134 results on '"Francescangeli, F."'
Search Results
2. Multidisciplinary study to monitor consequences of pollution on intertidal benthic ecosystems (Hauts de France, English Channel, France): Comparison with natural areas
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Francescangeli, F., Quijada, M., Armynot du Châtelet, E., Frontalini, F., Trentesaux, A., Billon, G., and Bouchet, V.M.P.
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- 2020
- Full Text
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3. Infilling of the Canche Estuary (eastern English Channel, France): Insight from benthic foraminifera and historical pictures
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Francescangeli, F., Portela, M., Armynot du Chatelet, E., Billon, G., Andersen, T.J., Bouchet, V.M.P., and Trentesaux, A.
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- 2018
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4. Benthic foraminifera in transitional environments in the English Channel and the southern North Sea: A proxy for regional-scale environmental and paleo-environmental characterisations
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Armynot du Châtelet, E., Francescangeli, F., Bouchet, V.M.P., and Frontalini, F.
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- 2018
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5. Does elevation matter? Living foraminiferal distribution in a hyper tidal salt marsh (Canche Estuary, Northern France)
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Francescangeli, F., Bouchet, V.M.P., Trentesaux, A., and Armynot du Chatelet, E.
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- 2017
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6. Palaeo-ecological quality status based on foraminifera of Boulogne-sur-Mer harbour (Pas-de-Calais, Northeastern France) over the last 200 years
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Francescangeli, F., Armynot du Chatelet, E., Billon, G., Trentesaux, A., and Bouchet, V.M.P.
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- 2016
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7. An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile
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De Angelis, M. L., Francescangeli, F., Nicolazzo, C., Signore, M., Giuliani, Alessandro, Colace, L., Boe, A., Magri, V., Baiocchi, M., Ciardi, A., Scarola, F., Spada, M., La Torre, F., Gazzaniga, P., Biffoni, M., De Maria Marchiano, Ruggero, Zeuner, A., Giuliani A., De Maria R. (ORCID:0000-0003-2255-0583), De Angelis, M. L., Francescangeli, F., Nicolazzo, C., Signore, M., Giuliani, Alessandro, Colace, L., Boe, A., Magri, V., Baiocchi, M., Ciardi, A., Scarola, F., Spada, M., La Torre, F., Gazzaniga, P., Biffoni, M., De Maria Marchiano, Ruggero, Zeuner, A., Giuliani A., and De Maria R. (ORCID:0000-0003-2255-0583)
- Abstract
Background: Circulating tumor cells (CTCs) are responsible for the metastatic dissemination of colorectal cancer (CRC) to the liver, lungs and lymph nodes. CTCs rarity and heterogeneity strongly limit the elucidation of their biological features, as well as preclinical drug sensitivity studies aimed at metastasis prevention. Methods: We generated organoids from CTCs isolated from an orthotopic CRC xenograft model. CTCs-derived organoids (CTCDOs) were characterized through proteome profiling, immunohistochemistry, immunofluorescence, flow cytometry, tumor-forming capacity and drug screening assays. The expression of intra- and extracellular markers found in CTCDOs was validated on CTCs isolated from the peripheral blood of CRC patients. Results: CTCDOs exhibited a hybrid epithelial-mesenchymal transition (EMT) state and an increased expression of stemness-associated markers including the two homeobox transcription factors Goosecoid and Pancreatic Duodenal Homeobox Gene-1 (PDX1), which were also detected in CTCs from CRC patients. Functionally, CTCDOs showed a higher migratory/invasive ability and a different response to pathway-targeted drugs as compared to xenograft-derived organoids (XDOs). Specifically, CTCDOs were more sensitive than XDOs to drugs affecting the Survivin pathway, which decreased the levels of Survivin and X-Linked Inhibitor of Apoptosis Protein (XIAP) inducing CTCDOs death. Conclusions: These results indicate that CTCDOs recapitulate several features of colorectal CTCs and may be used to investigate the features of metastatic CRC cells, to identify new prognostic biomarkers and to devise new potential strategies for metastasis prevention.
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- 2022
8. A microRNA code for prostate cancer metastasis
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Bonci, D, Coppola, V, Patrizii, M, Addario, A, Cannistraci, A, Francescangeli, F, Pecci, R, Muto, G, Collura, D, Bedini, R, Zeuner, A, Valtieri, M, Sentinelli, S, Benassi, M S, Gallucci, M, Carlini, P, Piccolo, S, and De Maria, R
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- 2016
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9. Assessing the ecological quality status of the highly polluted Bagnoli area (Tyrrhenian Sea, Italy) using foraminiferal eDNA metabarcoding
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Cavaliere, M., primary, Barrenechea Angeles, I., additional, Montresor, M., additional, Bucci, C., additional, Brocani, L., additional, Balassi, E., additional, Margiotta, F., additional, Francescangeli, F., additional, Bouchet, V.M.P., additional, Pawlowski, J., additional, and Frontalini, F., additional
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- 2021
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10. BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition
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Coppola, V, Musumeci, M, Patrizii, M, Cannistraci, A, Addario, A, Maugeri-Saccà, M, Biffoni, M, Francescangeli, F, Cordenonsi, M, Piccolo, S, Memeo, L, Pagliuca, A, Muto, G, Zeuner, A, De Maria, R, and Bonci, D
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- 2013
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11. Impact of the Middle Eocene Climatic Optimum (MECO) on Foraminiferal and Calcareous Nannofossil Assemblages in the Neo-Tethyan Baskil Section (Eastern Turkey): Paleoenvironmental and Paleoclimatic Reconstructions
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D'Onofrio R.[1], Zaky A.S.[2, Frontalini F.[4], Luciani V.[1], Catanzariti R.[5], Francescangeli F.[6], Giorgioni M.[7], Coccioni R.[4], Özcan E.[8], and Jovane L.[9]
- Subjects
calcareous nannofossils ,Technology ,biota resilience ,QH301-705.5 ,QC1-999 ,Holocene climatic optimum ,benthic foraminifera ,middle eocene climatic optimum ,Neo-Tethys ,Foraminifera ,Paleontology ,chemistry.chemical_compound ,550 Earth sciences & geology ,General Materials Science ,Water cycle ,Biology (General) ,Instrumentation ,QD1-999 ,Fluid Flow and Transfer Processes ,δ13C ,biology ,Process Chemistry and Technology ,Physics ,General Engineering ,Biota ,planktic foraminifera ,biology.organism_classification ,Engineering (General). Civil engineering (General) ,Seafloor spreading ,Computer Science Applications ,Chemistry ,chemistry ,Benthic zone ,Carbonate ,TA1-2040 ,warming event analogues ,Geology ,OCEANOGRAFIA - Abstract
The Middle Eocene Climatic Optimum (MECO; ~40 Ma), which interrupted for ~500–600 kyr the long-term cooling trend culminating at the Eocene/Oligocene boundary, still requires a comprehensive understanding of the biotic resilience. Here we present a high-resolution integrated foraminiferal and calcareous nannofossil study across the MECO from the expanded and continuous Tethyan Baskil section (eastern Turkey) that offers a complete magneto-biostratigraphic and geochemical framework. The five MECO phases identified reveal a transition from oligotrophic (pre-MECO) to eu-mesotrophic conditions, possibly related to accelerated hydrological cycle, during the initial MECO and MECO δ13C negative excursion phases. The MECO WARMING PEAK phase, marking the highest carbonate dissolution interval, records the most striking biotic changes, such as peak in warm and eutrophic nannofossils, virtual disappearance of the oligotrophic planktic foraminiferal large Acarinina and Morozovelloides, and peak in eutrophic deep dwellers Subbotina. Benthic foraminifera suggest in this phase an improvement in the quality of organic matter to the seafloor. The post-MECO phase shows only a partial recovery of the pre-event conditions. Large Acarinina and Morozovelloides did not recover their abundance, possibly due to cooler conditions in this phase. Our reconstruction reveals how paleoenvironment and marine biota from the studied Neo-Tethyan setting reacted to the MECO perturbations.
