic options for the targeting of GSCs, indicating that the combined inhibition of cell-cycle checkpoints and DNA repair proteins provides the most effective means to overcome resistance of GSC to genotoxic insults. Electronic supplementary material The online version of this article (10.1186/s13046-019-1293-x) contains supplementary material, which is available to authorized users.
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- 2019
30. ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of beta TrCP
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Alberto Gulino, Stéphanie Puget, Carlo Capalbo, Daniele Guardavaccaro, Olivier Ayrault, Doriana Fruci, Giuseppe Giannini, Paola Infante, Luca Busino, Mirella Tanori, Laura Di Magno, Diana Bellavia, Ludovica Lospinoso Severini, Miriam Caimano, Flavia Bernardi, Ombretta Melaiu, Enrico De Smaele, Franco Locatelli, Gerry Melino, Lucia Di Marcotullio, Gianluca Canettieri, Julie Talbot, Angelo Peschiaroli, Francesca Bufalieri, Simonetta Pazzaglia, Marta Moretti, Paolo Romania, Bufalieri, F., Infante, P., Bernardi, F., Caimano, M., Romania, P., Moretti, M., Lospinoso Severini, L., Talbot, J., Melaiu, O., Tanori, M., Di Magno, L., Bellavia, D., Capalbo, C., Puget, S., De Smaele, E., Canettieri, G., Guardavaccaro, D., Busino, L., Peschiaroli, A., Pazzaglia, S., Giannini, G., Melino, G., Locatelli, F., Gulino, A., Ayrault, O., Fruci, D., Di Marcotullio, L., Bufalieri, Francesca [0000-0002-9571-318X], Capalbo, Carlo [0000-0001-8445-6782], De Smaele, Enrico [0000-0003-4524-4423], Busino, Luca [0000-0001-6758-9276], Melino, Gerry [0000-0001-9428-5972], Fruci, Doriana [0000-0003-3388-7296], and Apollo - University of Cambridge Repository
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animal structures ,ERAP1 ,Hedgehog ,tumorigenesis ,Carcinogenesis ,Molecular biology ,Science ,Regulator ,General Physics and Astronomy ,medicine.disease_cause ,medulloblastoma ,Aminopeptidases ,USP47 ,General Biochemistry, Genetics and Molecular Biology ,Article ,Minor Histocompatibility Antigens ,Mice ,Ubiquitin ,ubiquitin ,medicine ,ERAP ,Animals ,Hedgehog Proteins ,E3 ligasi ,lcsh:Science ,Transcription factor ,Tissue homeostasis ,Cancer ,Multidisciplinary ,biology ,Protein Stability ,Settore BIO/11 ,ubiquitin, medulloblastoma, ERAP ,General Chemistry ,beta-Transducin Repeat-Containing Proteins ,Ubiquitin ligase ,Cell biology ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Proteolysis ,biology.protein ,NIH 3T3 Cells ,lcsh:Q ,Ubiquitin-Specific Proteases ,Signal transduction ,Signal Transduction - Abstract
The Hedgehog (Hh) pathway is essential for embryonic development and tissue homeostasis. Aberrant Hh signaling may occur in a wide range of human cancers, such as medulloblastoma, the most common brain malignancy in childhood. Here, we identify endoplasmic reticulum aminopeptidase 1 (ERAP1), a key regulator of innate and adaptive antitumor immune responses, as a previously unknown player in the Hh signaling pathway. We demonstrate that ERAP1 binds the deubiquitylase enzyme USP47, displaces the USP47-associated βTrCP, the substrate-receptor subunit of the SCFβTrCP ubiquitin ligase, and promotes βTrCP degradation. These events result in the modulation of Gli transcription factors, the final effectors of the Hh pathway, and the enhancement of Hh activity. Remarkably, genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo. Our findings unveil an unexpected role for ERAP1 in cancer and indicate ERAP1 as a promising therapeutic target for Hh-driven tumors., ERAP1 is an endoplasmic reticulum aminopeptidase that trims MHC Class-I peptides for antigen presentation. Here, the authors show that ERAP1 enhances Hedgehog signalling by sequestering USP47 from βTrCP and promoting tumorigenesis through βTrCP degradation and increased Gli protein stability.
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- 2019
31. Push-pull configuration of high-power MOSFETs for generation of nanosecond pulses for electropermeabilization of cells
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Arianna Casciati, Mariateresa Mancuso, John Bishop, A. Zambotti, I. W. Davies, Mirella Tanori, Christopher Paul Hancock, Caterina Merla, Malcolm White, Cristiano Palego, Davies, I. W., Merla, C., Casciati, A., Tanori, M., Zambotti, A., Mancuso, M., Bishop, J., White, M., Palego, C., and Hancock, C. P.
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Materials science ,medical and biological effect ,passive components and circuits ,7. Clean energy ,Generator (circuit theory) ,03 medical and health sciences ,0302 clinical medicine ,Circuit design and applications ,Electric field ,Electrical and Electronic Engineering ,Power MOSFET ,EM field theory and numerical technique ,030304 developmental biology ,Si-based devices and IC technologies ,EM field theory and numerical techniques ,0303 health sciences ,business.industry ,Pulse (signal processing) ,passive components and circuit ,Ranging ,Nanosecond ,6. Clean water ,Energy conservation ,030220 oncology & carcinogenesis ,Optoelectronics ,medical and biological effects ,Circuit design and application ,business ,Joule heating - Abstract
A power MOSFET-based push–pull configuration nanosecond-pulse generator has been designed, constructed, and characterized to permeabilize cells for biological and medical applications. The generator can deliver pulses with durations ranging from 80 ns up to 1 µs and pulse amplitudes up to 1.4 kV. The unit has been tested for in vitro experiments on a medulloblastoma cell line. Following the exposure of cells to 100, 200, and 300 ns electric field pulses, permeabilization tests were carried out, and viability tests were conducted to verify the performance of the generator. The maximum temperature rise of the biological load was also calculated based on Joule heating energy conservation and experimental validation. Our results indicate that the developed device has good capabilities to achieve well-controlled electro-manipulation in vitro.
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- 2019
32. Alterations in Morphology and Adult Neurogenesis in the Dentate Gyrus of Patched1 Heterozygous Mice
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Francesca Antonelli, Arianna Casciati, Mirella Tanori, Barbara Tanno, Maria V. Linares-Vidal, Noemi Serra, Monserrat Bellés, Alessandro Pannicelli, Anna Saran, Simonetta Pazzaglia, Pazzaglia, S., Saran, A., Pannicelli, A., Tanno, B., Tanori, M., Casciati, A., and Antonelli, F.
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0301 basic medicine ,TLX nuclear receptor ,Notch pathway ,Notch signaling pathway ,Hippocampus ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Sonic hedgehog ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Molecular Biology ,Original Research ,Expression profiles of neurogenesis-related genes ,Hippocampal neurogenesis and neuronal lineage differentiation ,biology ,Behavioral effect ,Dentate gyrus ,Neurogenesis ,Behavioral effects ,Neural stem cell ,Hedgehog signaling pathway ,Expression profiles of neurogenesis-related gene ,Cell biology ,030104 developmental biology ,Sonic hedgehog pathway ,biology.protein ,Stem cell ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Many genes controlling neuronal development also regulate adult neurogenesis. We investigated in vivo the effect of Sonic hedgehog (Shh) signaling activation on patterning and neurogenesis of the hippocampus and behavior of Patched1 (Ptch1) heterozygous mice (Ptch1+/−). We demonstrated for the first time, that Ptch1+/− mice exhibit morphological, cellular and molecular alterations in the dentate gyrus (DG), including elongation and reduced width of the DG as well as deregulations at multiple steps during lineage progression from neural stem cells to neurons. By using stage-specific cellular markers, we detected reduction of quiescent stem cells, newborn neurons and astrocytes and accumulation of proliferating intermediate progenitors, indicative of defects in the dynamic transition among neural stages. Phenotypic alterations in Ptch1+/− mice were accompanied by expression changes in Notch pathway downstream components and TLX nuclear receptor, as well as perturbations in inflammatory and synaptic networks and mouse behavior, pointing to complex biological interactions and highlighting cooperation between Shh and Notch signaling in the regulation of neurogenesis. © 2018 Antonelli, Casciati, Tanori, Tanno, Linares-Vidal, Serra, Bellés, Pannicelli, Saran and Pazzaglia.
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- 2018
33. Push-Pull Configuration of High Power MOSFETs for Generation of Nanosecond Pulses for Electropermeabilization of Isolated Cancer Stem Cells
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Chris Hancock, Caterina Merla, I. W. Davies, Cristiano Palego, Mirella Tanori, A. Zambotti, J. Bishop, Zambotti, A., Tanori, M., and Merla, C.
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electroporation ,cancer stem cells ,cancer stem cell ,Materials science ,high-voltage ,high power MOSFETs ,nanosecond pulses ,push-pull ,02 engineering and technology ,high power MOSFET ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,MOSFET ,0202 electrical engineering, electronic engineering, information engineering ,Power MOSFET ,Push pull ,nanosecond pulse ,business.industry ,Electroporation ,020206 networking & telecommunications ,Nanosecond ,6. Clean water ,Optoelectronics ,030211 gastroenterology & hepatology ,Stem cell ,business - Abstract
This paper presents the instrumentation and use of a novel electroporation generator, configured of MOSFETs in a push-pull configuration, with an artificial 50 Omega buffer for possible real-time neutralization of cancer stem cells. The results from an initial bench study investigates the development of an electroporation generator capable of delivering non-thermal treatment with an original cuvette housing unit and its effects on isolated cancer stem cell. Initial permeabilization investigation of cancer stem cells were conducted, indicating that the developed protocols and devices have a strong potential future use in achieving electro-manipulation of cancer stem cells. © 2018 European Microwave Association.