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- 2021
12. Indicative value of benthic foraminifera for biomonitoring: Assignment to ecological groups of sensitivity to total organic carbon of species from European intertidal areas and transitional waters
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Bouchet, V.M.P. Frontalini, F. Francescangeli, F. Sauriau, P.-G. Geslin, E. Martins, M.V.A. Almogi-Labin, A. Avnaim-Katav, S. Di Bella, L. Cearreta, A. Coccioni, R. Costelloe, A. Dimiza, M.D. Ferraro, L. Haynert, K. Martínez-Colón, M. Melis, R. Schweizer, M. Triantaphyllou, M.V. Tsujimoto, A. Wilson, B. Armynot du Châtelet, E.
- Abstract
This work contributes to the ongoing work aiming at confirming benthic foraminifera as a biological quality element. In this study, benthic foraminifera from intertidal and transitional waters from the English Channel/European Atlantic coast and the Mediterranean Sea were assigned to five ecological groups using the weighted-averaging optimum with respect to TOC of each species. It was however not possible to assign typical salt marsh species due to the presence of labile and refractory organic matter that hampers TOC characterization. Tests of this study species' lists with Foram-AMBI on two independent datasets showed a significant correlation between Foram-AMBI and TOC, confirming the strong relation between foraminifera and TOC. For one of the validation datasets, associated macrofaunal data were available and a significant correlation was found between the foraminiferal Foram-AMBI and the macrofaunal AMBI. The here proposed lists should be further tested with sensitivity-based indices in different European regional settings. © 2021 Elsevier Ltd
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- 2021
13. Relative abundances of benthic foraminifera in response to total organic carbon in sediments: Data from European intertidal areas and transitional waters
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Bouchet, V.M.P. Frontalini, F. Francescangeli, F. Sauriau, P.-G. Geslin, E. Martins, M.V.A. Almogi-Labin, A. Avnaim-Katav, S. Bella, L.D. Cearreta, A. Coccioni, R. Costelloe, A. Dimiza, M.D. Ferraro, L. Haynert, K. Martínez-Colón, M. Melis, R. Schweizer, M. Triantaphyllou, M.V. Tsujimoto, A. Wilson, B. Armynot du Châtelet, E.
- Abstract
We gathered total organic carbon (%) and relative abundances of benthic foraminifera in intertidal areas and transitional waters from the English Channel/European Atlantic Coast (587 samples) and the Mediterranean Sea (301 samples) regions from published and unpublished datasets. This database allowed to calculate total organic carbon optimum and tolerance range of benthic foraminifera in order to assign them to ecological groups of sensitivity. Optima and tolerance range were obtained by mean of the weighted-averaging method. The data are related to the research article titled “Indicative value of benthic foraminifera for biomonitoring: assignment to ecological groups of sensitivity to total organic carbon of species from European intertidal areas and transitional waters” [1]. © 2021 The Authors
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- 2021
14. Repeated exposure to subinfectious doses of sars-cov-2 may promote t cell immunity and protection against severe covid-19
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De Angelis, M. L., Francescangeli, F., Rossi, R., Giuliani, A., De Maria Marchiano, Ruggero, Zeuner, A., De Maria R. (ORCID:0000-0003-2255-0583), De Angelis, M. L., Francescangeli, F., Rossi, R., Giuliani, A., De Maria Marchiano, Ruggero, Zeuner, A., and De Maria R. (ORCID:0000-0003-2255-0583)
- Abstract
Europe is experiencing a third wave of COVID-19 due to the spread of highly transmissible SARS-CoV-2 variants. A number of positive and negative factors constantly shape the rates of COVID-19 infections, hospitalization, and mortality. Among these factors, the rise in increasingly transmissible variants on one side and the effect of vaccinations on the other side create a picture deeply different from that of the first pandemic wave. Starting from the observation that in several European countries the number of COVID-19 infections in the second and third pandemic wave increased without a proportional rise in disease severity and mortality, we hypothesize the existence of an additional factor influencing SARS-CoV-2 dynamics. This factor consists of an immune defence against severe COVID-19, provided by SARS-CoV-2-specific T cells progressively developing upon natural exposure to low virus doses present in populated environments. As suggested by recent studies, low-dose viral particles entering the respiratory and intestinal tracts may be able to induce T cell memory in the absence of inflammation, potentially resulting in different degrees of immunization. In this scenario, non-pharmaceutical interventions would play a double role, one in the short term by reducing the detrimental spreading of SARS-CoV-2 particles, and one in the long term by allowing the development of a widespread (although heterogeneous and uncontrollable) form of immune protection.
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- 2021
15. Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer
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Musumeci, M, Coppola, V, Addario, A, Patrizii, M, Maugeri-Saccà, M, Memeo, L, Colarossi, C, Francescangeli, F, Biffoni, M, Collura, D, Giacobbe, A, D'Urso, L, Falchi, M, Venneri, M A, Muto, G, De Maria, R, and Bonci, D
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- 2011
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16. Foraminiferal-based biotic indices to assess the ecological quality status of the Gulf of Gabes (Tunisia): Present limitations and future perspectives
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El Kateb, A, Stalder, C, Martínez-Colón, M, Mateu-Vicens, G, Francescangeli, F, Coletti, G, Stainbank, S, Spezzaferri, S, El Kateb, Akram, Stalder, Claudio, Martínez-Colón, Michael, Mateu-Vicens, Guillem, Francescangeli, Fabio, Coletti, Giovanni, Stainbank, Stephanie, Spezzaferri, Silvia, El Kateb, A, Stalder, C, Martínez-Colón, M, Mateu-Vicens, G, Francescangeli, F, Coletti, G, Stainbank, S, Spezzaferri, S, El Kateb, Akram, Stalder, Claudio, Martínez-Colón, Michael, Mateu-Vicens, Guillem, Francescangeli, Fabio, Coletti, Giovanni, Stainbank, Stephanie, and Spezzaferri, Silvia
- Abstract
Biotic indices are tools to assess the ecological status of marine systems, and can be based on different metrics (such as ecological groups, specific diversity). The present study applies five biotic indices based on living (stained) benthic foraminiferal assemblages to assess ecological conditions in a wide area of the Mediterranean Sea in the heavily polluted Gulf of Gabes and along the western and eastern coasts of the Djerba Island, with the eastern coast considered as “pristine”. The applied indices are based on epiphytic foraminifera e.g., the “long versus short life span” index (ILS) and the modified FoRAM-Index (FI’), benthic foraminiferal assemblage composition and diversity, e.g., the Tolerant Species index (TSstd), the Foram Stress Index (FSI), the diversity Index (exp(H’bc)) and the newly developed Foram-AZTI Marine Biotic Index (Foram-AMBI). This latter index was tested using species of benthic foraminifera presently assigned to ecological groups in the Mediterranean Sea. All indices confirm good ecological conditions eastern of Djerba. The FI’ and ILS, % TSstd, FSI, indicate a severe anthropogenic impact especially in the central part of the Gulf of Gabes, next to the phosphate industry of Skhira and along the western coast of Djerba Island and confirm direct observations and geochemical data. The indices based on epiphytic foraminifera seem to better reflect actual environmental conditions in the investigated region because of the extended Posidonia oceanica meadow in the area. The exp(H’bc) reflects lower degrees of pollution. The application of the Foram-AMBI index presents limitations that prevent its current use. It strongly underestimates the pollution impact along the Tunisian coast, and additional work is needed to increase the number of species attributed to ecological groups and to possibly modify the coefficients to be used in its equation.