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- 2018
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34. Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis
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Anna Saran, Simona Leonardi, Francesca Antonelli, Gabriele Babini, Emanuela Pasquali, Barbara Tanno, Ilaria De Stefano, Arianna Casciati, Mariateresa Mancuso, Alessandro Pannicelli, Paola Giardullo, Simonetta Pazzaglia, Francesco Berardinelli, Antonella Sgura, Mirella Tanori, Pazzaglia, S., Saran, A., Mancuso, M., Pannicelli, A., Tanno, B., Antonelli, F., Pasquali, E., Leonardi, S., Casciati, A., Tanori, M., Tanori, Mirella, Casciati, Arianna, Berardinelli, Francesco, Leonardi, Simona, Pasquali, Emanuela, Antonelli, Francesca, Tanno, Barbara, Pannicelli, Alessandro, Babini, Gabriele, De Stefano, Ilaria, Sgura, Antonella, Mancuso, Mariateresa, Saran, Anna, and Pazzaglia, Simonetta
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0301 basic medicine ,Senescence ,Expression profiles ,DNA repair ,DNA damage ,Poly ADP ribose polymerase ,Apoptosis ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Germline mutation ,Expression profile ,Cerebellum ,medicine ,Genetics ,Medulloblastoma ,fungi ,Apoptosi ,medicine.disease ,030104 developmental biology ,Oncology ,Cancer research ,Homologous recombination ,Carcinogenesis ,Research Paper - Abstract
// Mirella Tanori 1 , Arianna Casciati 1 , Francesco Berardinelli 2 , Simona Leonardi 1 , Emanuela Pasquali 1 , Francesca Antonelli 1 , Barbara Tanno 1 , Paola Giardullo 2,3 , Alessandro Pannicelli 4 , Gabriele Babini 5 , Ilaria De Stefano 3 , Antonella Sgura 2 , Mariateresa Mancuso 1 , Anna Saran 1 and Simonetta Pazzaglia 1 1 Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), CR-Casaccia, Rome, Italy 2 Department of Science, University Roma Tre, Rome, Italy 3 Department of Radiation Physics, Universita degli Studi Guglielmo Marconi, Rome, Italy 4 Technical Unit of Energetic Efficiency, ENEA, Rome, Italy 5 Department of Physics, University of Pavia, Pavia, Italy Correspondence to: Simonetta Pazzaglia, email: // Keywords : cerebellum, expression profiles, medulloblastoma, apoptosis, senescence Received : June 14, 2016 Accepted : June 26, 2016 Published : July 07, 2016 Abstract Mutations in DNA repair pathways are frequent in human cancers. Hence, gaining insights into the interaction of DNA repair genes is key to development of novel tumor-specific treatment strategies. In this study, we tested the functional relationship in development and oncogenesis between the homologous recombination (HR) factor Rad54 and Parp-1 , a nuclear enzyme that plays a multifunctional role in DNA damage signaling and repair. We introduced single or combined Rad54 and Parp-1 inactivating germline mutations in Ptc1 heterozygous mice, a well-characterized model of medulloblastoma, the most common malignant pediatric brain tumor. Our study reveals that combined inactivation of Rad54 and Parp-1 causes a marked growth delay culminating in perinatallethality, providing for the first time evidence of synthetic lethal interactions between Rad54 and Parp-1 in vivo . Although the double mutation hampered investigation of Rad54 and Parp-1 interactions in cerebellum tumorigenesis, insights were gained by showing accumulation of endogenous DNA damage and increased apoptotic rate in granule cell precursors (GCPs). A network-based approach to detect differential expression of DNA repair genes in the cerebellum revealed perturbation of p53 signaling in Rad54 -/- / Parp-1 -/- / Ptc1 +/- , and MEFs from combined Rad54/Parp-1 mutants showed p53/p21-dependent typical senescent features. These findings help elucidate the genetic interplay between Rad54 and Parp-1 by suggesting that p53/p21-mediated apoptosis and/or senescence may be involved in synthetic lethal interactions occurring during development and inhibition of tumor growth.
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- 2017
35. Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum
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Simona Leonardi, Ilaria De Stefano, Mirella Tanori, Anna Saran, Paola Giardullo, Emanuela Pasquali, Simonetta Pazzaglia, Arianna Casciati, Mariateresa Mancuso, Pazzaglia, S., Saran, A., Mancuso, M., Giardullo, P., Casciati, A., Leonardi, S., and Tanori, M.
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P21 ,DNA Repair ,Apoptosis ,Carcinogenesis ,DNA repair ,Medulloblastoma ,Neural stem cells ,Progenitor cells ,Ptc1+/- mice ,DNA damage ,Biology ,medicine.disease_cause ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Neural Stem Cells ,Cerebellum ,medicine ,Animals ,Progenitor cell ,Carcinogenesi ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Stem Cells ,Neurogenesis ,Apoptosi ,Cell Differentiation ,Cell Biology ,Embryonic stem cell ,Neural stem cell ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,nervous system ,030220 oncology & carcinogenesis ,Immunology ,Molecular Medicine ,Stem cell ,DNA Damage ,Developmental Biology - Abstract
Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long-term consequences of genotoxic exposure. Patched1 heterozygous mice (Ptc1+/−) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1+/− mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and fate-restricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long-term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate-restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low-dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation-stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors.
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- 2013
36. Dose and Spatial Effects in Long-Distance Radiation Signaling In Vivo: Implications for Abscopal Tumorigenesis
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Arianna Casciati, Mirella Tanori, Anna Saran, Mariateresa Mancuso, Emanuela Pasquali, Ilaria De Stefano, Simona Leonardi, Paola Giardullo, Simonetta Pazzaglia, Saran, A., Pazzaglia, S., Tanori, M., Casciati, A., Leonardi, S, and Mancuso, M.
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Patched Receptors ,Cancer Research ,Programmed cell death ,Pathology ,medicine.medical_specialty ,Neoplasms, Radiation-Induced ,Time Factors ,Central nervous system ,Receptors, Cell Surface ,medicine.disease_cause ,Radiation Tolerance ,Ionizing radiation ,Mice ,Radiation Protection ,In vivo ,Cerebellum ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Irradiation ,Cerebellar Neoplasms ,Germ-Line Mutation ,Radiation ,Cell Death ,business.industry ,Dose-Response Relationship, Radiation ,Bystander Effect ,Patched-1 Receptor ,Dose–response relationship ,medicine.anatomical_structure ,Oncology ,Apoptosis ,Cancer research ,Carcinogenesis ,business ,Whole-Body Irradiation - Abstract
Purpose: To investigate the dose and spatial dependence of abscopal radiation effects occurring in vivo in the mouse, along with their tumorigenic potential in the central nervous system (CNS) of a radiosensitive mouse model. Methods and Materials: Patched1 (Ptch1)+/- mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene and uniquely susceptible to radiation damage in neonatal cerebellum, were exposed directly to ionizing radiation (1, 2, or 3 Gy of x-rays) or treated in a variety of partial-body irradiation protocols, in which the animals' head was fully protected by suitable lead cylinders while the rest of the body was exposed to x-rays in full or in part. Apoptotic cell death was measured in directly irradiated and shielded cerebellum shortly after irradiation, and tumor development was monitored in lifetime groups. The same endpoints were measured using different shielding geometries in mice irradiated with 3 or 10 Gy of x-rays. Results: Although dose-dependent cell death was observed in off-target cerebellum for all doses and shielding conditions tested, a conspicuous lack of abscopal response for CNS tumorigenesis was evident at the lowest dose of 1 Gy. By changing the amount of exposed body volume, the shielding geometry could also significantly modulate tumorigenesis depending on dose. Conclusions: We conclude that interplay between radiation dose and exposed tissue volume plays a critical role in nontargeted effects occurring in mouse CNS under conditions relevant to humans. These findings may help understanding the mechanisms of long-range radiation signaling in harmful effects, including carcinogenesis, occurring in off-target tissues. © 2013 Elsevier Inc. All rights reserved.
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- 2013
37. The Radiation Bystander Effect and its Potential Implications for Human Health
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Simona Leonardi, Anna Saran, Emanuela Pasquali, Mirella Tanori, V. Di Majo, Mariateresa Mancuso, Paola Giardullo, Simonetta Pazzaglia, Mancuso, M, Pasquali, E, Giardullo, P, Leonardi, S, Tanori, M, Di Majo, V, Pazzaglia, S, and Saran, A.
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Radiobiology ,Cancer ,Bystander Effect ,Cell Communication ,General Medicine ,Biology ,medicine.disease ,Biochemistry ,In vitro ,Ionizing radiation ,Mediator ,In vivo ,Neoplasms ,Radiation, Ionizing ,Immunology ,Bystander effect ,Cancer research ,medicine ,Animals ,Humans ,Molecular Medicine ,Irradiation ,Molecular Biology ,DNA Damage - Abstract
A long-held dogma in radiation biology has been that the biological effects of exposure to ionizing radiation occur as a result of damage in directly irradiated cells and that no effect would occur in neighboring unirradiated cells. This paradigm has been frequently challenged by reports of radiation effects in unirradiated or 'bystander' cells receiving signals from directly irradiated cells, an issue that may have substantial impact on radiation risk assessment and development of radiation-based therapies. Radiation-induced bystander effects have been shown in single-cell systems in vitro for an array of cancer relevant endpoints, and may trigger damage in more complex 3-D tissue systems. They may be mediated by soluble factors released by irradiated cells into the extracellular environment and/or by the passage of mediator molecules through gap-junction intercellular communication. To date, evidence that radiation-associated bystander or abscopal responses are effectual in vivo has been limited, but new data suggest that they may significantly affect tumor development in susceptible mouse models. Further understanding of how the signal/s is transmitted to unirradiated cells and tissues and how it provokes long-range and significant responses is crucial. By summarizing the existing evidence of radiation induced bystander-like effects in various systems with emphasis on in vivo findings, we will discuss the potential mechanisms involved in these observations and how effects in bystander cells contribute to uncertainties in assessing cancer risks associated with radiation exposure.
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- 2012
38. MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma
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Mariateresa Mancuso, Emanuela Pasquali, Romina Alfonsi, Fabrizio Colaceci, Anna Saran, Gessica Filocamo, Armin Lahm, Simonetta Pazzaglia, Mirko Brunetti, Christian Steinkühler, Mirella Tanori, Lucia Di Marcotullio, Romina Sasso, Pazzaglia, S., Saran, A., Mancuso, M., Pasquali, E., and Tanori, M.
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0301 basic medicine ,Cancer Research ,Cell Survival ,small molecule ,Antineoplastic Agents ,medicine.disease_cause ,Hedgehog pathway ,03 medical and health sciences ,Mice ,Random Allocation ,GLI1 ,medicine ,Animals ,Humans ,Hedgehog Proteins ,Cerebellar Neoplasms ,Hedgehog ,Cell Proliferation ,Medulloblastoma ,biology ,Cell Cycle ,Wnt signaling pathway ,Isoxazoles ,Cell cycle ,Triazoles ,medicine.disease ,Xenograft Model Antitumor Assays ,Hedgehog signaling pathway ,030104 developmental biology ,Oncology ,PTCH1 ,Carcinoma, Basal Cell ,Immunology ,biology.protein ,Cancer research ,Hedgehog pathway, medulloblastoma, small molecule, hedgehog inhibitor ,hedgehog inhibitor ,Carcinogenesis ,Neoplasm Transplantation ,Signal Transduction - Abstract
Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/− mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for the treatment of medulloblastoma and BCC. Results clearly demonstrated a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/− mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidated the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in tumor cells, showing the maximum inhibitory effect on Gli1. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF, and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Mol Cancer Ther; 15(6); 1177–89. ©2016 AACR.