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- 2020
17. A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer
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Francescangeli, F., Contavalli, Paola, De Angelis, M. L., Careccia, Silvia, Signore, M., Haas, Tobias Longin, Salaris, F., Baiocchi, M., Boe, A., Giuliani, A., Tcheremenskaia, O., Pagliuca, A., Guardiola, O., Minchiotti, G., Colace, L., Ciardi, A., D'Andrea, V., La Torre, F., Medema, J., De Maria Marchiano, Ruggero, Zeuner, A., Contavalli P., Careccia S., Haas T. L. (ORCID:0000-0003-2336-0263), De Maria R. (ORCID:0000-0003-2255-0583), Francescangeli, F., Contavalli, Paola, De Angelis, M. L., Careccia, Silvia, Signore, M., Haas, Tobias Longin, Salaris, F., Baiocchi, M., Boe, A., Giuliani, A., Tcheremenskaia, O., Pagliuca, A., Guardiola, O., Minchiotti, G., Colace, L., Ciardi, A., D'Andrea, V., La Torre, F., Medema, J., De Maria Marchiano, Ruggero, Zeuner, A., Contavalli P., Careccia S., Haas T. L. (ORCID:0000-0003-2336-0263), and De Maria R. (ORCID:0000-0003-2255-0583)
- Abstract
Background : Quiescent/slow cycling cells have been identified in several tumors and correlated with therapy resistance. However, the features of chemoresistant populations and the molecular factors linking quiescence to chemoresistance are largely unknown. Methods: A population of chemoresistant quiescent/slow cycling cells was isolated through PKH26 staining (which allows to separate cells on the basis of their proliferation rate) from colorectal cancer (CRC) xenografts and subjected to global gene expression and pathway activation analyses. Factors expressed by the quiescent/slow cycling population were analyzed through lentiviral overexpression approaches for their ability to induce a dormant chemoresistant state both in vitro and in mouse xenografts. The correlation between quiescence-associated factors, CRC consensus molecular subtype and cancer prognosis was analyzed in large patient datasets. Results: Untreated colorectal tumors contain a population of quiescent/slow cycling cells with stem cell features (quiescent cancer stem cells, QCSCs) characterized by a predetermined mesenchymal-like chemoresistant phenotype. QCSCs expressed increased levels of ZEB2, a transcription factor involved in stem cell plasticity and epithelial-mesenchymal transition (EMT), and of antiapototic factors pCRAF and pASK1. ZEB2 overexpression upregulated pCRAF/pASK1 levels resulting in increased chemoresistance, enrichment of cells with stemness/EMT traits and proliferative slowdown of tumor xenografts. In parallel, chemotherapy treatment of tumor xenografts induced the prevalence of QCSCs with a stemness/EMT phenotype and activation of the ZEB2/pCRAF/pASK1 axis, resulting in a chemotherapy-unresponsive state. In CRC patients, increased ZEB2 levels correlated with worse relapse-free survival and were strongly associated to the consensus molecular subtype 4 (CMS4) characterized by dismal prognosis, decreased proliferative rates and upregulation of EMT genes. Conclusions: These resul
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- 2020
18. A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors
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Orienti, I., Francescangeli, F., De Angelis, M. L., Fecchi, K., Bongiorno-Borbone, L., Signore, M., Peschiaroli, A., Boe, A., Bruselles, A., Costantino, A., Eramo, A., Salvati, V., Sette, G., Contavalli, P., Zolla, L., Oki, T., Kitamura, T., Spada, M., Giuliani, A., Baiocchi, M., La Torre, F., Melino, G., Tartaglia, M., De Maria, R., Zeuner, A., Salvati V., Sette G., Contavalli P., Spada M., De Maria R. (ORCID:0000-0003-2255-0583), Orienti, I., Francescangeli, F., De Angelis, M. L., Fecchi, K., Bongiorno-Borbone, L., Signore, M., Peschiaroli, A., Boe, A., Bruselles, A., Costantino, A., Eramo, A., Salvati, V., Sette, G., Contavalli, P., Zolla, L., Oki, T., Kitamura, T., Spada, M., Giuliani, A., Baiocchi, M., La Torre, F., Melino, G., Tartaglia, M., De Maria, R., Zeuner, A., Salvati V., Sette G., Contavalli P., Spada M., and De Maria R. (ORCID:0000-0003-2255-0583)
- Abstract
Fenretinide is a synthetic retinoid characterized by anticancer activity in preclinical models and favorable toxicological profile, but also by a low bioavailability that hindered its clinical efficacy in former clinical trials. We developed a new formulation of fenretinide complexed with 2-hydroxypropyl-beta-cyclodextrin (nanofenretinide) characterized by an increased bioavailability and therapeutic efficacy. Nanofenretinide was active in cell lines derived from multiple solid tumors, in primary spheroid cultures and in xenografts of lung and colorectal cancer, where it inhibited tumor growth independently from the mutational status of tumor cells. A global profiling of pathways activated by nanofenretinide was performed by reverse-phase proteomic arrays and lipid analysis, revealing widespread repression of the mTOR pathway, activation of apoptotic, autophagic and DNA damage signals and massive production of dihydroceramide, a bioactive lipid with pleiotropic effects on several biological processes. In cells that survived nanofenretinide treatment there was a decrease of factors involved in cell cycle progression and an increase in the levels of p16 and phosphorylated p38 MAPK with consequent block in G0 and early G1. The capacity of nanofenretinide to induce cancer cell death and quiescence, together with its elevated bioavailability and broad antitumor activity indicate its potential use in cancer treatment and chemoprevention.
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- 2019
19. A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells
- Author
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Orienti, I., Salvati, Valentina, Sette, Giovanni, Zucchetti, M., Bongiorno-Borbone, L., Peschiaroli, A., Zolla, L., Francescangeli, F., Ferrari, M., Matteo, C., Bello, E., Di Virgilio, A., Falchi, M., De Angelis, M. L., Baiocchi, M., Melino, G., De Maria Marchiano, Ruggero, Zeuner, A., Eramo, A., Salvati V., Sette G., De Maria R. (ORCID:0000-0003-2255-0583), Orienti, I., Salvati, Valentina, Sette, Giovanni, Zucchetti, M., Bongiorno-Borbone, L., Peschiaroli, A., Zolla, L., Francescangeli, F., Ferrari, M., Matteo, C., Bello, E., Di Virgilio, A., Falchi, M., De Angelis, M. L., Baiocchi, M., Melino, G., De Maria Marchiano, Ruggero, Zeuner, A., Eramo, A., Salvati V., Sette G., and De Maria R. (ORCID:0000-0003-2255-0583)
- Abstract
Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.