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- 2015
39. Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo
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Anna Saran, Mirella Tanori, Paola Giardullo, Emanuela Pasquali, S. Rebessi, Simona Leonardi, Mariateresa Mancuso, F. Borra, V. Di Majo, Christian C. Naus, Simonetta Pazzaglia, Mancuso, M, Pasquali, E, Leonardi, S, Rebessi, S, Tanori, M, Giardullo, P, Borra, F, Pazzaglia, S, Naus, Cc, Di Majo, V, and Saran, A.
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Nervous system ,Cancer Research ,Neoplasms, Radiation-Induced ,Biology ,medicine.disease_cause ,Radiation Dosage ,Transduction (genetics) ,Mice ,Adenosine Triphosphate ,Downregulation and upregulation ,In vivo ,Cerebellum ,Genetics ,medicine ,Bystander effect ,Animals ,Cerebellar Neoplasms ,Molecular Biology ,Carcinogen ,Sequence Deletion ,Gap junction ,Gap Junctions ,Bystander Effect ,Cell biology ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Connexin 43 ,Immunology ,Carcinogenesis ,DNA Damage ,Signal Transduction - Abstract
Ionizing radiation is a genotoxic agent and human carcinogen. Recent work has questioned long-held dogmas by showing that cancer-associated genetic alterations occur in cells and tissues not directly exposed to radiation, questioning the robustness of the current system of radiation risk assessment. In vitro, diverse mechanisms involving secreted soluble factors, gap junction intercellular communication (GJIC) and oxidative metabolism are proposed to mediate these indirect effects. In vivo, the mechanisms behind long-range 'bystander' responses remain largely unknown. Here, we investigate the role of GJIC in propagating radiation stress signals in vivo, and in mediating radiation-associated bystander tumorigenesis in mouse central nervous system using a mouse model in which intercellular communication is downregulated by targeted deletion of the connexin43 (Cx43) gene. We show that GJIC is critical for transmission of oncogenic radiation damage to the non-targeted cerebellum, and that a mechanism involving adenosine triphosphate release and upregulation of Cx43, the major GJIC constituent, regulates transduction of oncogenic damage to unirradiated tissues in vivo. Our data provide a novel hypothesis for transduction of distant bystander effects and suggest that the highly branched nervous system, similar to the vascular network, has an important role.
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- 2011
40. Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum
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Leon H.F. Mullenders, Michael J. Atkinson, Anna Saran, Emanuela Pasquali, Simona Leonardi, Paola Giardullo, Mariateresa Mancuso, Mirella Tanori, V. Di Majo, G. Taccioli, J. Essers, Roland Kanaar, Simonetta Pazzaglia, Tanori, M, Pasquali, E, Leonardi, S, Giardullo, P, Di Majo, V, Taccioli, G, Essers, J, Kanaar, R, Mullenders, Lh, Atkinson, Mj, Mancuso, M, Saran, A, Pazzaglia, S., Surgery, and Molecular Genetics
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Patched Receptors ,Risk ,Cancer Research ,DNA End-Joining Repair ,DNA repair ,DNA damage ,Loss of Heterozygosity ,Receptors, Cell Surface ,DNA-Activated Protein Kinase ,Biology ,medulloblastoma ,medicine.disease_cause ,Genomic Instability ,Mice ,SDG 3 - Good Health and Well-being ,Genetics ,medicine ,Animals ,LOH ,Cerebellar Neoplasms ,Homologous Recombination ,Molecular Biology ,Gene ,DNA-PKcs ,radiation ,Rad54 ,Kinase ,fungi ,DNA Helicases ,Nuclear Proteins ,Molecular biology ,Patched-1 Receptor ,Apoptosis ,Homologous recombination ,Carcinogenesis ,DNA Damage - Abstract
Heterozygous Patched1 (Ptc1(+/-)) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1(+/-) mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1(+/-) mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability. Oncogene (2011) 30, 4740-4749; doi:10.1038/onc.2011.178; published online 23 May 2011
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- 2011
41. A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis
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Lieve Moons, Tine Verreet, Arlette Michaux, Peter Paul De Deyn, Uwe Himmelreich, Debby Van Dam, Mohammed Abderrafi Benotmane, Anna Saran, Roel Quintens, Arianna Casciati, Liselotte Leysen, Mieke Neefs, Sarah Baatout, Emiliano D'Agostino, Ann Janssen, Greetje Vande Velde, Mieke Verslegers, Mirella Tanori, Simonetta Pazzaglia, Saran, A., Pazzaglia, S., Casciati, A., Tanori, M., and Molecular Neuroscience and Ageing Research (MOLAR)
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Pathology ,medicine.medical_specialty ,Brain development ,Apoptosis ,Cognitive dysfunction ,MRI ,Radiation ,NEURONAL DEVELOPMENT ,Cognitive Neuroscience ,Hippocampus ,Morris water navigation task ,Biology ,Hippocampal formation ,Pathology and Forensic Medicine ,DEVELOPING BRAIN ,Cortex (anatomy) ,CEREBRAL-CORTEX ,medicine ,Neuroinflammation ,MOUSE-BRAIN ,Neocortex ,Research ,Neurogenesis ,Apoptosi ,NERVOUS-SYSTEM ,3. Good health ,MORRIS WATER MAZE ,ADULT HIPPOCAMPAL NEUROGENESIS ,MICE ,medicine.anatomical_structure ,Cerebral cortex ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,IONIZING-RADIATION ,Human medicine ,GAMMA-IRRADIATION - Abstract
Background In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive. Methods Mice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry. Results Irradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age. Conclusions Our findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field. article URL: http://www.jneurodevdisorders.com/content/pdf/1866-1955-7-3.pdf ispartof: Journal of Neurodevelopmental Disorders vol:7 issue:3 pages:1-21 ispartof: location:England status: published
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42. On the effects of 30.5 GHz sinusoidal wave exposure on glioblastoma organoids.
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Rampazzo E, Persano L, Karim N, Hodgking G, Pinto R, Casciati A, Tanori M, Zambotti A, Bresolin S, Cani A, Pannicelli A, Davies IW, Hancock C, Palego C, Viola G, Mancuso M, and Merla C
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Introduction: Glioblastoma (grade IV) is the most aggressive primary brain tumor in adults, representing one of the biggest therapeutic challenges due to its highly aggressive nature. In this study, we investigated the impact of millimeter waves on tridimensional glioblastoma organoids derived directly from patient tumors. Our goal was to explore novel therapeutic possibilities in the fight against this challenging disease., Methods: The exposure setup was meticulously developed in-house, and we employed a comprehensive dosimetry approach, combining numerical and experimental methods. Biological endpoints included a global transcriptional profiling analysis to highlight possible deregulated pathways, analysis of cell morphological changes, and cell phenotypic characterization which are all important players in the control of glioblastoma progression., Results and Discussion: Our results revealed a significant effect of continuous millimeter waves at 30.5 GHz on cell proliferation and apoptosis, although without affecting the differentiation status of glioblastoma cells composing the organoids. Excitingly, when applying a power level of 0.1 W (Root Mean Square), we discovered a remarkable (statistically significant) therapeutic effect when combined with the chemotherapeutic agent Temozolomide, leading to increased glioblastoma cell death. These findings present a promising interventional window for treating glioblastoma cells, harnessing the potential therapeutic benefits of 30.5 GHz CW exposure. Temperature increase during treatments was carefully monitored and simulated with a good agreement, demonstrating a negligible involvement of the temperature elevation for the observed effects. By exploring this innovative approach, we pave the way for improved future treatments of glioblastoma that has remained exceptionally challenging until now., Competing Interests: Authors GH, ID, and CH were employed by the company CREO Medical Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rampazzo, Persano, Karim, Hodgking, Pinto, Casciati, Tanori, Zambotti, Bresolin, Cani, Pannicelli, Davies, Hancock, Palego, Viola, Mancuso and Merla.)
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- 2024
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43. Involvement of Mitochondria in the Selective Response to Microsecond Pulsed Electric Fields on Healthy and Cancer Stem Cells in the Brain.
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Casciati A, Taddei AR, Rampazzo E, Persano L, Viola G, Cani A, Bresolin S, Cesi V, Antonelli F, Mancuso M, Merla C, and Tanori M
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- Cell Membrane metabolism, Electricity, Cytoskeleton metabolism, Brain metabolism, Mitochondria metabolism, Neoplasms metabolism
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In the last few years, pulsed electric fields have emerged as promising clinical tools for tumor treatments. This study highlights the distinct impact of a specific pulsed electric field protocol, PEF-5 (0.3 MV/m, 40 μs, 5 pulses), on astrocytes (NHA) and medulloblastoma (D283) and glioblastoma (U87 NS) cancer stem-like cells (CSCs). We pursued this goal by performing ultrastructural analyses corroborated by molecular/omics approaches to understand the vulnerability or resistance mechanisms triggered by PEF-5 exposure in the different cell types. Electron microscopic analyses showed that, independently of exposed cells, the main targets of PEF-5 were the cell membrane and the cytoskeleton, causing membrane filopodium-like protrusion disappearance on the cell surface, here observed for the first time, accompanied by rapid cell swelling. PEF-5 induced different modifications in cell mitochondria. A complete mitochondrial dysfunction was demonstrated in D283, while a mild or negligible perturbation was observed in mitochondria of U87 NS cells and NHAs, respectively, not sufficient to impair their cell functions. Altogether, these results suggest the possibility of using PEF-based technology as a novel strategy to target selectively mitochondria of brain CSCs, preserving healthy cells.
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- 2024
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44. Characterization of Early and Late Damage in a Mouse Model of Pelvic Radiation Disease.
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Vitali R, Palone F, De Stefano I, Fiorente C, Novelli F, Pasquali E, Fratini E, Tanori M, Leonardi S, Tanno B, Colantoni E, Soldi S, Galletti S, Grimaldi M, Morganti AG, Fuccio L, Pazzaglia S, Pioli C, Mancuso M, and Vesci L
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- Mice, Animals, X-Rays, Disease Models, Animal, Apoptosis radiation effects, Inflammation, Radiation Injuries
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Pelvic radiation disease (PRD), a frequent side effect in patients with abdominal/pelvic cancers treated with radiotherapy, remains an unmet medical need. Currently available preclinical models have limited applications for the investigation of PRD pathogenesis and possible therapeutic strategies. In order to select the most effective irradiation protocol for PRD induction in mice, we evaluated the efficacy of three different locally and fractionated X-ray exposures. Using the selected protocol (10 Gy/day × 4 days), we assessed PRD through tissue (number and length of colon crypts) and molecular (expression of genes involved in oxidative stress, cell damage, inflammation, and stem cell markers) analyses at short (3 h or 3 days after X-ray) and long (38 days after X-rays) post-irradiation times. The results show that a primary damage response in term of apoptosis, inflammation, and surrogate markers of oxidative stress was found, thus determining a consequent impairment of cell crypts differentiation and proliferation as well as a local inflammation and a bacterial translocation to mesenteric lymph nodes after several weeks post-irradiation. Changes were also found in microbiota composition, particularly in the relative abundance of dominant phyla, related families, and in alpha diversity indices, as an indication of dysbiotic conditions induced by irradiation. Fecal markers of intestinal inflammation, measured during the experimental timeline, identified lactoferrin, along with elastase, as useful non-invasive tools to monitor disease progression. Thus, our preclinical model may be useful to develop new therapeutic strategies for PRD treatment.