- Published
- 2019
20. Infilling of the Canche Estuary (eastern English Channel, France):Insight from benthic foraminifera and historical pictures
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Francescangeli, F., Portela, M., du Chatelet, Armynot E., Billon, G., Andersen, Thorbjørn Joest, Bouchet, V. M. P., Trentesaux, A., Francescangeli, F., Portela, M., du Chatelet, Armynot E., Billon, G., Andersen, Thorbjørn Joest, Bouchet, V. M. P., and Trentesaux, A.
- Published
- 2018
21. Renal cancer: New models and approach for personalizing therapy
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Di Martino, Susanna, De Luca, G, Grassi, L, Federici, G, Alfonsi, Romina, Signore, M, Addario, A, De Salvo, L, Francescangeli, F, Sanchez, M, Tirelli, V, Muto, G, Sperduti, I, Sentinelli, S, Costantini, M, Pasquini, L, Milella, M, Haoui, M, Simone, G, Gallucci, M, De Maria Marchiano, Ruggero, Bonci, D., di Martino S, Alfonsi R, De Maria Marchiano R (ORCID:0000-0003-2255-0583), Di Martino, Susanna, De Luca, G, Grassi, L, Federici, G, Alfonsi, Romina, Signore, M, Addario, A, De Salvo, L, Francescangeli, F, Sanchez, M, Tirelli, V, Muto, G, Sperduti, I, Sentinelli, S, Costantini, M, Pasquini, L, Milella, M, Haoui, M, Simone, G, Gallucci, M, De Maria Marchiano, Ruggero, Bonci, D., di Martino S, Alfonsi R, and De Maria Marchiano R (ORCID:0000-0003-2255-0583)
- Abstract
Background: Clear cell RCC (ccRCC) accounts for approximately 75% of the renal cancer cases. Surgery treatment seems to be the best efficacious approach for the majority of patients. However, a consistent fraction (30%) of cases progress after surgery with curative intent. It is currently largely debated the use of adjuvant therapy for high-risk patients and the clinical and molecular parameters for stratifying beneficiary categories. In addition, the treatment of advanced forms lacks reliable driver biomarkers for the appropriated therapeutic choice. Thus, renal cancer patient management urges predictive molecular indicators and models for therapy-decision making. Methods: Here, we developed and optimized new models and tools for ameliorating renal cancer patient management. We isolated from fresh tumor specimens heterogeneous multi-clonal populations showing epithelial and mesenchymal characteristics coupled to stem cell phenotype. These cells retained long lasting-tumor-propagating capacity provided a therapy monitoring approach in vitro and in vivo while being able to form parental tumors when orthotopically injected and serially transplanted in immunocompromised murine hosts. Results: In line with recent evidence of multiclonal cancer composition, we optimized in vitro cultures enriched of multiple tumor-propagating populations. Orthotopic xenograft masses recapitulated morphology, grading and malignancy of parental cancers. High-grade but not the low-grade neoplasias, resulted in efficient serial transplantation in mice. Engraftment capacity paralleled grading and recurrence frequency advocating for a prognostic value of our developed model system. Therefore, in search of novel molecular indicators for therapy decision-making, we used Reverse-Phase Protein Arrays (RPPA) to analyze a panel of total and phosphorylated proteins in the isolated populations. Tumor-propagating cells showed several deregulated kinase cascades associated with grading, including angiog
- Published
- 2018
22. Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells
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Francescangeli, F, Patrizii, M, Signore, M, Federici, G, Di Franco, S, Pagliuca, A, Baiocchi, M, Biffoni, M, Ricci Vitiani, L, Todaro, M, De Maria Marchiano, Ruggero, R, Zeuner, A., Francescangeli F, Pagliuca A, De Maria Marchiano (ORCID:0000-0003-2255-0583), Francescangeli, F, Patrizii, M, Signore, M, Federici, G, Di Franco, S, Pagliuca, A, Baiocchi, M, Biffoni, M, Ricci Vitiani, L, Todaro, M, De Maria Marchiano, Ruggero, R, Zeuner, A., Francescangeli F, Pagliuca A, and De Maria Marchiano (ORCID:0000-0003-2255-0583)
- Abstract
Tumor-initiating cells are responsible for tumor mainte- nance and relapse in solid and hematologic cancers. Although tumor-initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the prolifera- tive activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo-like kinase1 (Plk1), a mitotic kinase essential for cell prolifera- tion, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer-initiating cells in vitro. In vivo, Plk1 inhibi- tors killed CD1331 colon cancer cells leading to complete growth arrest of colon cancer stem cell-derived xenografts, whereas chemotherapeutic agents only slowed tumor pro- gression. While chemotherapy treatment increased CD1331 cell proliferation, treatment with Plk1 inhibitors eliminated all proliferating tumor-initiating cells. Quiescent CD1331 cells that survived the treatment with Plk1 inhibitors could be killed by subsequent Plk1 inhibition when they exited from quiescence. Altogether, these results provide a new insight into the proliferative status of colon tumor-initiating cells both in basal conditions and in response to therapy and indicate Plk1 inhibitors as potentially useful in the treatment of colorectal cancer.
- Published
- 2012
23. Biogeochemical characterisation of 200 years local changes in a transitional environment. What is the foraminifera's message?
- Author
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Francescangeli, F., Armynot du Chatelet, E., Trentesaux, A., Billon, G., Andersen, T.J., Bouchet, V., Laboratoire d’Océanologie et de Géosciences (LOG) - UMR 8187 (LOG), Institut national des sciences de l'Univers (INSU - CNRS)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Nord]), Processus et bilan des domaines sédimentaires (PBDS), Université de Lille, Sciences et Technologies-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 (LASIRE), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Institut national des sciences de l'Univers (INSU - CNRS), and Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille Institut (CLIL)
- Subjects
[CHIM.ANAL]Chemical Sciences/Analytical chemistry ,[SDU.STU.GC]Sciences of the Universe [physics]/Earth Sciences/Geochemistry ,[SDU.ENVI]Sciences of the Universe [physics]/Continental interfaces, environment - Published
- 2015
24. A microRNA code for prostate cancer metastasis
- Author
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Bonci, D., Coppola, Valeria, Patrizii, M., Addario, A., Cannistraci, A., Francescangeli, Federica, Pecci, R., Muto, G., Collura, D., Bedini, R., Zeuner, A., Valtieri, M., Sentinelli, S., Benassi, M. S., Gallucci, M., Carlini, P., Piccolo, S., De Maria Marchiano, Ruggero, Coppola, V., Francescangeli, F., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Bonci, D., Coppola, Valeria, Patrizii, M., Addario, A., Cannistraci, A., Francescangeli, Federica, Pecci, R., Muto, G., Collura, D., Bedini, R., Zeuner, A., Valtieri, M., Sentinelli, S., Benassi, M. S., Gallucci, M., Carlini, P., Piccolo, S., De Maria Marchiano, Ruggero, Coppola, V., Francescangeli, F., and De Maria Marchiano, R. (ORCID:0000-0003-2255-0583)
- Abstract
Although the development of bone metastasis is a major detrimental event in prostate cancer, the molecular mechanisms responsible for bone homing and destruction remain largely unknown. Here we show that loss of miR-15 and miR-16 in cooperation with increased miR-21 expression promote prostate cancer spreading and bone lesions. This combination of microRNA endows bone-metastatic potential to prostate cancer cells. Concomitant loss of miR-15/miR-16 and gain of miR-21 aberrantly activate TGF-Î2 and Hedgehog signaling, that mediate local invasion, distant bone marrow colonization and osteolysis by prostate cancer cells. These findings establish a new molecular circuitry for prostate cancer metastasis that was validated in patients' cohorts. Our data indicate a network of biomarkers and druggable pathways to improve patient treatment.
- Published
- 2016
25. Biodiversity trends of the meiofauna and foraminifera assemblages of Lake Varano (southern Italy)
- Author
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Frontalini, Fabrizio, Semprucci, Federica, Armynot du Châtelet, E., Francescangeli, F., Margaritelli, G., Rettori, R., Spagnoli, F., Balsamo, Maria, and Coccioni, Rodolfo
- Subjects
transitional environment ,conservation ,bioindicator ,biodiversity, bioindicator, conservation, transitional environment ,biodiversity - Published
- 2014
26. Biodiversity trends of the meiofaunal and foraminiferal assemblages of Lake Varano (South Italy)
- Author
-
Frontalini, F., Semprucci, F., ARMYNOT DU CHÂTELET, E., Francescangeli, F., Margaritelli, G., Rettori, Roberto, Spagnoli, F., Balsamo, M., and Coccioni, R.
- Published
- 2014
27. Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer
- Author
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Francescangeli, Federica, Contavalli, Paola, De Angelis, Maria Laura, Baiocchi, M., Gambara, G., Pagliuca, Alfredo, Fiorenzano, A., Prezioso, C., Boe, A., Todaro, M., Stassi, G., Castro, N. P., Watanabe, K., Salomon, D. S., De Maria Marchiano, Ruggero, Minchiotti, G., Zeuner, A., Francescangeli, F., Contavalli, P., De Angelis, M. L., Pagliuca, A., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Francescangeli, Federica, Contavalli, Paola, De Angelis, Maria Laura, Baiocchi, M., Gambara, G., Pagliuca, Alfredo, Fiorenzano, A., Prezioso, C., Boe, A., Todaro, M., Stassi, G., Castro, N. P., Watanabe, K., Salomon, D. S., De Maria Marchiano, Ruggero, Minchiotti, G., Zeuner, A., Francescangeli, F., Contavalli, P., De Angelis, M. L., Pagliuca, A., and De Maria Marchiano, R. (ORCID:0000-0003-2255-0583)
- Abstract
Stemness was recently depicted as a dynamic condition in normal and tumor cells. We found that the embryonic protein Cripto-1 (CR1) was expressed by normal stem cells at the bottom of colonic crypts and by cancer stem cells (CSCs) in colorectal tumor tissues. CR1-positive populations isolated from patient-derived tumor spheroids exhibited increased clonogenic capacity and expression of stem-cell-related genes. CR1 expression in tumor spheroids was variable over time, being subject to a complex regulation of the intracellular, surface and secreted protein, which was related to changes of the clonogenic capacity at the population level. CR1 silencing induced CSC growth arrest in vitro with a concomitant decrease of SrcAkt signaling, while in vivo it inhibited the growth of CSC-derived tumor xenografts and reduced CSC numbers. Importantly, CR1 silencing in established xenografts through an inducible expression system decreased CSC growth in both primary and metastatic tumors, indicating an essential role of CR1 in the regulation the CSC compartment. These results point to CR1 as a novel and dynamically regulated effector of stem cell functions in colorectal cancer.
- Published
- 2015
28. Benthic foraminiferal assemblages and biotopes in a coastal lake: the case study of Lake Varano (southern Italy)
- Author
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Frontalini, Fabrizio, Margaritelli, G., Francescangeli, F., Rettori, R., Armynot du Chatelet, E., and Coccioni, Rodolfo
- Published
- 2013
29. A microRNA code for prostate cancer metastasis
- Author
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Bonci, D, primary, Coppola, V, additional, Patrizii, M, additional, Addario, A, additional, Cannistraci, A, additional, Francescangeli, F, additional, Pecci, R, additional, Muto, G, additional, Collura, D, additional, Bedini, R, additional, Zeuner, A, additional, Valtieri, M, additional, Sentinelli, S, additional, Benassi, M S, additional, Gallucci, M, additional, Carlini, P, additional, Piccolo, S, additional, and De Maria, R, additional
- Published
- 2015
- Full Text
- View/download PDF
30. Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer
- Author
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Francescangeli, F, primary, Contavalli, P, additional, De Angelis, M L, additional, Baiocchi, M, additional, Gambara, G, additional, Pagliuca, A, additional, Fiorenzano, A, additional, Prezioso, C, additional, Boe, A, additional, Todaro, M, additional, Stassi, G, additional, Castro, N P, additional, Watanabe, K, additional, Salomon, D S, additional, De Maria, R, additional, Minchiotti, G, additional, and Zeuner, A, additional
- Published
- 2015
- Full Text
- View/download PDF
31. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer
- Author
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Zeuner, A., Francescangeli, F., Contavalli, P., Zapparelli, G., Apuzzo, T., Eramo, A., Baiocchi, M., De Angelis, M. L., Biffoni, M., Sette, G., Todaro, M., Stassi, G., De Maria Marchiano, R., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Zeuner, A., Francescangeli, F., Contavalli, P., Zapparelli, G., Apuzzo, T., Eramo, A., Baiocchi, M., De Angelis, M. L., Biffoni, M., Sette, G., Todaro, M., Stassi, G., De Maria Marchiano, R., and De Maria Marchiano, R. (ORCID:0000-0003-2255-0583)
- Abstract
Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC.
- Published
- 2014
32. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer
- Author
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Zeuner, A, Francescangeli, F, Contavalli, Paola, Zapparelli, G, Apuzzo, T, Eramo, A, Baiocchi, M, De Angelis, M. L, Biffoni, M, Sette, G, Todaro, M, Stassi, G, De Maria Marchiano, Ruggero, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Zeuner, A, Francescangeli, F, Contavalli, Paola, Zapparelli, G, Apuzzo, T, Eramo, A, Baiocchi, M, De Angelis, M. L, Biffoni, M, Sette, G, Todaro, M, Stassi, G, De Maria Marchiano, Ruggero, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
- Abstract
Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC.