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- 2023
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45. Safety in Rats of a Novel Nasal Spray Formulation for the Prevention of Airborne Viral Infections.
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Tanori M, Pitaro M, Fratini E, Colantoni E, Amoresano A, Celentano S, Chiaramonte B, and Mancuso M
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Hexedra+
® is a nasal spray containing hydroxypropyl methylcellulose, beta-cyclodextrin, and usnic acid. It has been developed with the aim of reducing the risk of transmission of airborne viral infections, with particular reference to influenza and COVID-19. As part of the preclinical development of the product, we carried out a study on thirty male Wistar rats divided into three study groups and treated with Hexedra+, an alternative formulation containing a double concentration of usnic acid (0.015% instead of 0.0075%) or saline solution. Products were administered at the dose of 30 μL into each nostril, three times a day for seven consecutive days by means of a micropipette. By the end of the treatment period, no significant changes were observed in body weight. Histological examination of nasal mucosa and soft organs did not show any significant difference in the three study groups. Serum transaminase level remained in the normal limit in all the animals treated. The serum level of usnic acid was measured in order to assess the absorption of the molecule through the nasal mucosa. By the end of the study period, the usnic acid serum level was negligible in all the animals treated. In conclusion, the safety profile of Hexedra+ appears favorable in the animal model studied.- Published
- 2023
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46. Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways.
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Cuciniello R, Di Meo F, Sulli M, Demurtas OC, Tanori M, Mancuso M, Villano C, Aversano R, Carputo D, Baldi A, Diretto G, Filosa S, and Crispi S
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- Humans, Animals, Mice, Seeds, Metabolic Networks and Pathways, Proto-Oncogene Proteins c-mdm2, Grape Seed Extract pharmacology, Proanthocyanidins pharmacology, Vitis, Mesothelioma
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Grapevine ( Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.
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- 2023
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47. Liver Steatosis and Steatohepatitis Alter Bile Acid Receptors in Brain and Induce Neuroinflammation: A Contribution of Circulating Bile Acids and Blood-Brain Barrier.
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Fiaschini N, Mancuso M, Tanori M, Colantoni E, Vitali R, Diretto G, Lorenzo Rebenaque L, Stronati L, and Negroni A
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- Animals, Mice, Blood-Brain Barrier metabolism, Occludin metabolism, Endothelial Cells metabolism, Neuroinflammatory Diseases, Brain metabolism, Bile Acids and Salts, Non-alcoholic Fatty Liver Disease metabolism
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A tight relationship between gut-liver diseases and brain functions has recently emerged. Bile acid (BA) receptors, bacterial-derived molecules and the blood-brain barrier (BBB) play key roles in this association. This study was aimed to evaluate how non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) impact the BA receptors Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) expression in the brain and to correlate these effects with circulating BAs composition, BBB integrity and neuroinflammation. A mouse model of NAFLD was set up by a high-fat and sugar diet, and NASH was induced with the supplementation of dextran-sulfate-sodium (DSS) in drinking water. FXR, TGR5 and ionized calcium-binding adaptor molecule 1 (Iba-1) expression in the brain was detected by immunohistochemistry, while Zonula occludens (ZO)-1, Occludin and Plasmalemmal Vesicle Associated Protein-1 (PV-1) were analyzed by immunofluorescence. Biochemical analyses investigated serum BA composition, lipopolysaccharide-binding protein (LBP) and S100β protein (S100β) levels. Results showed a down-regulation of FXR in NASH and an up-regulation of TGR5 and Iba-1 in the cortex and hippocampus in both treated groups as compared to the control group. The BA composition was altered in the serum of both treated groups, and LBP and S100β were significantly augmented in NASH. ZO-1 and Occludin were attenuated in the brain capillary endothelial cells of both treated groups versus the control group. We demonstrated that NAFLD and NASH provoke different grades of brain dysfunction, which are characterized by the altered expression of BA receptors, FXR and TGR5, and activation of microglia. These effects are somewhat promoted by a modification of circulating BAs composition and by an increase in LBP that concur to damage BBB, thus favoring neuroinflammation., Competing Interests: The authors declare no conflict of interest.
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- 2022
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48. Effects of Ultra-Short Pulsed Electric Field Exposure on Glioblastoma Cells.