- Published
- 2014
33. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer
- Author
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Zeuner, A, primary, Francescangeli, F, additional, Contavalli, P, additional, Zapparelli, G, additional, Apuzzo, T, additional, Eramo, A, additional, Baiocchi, M, additional, De Angelis, M L, additional, Biffoni, M, additional, Sette, G, additional, Todaro, M, additional, Stassi, G, additional, and De Maria, R, additional
- Published
- 2014
- Full Text
- View/download PDF
34. BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial-mesenchymal transition
- Author
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Coppola, Valeria, Musumeci, M., Patrizii, M., Cannistraci, A., Addario, A., Maugeri-Saccà, M., Biffoni, M., Francescangeli, Federica, Cordenonsi, M., Piccolo, S., Memeo, L., Pagliuca, Alfredo, Muto, G., Zeuner, A., De Maria Marchiano, Ruggero, Bonci, D., Coppola, V., Francescangeli, F., Pagliuca, A., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Coppola, Valeria, Musumeci, M., Patrizii, M., Cannistraci, A., Addario, A., Maugeri-Saccà, M., Biffoni, M., Francescangeli, Federica, Cordenonsi, M., Piccolo, S., Memeo, L., Pagliuca, Alfredo, Muto, G., Zeuner, A., De Maria Marchiano, Ruggero, Bonci, D., Coppola, V., Francescangeli, F., Pagliuca, A., and De Maria Marchiano, R. (ORCID:0000-0003-2255-0583)
- Abstract
Prostate cancer is one of the leading causes of cancer-related death in men. Despite significant advances in prostate cancer diagnosis and management, the molecular events involved in the transformation of normal prostate cells into cancer cells have not been fully understood. It is generally accepted that prostate cancer derives from the basal compartment while expressing luminal markers. We investigated whether downregulation of the basal protein B-cell translocation gene 2 (BTG2) is implicated in prostate cancer transformation and progression. Here we show that BTG2 loss can shift normal prostate basal cells towards luminal markers expression, a phenotype also accompanied by the appearance of epithelial-mesenchymal transition (EMT) traits. We also show that the overexpression of microRNA (miR)-21 suppresses BTG2 levels and promotes the acquisition of luminal markers and EMT in prostate cells. Furthermore, by using an innovative lentiviral vector able to compete with endogenous mRNA through the overexpression of the 3â2-untranslated region of BTG2, we demonstrate that in prostate tumor cells, the levels of luminal and EMT markers can be reduced by derepression of BTG2 from microRNA-mediated control. Finally, we show that the loss of BTG2 expression confers to non-tumorigenic prostate cells ability to grow in an orthotopic murine model, thus demonstrating the central role of BTG2 downregulaton in prostate cancer biology. © 2013 Macmillan Publishers Limited. All rights reserved.
- Published
- 2013
35. The Notch2-Jagged1 interaction mediates stem cell factor signaling in erythropoiesis
- Author
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Zeuner, A., Francescangeli, Federica, Signore, M., Venneri, M. A., Pedini, F., Felli, N., Pagliuca, Alfredo, Conticello, C., De Maria Marchiano, Ruggero, Francescangeli, F., Pagliuca, A., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Zeuner, A., Francescangeli, Federica, Signore, M., Venneri, M. A., Pedini, F., Felli, N., Pagliuca, Alfredo, Conticello, C., De Maria Marchiano, Ruggero, Francescangeli, F., Pagliuca, A., and De Maria Marchiano, R. (ORCID:0000-0003-2255-0583)
- Abstract
Stem cell factor (SCF), the ligand for the c-kit receptor, is essential for the production of red blood cells during development and stress erythropoiesis. SCF promotes erythroblast proliferation and survival, while delaying erythroid differentiation through mechanisms that are largely unknown. In cultures of primary human differentiating erythroblasts, we found that SCF induces an increase in the expression of Notch2, a member of the Notch family implicated in the control of cell growth and differentiation. Functional inhibition of either Notch or its ligand Jagged1 inhibited the effects of SCF on erythroid cell expansion. SCF also induced the expression of Hes-1 and GATA-2, which may contribute to transduce Notch2 signals in response to SCF. Transduction of primary erythroid precursors with a dominant-negative Notch2 mutant inhibited both basal and SCF-mediated erythroblast expansion, and counteracted the effects of SCF on erythroblast differentiation. These findings provide a clue to understand the effects of increased proliferation and delayed differentiation elicited by SCF on the erythroid compartment and indicate Notch2 as a new player in the regulation of red cell differentiation. © 2011 Macmillan Publishers Limited All rights reserved.
- Published
- 2011
36. Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer
- Author
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Musumeci, M., Coppola, Valeria, Addario, A., Patrizii, M., Maugeri-Saccá, M., Memeo, L., Colarossi, C., Francescangeli, Federica, Biffoni, M., Collura, D., Giacobbe, A., D'Urso, L., Falchi, M., Venneri, M. A., Muto, G., De Maria Marchiano, Ruggero, Bonci, D., Coppola, V., Francescangeli, F., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Musumeci, M., Coppola, Valeria, Addario, A., Patrizii, M., Maugeri-Saccá, M., Memeo, L., Colarossi, C., Francescangeli, Federica, Biffoni, M., Collura, D., Giacobbe, A., D'Urso, L., Falchi, M., Venneri, M. A., Muto, G., De Maria Marchiano, Ruggero, Bonci, D., Coppola, V., Francescangeli, F., and De Maria Marchiano, R. (ORCID:0000-0003-2255-0583)
- Abstract
The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer. © 2011 Macmillan Publishers Limited All rights reserved.
- Published
- 2011
37. BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition
- Author
-
Coppola, V, primary, Musumeci, M, additional, Patrizii, M, additional, Cannistraci, A, additional, Addario, A, additional, Maugeri-Saccà, M, additional, Biffoni, M, additional, Francescangeli, F, additional, Cordenonsi, M, additional, Piccolo, S, additional, Memeo, L, additional, Pagliuca, A, additional, Muto, G, additional, Zeuner, A, additional, De Maria, R, additional, and Bonci, D, additional
- Published
- 2012
- Full Text
- View/download PDF
38. The Notch2–Jagged1 interaction mediates stem cell factor signaling in erythropoiesis
- Author
-
Zeuner, A, primary, Francescangeli, F, additional, Signore, M, additional, Venneri, M A, additional, Pedini, F, additional, Felli, N, additional, Pagliuca, A, additional, Conticello, C, additional, and De Maria, R, additional
- Published
- 2010
- Full Text
- View/download PDF
39. Vaginoplasty using autologous in vitro cultured vaginal tissue in a patient with Mayer-von-Rokitansky-Kuster-Hauser syndrome
- Author
-
Panici, P. B., primary, Bellati, F., additional, Boni, T., additional, Francescangeli, F., additional, Frati, L., additional, and Marchese, C., additional
- Published
- 2007
- Full Text
- View/download PDF
40. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer.
- Author
-
Zeuner, A, Francescangeli, F, Contavalli, P, Zapparelli, G, Apuzzo, T, Eramo, A, Baiocchi, M, De Angelis, M L, Biffoni, M, Sette, G, Todaro, M, Stassi, G, and De Maria, R
- Subjects
- *
CANCER stem cells , *BCL genes , *LUNG cancer & genetics , *NEOPLASTIC cell transformation , *CANCER chemotherapy - Abstract
Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
41. Understanding the Distributions of Benthic Foraminifera in the Adriatic Sea with Gradient Forest and Structural Equation Models
- Author
-
Masoud A. Rostami, Fabrizio Frontalini, Eric Armynot du Châtelet, Fabio Francescangeli, Maria Virginia Alves Martins, Rocco De Marco, Enrico Dinelli, Mario Tramontana, Lee A. Dyer, Romain Abraham, Viviane Bout-Roumazeilles, Marion Delattre, Federico Spagnoli, A. Rostami M., Frontalini F., Armynot du Chatelet E., Francescangeli F., Alves Martins M.V., De Marco R., Dinelli E., Tramontana M., Dyer L.A., Abraham R., Bout-Roumazeilles V., Delattre M., and Spagnoli F.
- Subjects
Fluid Flow and Transfer Processes ,machine learning ,depth ,Process Chemistry and Technology ,ecology ,benthic communities ,General Engineering ,General Materials Science ,Instrumentation ,Computer Science Applications - Abstract
In the last three decades, benthic foraminiferal ecology has been intensively investigated to improve the potential application of these marine organisms as proxies of the effects of climate change and other global change phenomena. It is still challenging to define the most important factors affecting foraminiferal communities and derived faunistic parameters. In this study, we examined the abiotic-biotic relationships of foraminiferal communities in the central-southern area of the Adriatic Sea using modern machine learning techniques. We combined gradient forest (Gf) and structural equation modeling (SEM) to test hypotheses about determinants of benthic foraminiferal assemblages. These approaches helped determine the relative effect of sizes of different environmental variables responsible for shaping living foraminiferal distributions. Four major faunal turnovers (at 13–28 m, 29–58 m, 59–215 m, and >215 m) were identified along a large bathymetric gradient (13–703 m water depth) that reflected the classical bathymetric distribution of benthic communities. Sand and organic matter (OM) contents were identified as the most relevant factors influencing the distribution of foraminifera either along the entire depth gradient or at selected bathymetric ranges. The SEM supported causal hypotheses that focused the factors that shaped assemblages at each bathymetric range, and the most notable causal relationships were direct effects of depth and indirect effects of the Gf-identified environmental parameters (i.e., sand, pollution load Index–PLI, organic matter–OM and total nitrogen–N) on foraminifera infauna and diversity. These results are relevant to understanding the basic ecology and conservation of foraminiferal communities.
- Published
- 2023
42. Foraminiferal-based biotic indices to assess the ecological quality status of the Gulf of Gabes (Tunisia): Present limitations and future perspectives
- Author
-
Giovanni Coletti, Silvia Spezzaferri, Stephanie Stainbank, Akram El Kateb, Guillem Mateu-Vicens, Michael Martínez-Colón, Fabio Francescangeli, Claudio Stalder, El Kateb, A, Stalder, C, Martínez-Colón, M, Mateu-Vicens, G, Francescangeli, F, Coletti, G, Stainbank, S, and Spezzaferri, S
- Subjects
0106 biological sciences ,Mediterranean climate ,Ecology ,biology ,General Decision Sciences ,010501 environmental sciences ,biology.organism_classification ,010603 evolutionary biology ,01 natural sciences ,Foraminifera ,Diversity index ,Mediterranean sea ,Benthic zone ,Posidonia oceanica ,Environmental science ,Biotic indices, Mediterranean, Benthic foraminifera, Pollution, Biomonitoring, FOBIMO, Foram-AMBI ,Ecology, Evolution, Behavior and Systematics ,0105 earth and related environmental sciences ,Global biodiversity ,Biotic index - Abstract
Biotic indices are tools to assess the ecological status of marine systems, and can be based on different metrics (such as ecological groups, specific diversity). The present study applies five biotic indices based on living (stained) benthic foraminiferal assemblages to assess ecological conditions in a wide area of the Mediterranean Sea in the heavily polluted Gulf of Gabes and along the western and eastern coasts of the Djerba Island, with the eastern coast considered as “pristine”. The applied indices are based on epiphytic foraminifera e.g., the “long versus short life span” index (ILS) and the modified FoRAM-Index (FI’), benthic foraminiferal assemblage composition and diversity, e.g., the Tolerant Species index (TSstd), the Foram Stress Index (FSI), the diversity Index (exp(H’bc)) and the newly developed Foram-AZTI Marine Biotic Index (Foram-AMBI). This latter index was tested using species of benthic foraminifera presently assigned to ecological groups in the Mediterranean Sea. All indices confirm good ecological conditions eastern of Djerba. The FI’ and ILS, % TSstd, FSI, indicate a severe anthropogenic impact especially in the central part of the Gulf of Gabes, next to the phosphate industry of Skhira and along the western coast of Djerba Island and confirm direct observations and geochemical data. The indices based on epiphytic foraminifera seem to better reflect actual environmental conditions in the investigated region because of the extended Posidonia oceanica meadow in the area. The exp(H’bc) reflects lower degrees of pollution. The application of the Foram-AMBI index presents limitations that prevent its current use. It strongly underestimates the pollution impact along the Tunisian coast, and additional work is needed to increase the number of species attributed to ecological groups and to possibly modify the coefficients to be used in its equation.
- Published
- 2020
43. A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors
- Author
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Angelita Costantino, Angelo Peschiaroli, Gerry Melino, Marco Tartaglia, Maria Laura De Angelis, Lucilla Bongiorno-Borbone, Marta Baiocchi, Alessandro Giuliani, Michele Signore, Alessandra Boe, Adriana Eramo, Ruggero De Maria, Alessandro Bruselles, Ann Zeuner, Paola Contavalli, Isabella Orienti, Federica Francescangeli, Toshio Kitamura, Massimo Spada, Filippo La Torre, Valentina Salvati, Giovanni Sette, Toshihiko Oki, Lello Zolla, Katia Fecchi, Signore, Michele [0000-0002-0262-842X], Melino, Gerry [0000-0001-9428-5972], Zeuner, Ann [0000-0002-8295-3715], Apollo - University of Cambridge Repository, Orienti I., Francescangeli F., De Angelis M.L., Fecchi K., Bongiorno-Borbone L., Signore M., Peschiaroli A., Boe A., Bruselles A., Costantino A., Eramo A., Salvati V., Sette G., Contavalli P., Zolla L., Oki T., Kitamura T., Spada M., Giuliani A., Baiocchi M., La Torre F., Melino G., Tartaglia M., De Maria R., and Zeuner A.
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Fenretinide ,DNA damage ,Colorectal cancer ,Immunology ,Antineoplastic Agents ,Apoptosis ,fenretinide, cyclodextrin, bioavailable formulation, solid tumors ,p38 Mitogen-Activated Protein Kinases ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Settore MED/04 - PATOLOGIA GENERALE ,Cell Line, Tumor ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,lcsh:QH573-671 ,Settore BIO/10 ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,lcsh:Cytology ,Cancer stem cells ,Cell Cycle ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,Bioavailability ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Colonic Neoplasms ,Cancer research ,Female ,fenretinide ,cancer stem cells ,cancer ,DNA Damage - Abstract
Fenretinide is a synthetic retinoid characterized by anticancer activity in preclinical models and favorable toxicological profile, but also by a low bioavailability that hindered its clinical efficacy in former clinical trials. We developed a new formulation of fenretinide complexed with 2-hydroxypropyl-beta-cyclodextrin (nanofenretinide) characterized by an increased bioavailability and therapeutic efficacy. Nanofenretinide was active in cell lines derived from multiple solid tumors, in primary spheroid cultures and in xenografts of lung and colorectal cancer, where it inhibited tumor growth independently from the mutational status of tumor cells. A global profiling of pathways activated by nanofenretinide was performed by reverse-phase proteomic arrays and lipid analysis, revealing widespread repression of the mTOR pathway, activation of apoptotic, autophagic and DNA damage signals and massive production of dihydroceramide, a bioactive lipid with pleiotropic effects on several biological processes. In cells that survived nanofenretinide treatment there was a decrease of factors involved in cell cycle progression and an increase in the levels of p16 and phosphorylated p38 MAPK with consequent block in G0 and early G1. The capacity of nanofenretinide to induce cancer cell death and quiescence, together with its elevated bioavailability and broad antitumor activity indicate its potential use in cancer treatment and chemoprevention.