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Casciati A, Tanori M, Gianlorenzi I, Rampazzo E, Persano L, Viola G, Cani A, Bresolin S, Marino C, Mancuso M, and Merla C
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- Adult, Cell Line, Tumor, Humans, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells metabolism, Brain Neoplasms pathology, Cerebellar Neoplasms pathology, Glioblastoma metabolism
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Glioblastoma multiforme (GBM) is the most common brain cancer in adults. GBM starts from a small fraction of poorly differentiated and aggressive cancer stem cells (CSCs) responsible for aberrant proliferation and invasion. Due to extreme tumor heterogeneity, actual therapies provide poor positive outcomes, and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary against GBM. Among emerging therapies, high intensity ultra-short pulsed electric fields (PEFs) are considered extremely promising and our previous results demonstrated the ability of a specific electric pulse protocol to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells and U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independent of CSC content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53/cell cycle checkpoints. PEF exposure also significantly reduced the ability to form new neurospheres and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stem-ness/differentiation genes. Our results confirm this physical stimulus as a promising treatment to destabilize GBM, opening up the possibility of developing effective PEF-mediated therapies.
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- 2022
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49. miRNA-Signature of Irradiated Ptch1+/- Mouse Lens is Dependent on Genetic Background.
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Tanno B, Babini G, Leonardi S, De Stefano I, Merla C, Novelli F, Antonelli F, Casciati A, Tanori M, Pasquali E, Giardullo P, Pazzaglia S, and Mancuso M
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- Animals, DNA Damage radiation effects, Disease Models, Animal, Dose-Response Relationship, Radiation, Gamma Rays, Genetic Background, Humans, Mice, Inbred C57BL, MicroRNAs, Patched-1 Receptor metabolism, Signal Transduction, Toll-Like Receptors metabolism, Whole-Body Irradiation, Mice, Cataract etiology, Lens, Crystalline radiation effects
- Abstract
One harmful long-term effect of ionizing radiation is cataract development. Recent studies have been focused on elucidating the mechanistic pathways involved in this pathogenesis. Since accumulating evidence has established a role of microRNAs in ocular diseases, including cataract, the goal of this work was to determine the microRNA signature of the mouse lens, at short time periods postirradiation, to understand the mechanisms related to radio-induced cataractogenesis. To evaluate the differences in the microRNA profiles, 10-week-old Patched1 heterozygous (Ptch1+/-) mice, bred onto two different genetic backgrounds (CD1 and C57Bl/6J), received whole-body 2 Gy γ-ray irradiation, and 24 h later lenses were collected. Next-generation sequencing and bioinformatics analysis revealed that genetic background markedly influenced the list of the deregulated microRNAs and the mainly predicted perturbed biological functions of 2 Gy irradiated Ptch1+/- mouse lenses. We identified a subset of microRNAs with a contra-regulated expression between strains, with a key role in regulating Toll-like receptor (TLR)-signaling pathways. Furthermore, a detailed analysis of miRNome data showed a completely different DNA damage response in mouse lenses 24 h postirradiation, mainly mediated by a marked upregulation of p53 signaling in Ptch1+/-/C57Bl/6J lenses that was not detected on a CD1 background. We propose a strict interplay between p53 and TLR signaling in Ptch1+/-/C57Bl/6J lenses shortly after irradiation that could explain both the resistance of this strain to developing lens opacities and the susceptibility of CD1 background to radiation-induced cataractogenesis through activation of epithelial-mesenchymal transition., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)
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- 2022
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50. Contribution of Genetic Background to the Radiation Risk for Cancer and Non-Cancer Diseases in Ptch1+/- Mice.
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De Stefano I, Leonardi S, Casciati A, Pasquali E, Giardullo P, Antonelli F, Novelli F, Babini G, Tanori M, Tanno B, Saran A, Mancusoa M, and Pazzaglia S
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- Animals, Dose-Response Relationship, Radiation, Gamma Rays, Genetic Background, Humans, Lens, Crystalline radiation effects, Mice, Inbred C57BL, Neurogenesis, Radiation Tolerance, Whole-Body Irradiation, Mice, Medulloblastoma ethnology, Neoplasms, Radiation-Induced etiology
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Experimental mouse studies are important to gain a comprehensive, quantitative and mechanistic understanding of the biological factors that modify individual risk of radiation-induced health effects, including age at exposure, dose, dose rate, organ/tissue specificity and genetic factors. In this study, neonatal Ptch1+/- mice bred on CD1 and C57Bl/6 background received whole-body irradiation at postnatal day 2. This time point represents a critical phase in the development of the eye lens, cerebellum and dentate gyrus (DG), when they are also particularly susceptible to radiation effects. Irradiation was performed with γ rays (60Co) at doses of 0.5, 1 and 2 Gy, delivered at 0.3 Gy/min or 0.063 Gy/min. Wild-type and mutant mice were monitored for survival, lens opacity, medulloblastoma (MB) and neurogenesis defects. We identified an inverse genetic background-driven relationship between the radiosensitivity to induction of lens opacity and MB and that to neurogenesis deficit in Ptch1+/- mutants. In fact, high incidence of radiation-induced cataract and MB were observed in Ptch1+/-/CD1 mutants that instead showed no consequence of radiation exposure on neurogenesis. On the contrary, no induction of radiogenic cataract and MB was reported in Ptch1+/-/C57Bl/6 mice that were instead susceptible to induction of neurogenesis defects. Compared to Ptch1+/-/CD1, the cerebellum of Ptch1+/-/C57Bl/6 mice showed increased radiosensitivity to apoptosis, suggesting that differences in processing radiation-induced DNA damage may underlie the opposite strain-related radiosensitivity to cancer and non-cancer pathologies. Altogether, our results showed lack of dose-rate-related effects and marked influence of genetic background on the radiosensitivity of Ptch1+/-mice, supporting a major contribution of individual sensitivity to radiation risk in the population., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)
- Published
- 2022
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