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- 2019
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44. A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells
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Giovanni Sette, Lello Zolla, Gerry Melino, Angelo Peschiaroli, Federica Francescangeli, Mariella Ferrari, Maria Laura De Angelis, Cristina Matteo, Ezia Bello, Antonio Di Virgilio, Massimo Zucchetti, Valentina Salvati, Mario Falchi, Isabella Orienti, Marta Baiocchi, Adriana Eramo, Ruggero De Maria, Ann Zeuner, Lucilla Bongiorno-Borbone, Orienti I., Salvati V., Sette G., Zucchetti M., Bongiorno-Borbone L., Peschiaroli A., Zolla L., Francescangeli F., Ferrari M., Matteo C., Bello E., Di Virgilio A., Falchi M., De Angelis M.L., Baiocchi M., Melino G., De Maria R., Zeuner A., and Eramo A.
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Bioavailability ,Cancer therapy ,Fenretinide ,Administration, Oral ,Apoptosis ,Mice, SCID ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Mice, Inbred NOD ,Tumor Cells, Cultured ,Medicine ,Tissue Distribution ,Melanoma ,Micelles ,media_common ,Settore BIO/11 ,Cancer stem cells ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncology ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Toxicity ,Drug delivery ,Neoplastic Stem Cells ,Female ,Drug ,media_common.quotation_subject ,Biological Availability ,Pharmacokinetic ,Antitumour activity ,Antineoplastic Agents ,Solid tumour ,lcsh:RC254-282 ,03 medical and health sciences ,Cancer stem cell ,In vivo ,Settore MED/04 - PATOLOGIA GENERALE ,Animals ,Humans ,Pharmacokinetics ,Cell Proliferation ,Solid tumours ,business.industry ,Research ,antitumour activity ,bioavailability ,cancer stem cells ,cancer therapy ,drug delivery ,fenretinide ,pharmacokinetics ,solid tumours ,solubility ,Xenograft Model Antitumor Assays ,030104 developmental biology ,chemistry ,Solubility ,Cancer cell ,Cancer research ,business - Abstract
Background An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin. Electronic supplementary material The online version of this article (10.1186/s13046-019-1383-9) contains supplementary material, which is available to authorized users.
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- 2019
45. Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors
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Orietta Picconi, Anna Rita Migliaccio, Gabriella Girelli, Emanuel F. Petricoin, Agostino Tafuri, Federica Francescangeli, Mario Falchi, Maria Mazzarini, Lilian Varricchio, Paola Contavalli, Fabrizio Martelli, Giulia Federici, Ann Zeuner, Federici G., Varricchio L., Martelli F., Falchi M., Picconi O., Francescangeli F., Contavalli P., Girelli G., Tafuri A., Petricoin E.F., Mazzarini M., Zeuner A., and Franco Migliaccio Anna Rita
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0301 basic medicine ,Cancer Research ,Stem cell factor ,Stimulation ,erythroid progenitors ,ckit ,erythropoiesis ,polycythemia vera ,stem cell factor ,Biology ,DEPTOR ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Polycythemia vera ,Tetraspanin ,erythroid progenitor ,medicine ,erythropoiesi ,PI3K/AKT/mTOR pathway ,Original Research ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell biology ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cord blood ,Erythropoiesis ,cKIT - Abstract
Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV.
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- 2019
46. Cancer stem cell-based models of colorectal cancer reveal molecular determinants of therapy resistance
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Giorgio Russo, Giorgio Stassi, Sara Vitale, Marta Baiocchi, Alessandro Bruselles, Federica Francescangeli, Eleonora Policicchio, Emanuela Pilozzi, Gabriele De Luca, Maria Laura De Angelis, Ruggero De Maria, Michele Signore, Alessandra Boe, Lucia Ricci-Vitiani, Ann Zeuner, Marco Tartaglia, Carla Azzurra Amoreo, Alfredo Pagliuca, De Angelis, M., Zeuner, A., Policicchio, E., Russo, G., Bruselles, A., Signore, M., Vitale, S., De Luca, G., Pilozzi, E., Boe, A., Stassi, G., Ricci-Vitiani, L., Amoreo, C., Pagliuca, A., Francescangeli, F., Tartaglia, M., De Maria, R., and Baiocchi, M
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0301 basic medicine ,Proteomics ,cancer stem cells ,Colorectal cancer ,Drug Resistance ,Mice, SCID ,Anti-EGFR therapy ,Cancer stem cells ,Cetuximab ,Proteomic arrays ,Animals ,Cells, Cultured ,Colorectal Neoplasms ,Drug Resistance, Neoplasm ,Female ,Gene Expression Profiling ,Humans ,Mice, Inbred NOD ,Mice, Transgenic ,Microarray Analysis ,Models, Biological ,Neoplastic Stem Cells ,Protein Kinase Inhibitors ,Signal Transduction ,Developmental Biology ,Cell Biology ,Transgenic ,Mice ,Models ,proteomic arrays ,cetuximab ,cell biology ,Epidermal growth factor receptor ,Cultured ,biology ,General Medicine ,Primary tumor ,Settore MED/46 - Scienze Tecniche Di Medicina Di Laboratorio ,Stem cell ,medicine.drug ,Cells ,colorectal cancer ,SCID ,03 medical and health sciences ,developmental biology ,Proteomic array ,Cancer stem cell ,In vivo ,Settore MED/04 - PATOLOGIA GENERALE ,medicine ,Settore MED/06 - ONCOLOGIA MEDICA ,Microarray analysis techniques ,business.industry ,medicine.disease ,Biological ,030104 developmental biology ,anti-EGFR therapy ,Immunology ,Cancer research ,biology.protein ,Neoplasm ,Inbred NOD ,business - Abstract
Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance. Significance Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer.
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- 2016
47. Aurora-A Is Essential for the Tumorigenic Capacity and Chemoresistance of Colorectal Cancer Stem Cells
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Alessandro Scopelliti, Matilde Todaro, Francesco Dieli, Antonino Agrusa, Vincenzo Eterno, Federica Francescangeli, Patrizia Cammareri, Giorgio Stassi, Ann Zeuner, Mary Pat Moyer, Cammareri, P, Scopelliti, A, Todaro, M, Eterno, V, Francescangeli, F, Moyer, MP, Agrusa, A, Dieli, F, Zeuner, A, and Stassi, G
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Cellular differentiation ,colorectal cancer stem cells ,Mice, Nude ,Cell Growth Processes ,Tumor initiation ,Protein Serine-Threonine Kinases ,Biology ,Mice ,Aurora Kinases ,Cell Movement ,Cancer stem cell ,Internal medicine ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Gene silencing ,Mitosis ,Aged ,Aurora Kinase A ,Centrosome ,Cell Cycle ,Gene Amplification ,Middle Aged ,medicine.disease ,Drug Resistance, Neoplasm ,Gene Knockdown Techniques ,Neoplastic Stem Cells ,Cancer research ,Female ,biological phenomena, cell phenomena, and immunity ,Stem cell ,Colorectal Neoplasms - Abstract
Colorectal cancer stem cells (CR-CSC) are responsible for the generation and maintenance of intestinal tumors and are highly resistant to conventional chemotherapeutic agents. Aurora-A, a serine-threonine kinase involved in mitosis regulation, plays multiple key functions in tumor initiation and progression. We found that Aurora-A is overexpressed in primary colorectal tumor cells, in the CR-CSC fraction, and in stem cell–derived differentiated cells, compared with normal colon tissue. Aurora-A expression was functionally linked to centrosome amplification in CR-CSC, as indicated by the decrease in cells with multiple centrosomes that followed Aurora-A silencing. Knockdown of Aurora-A resulted in growth inhibition of CR-CSC, alteration of cell cycle kinetics, and downregulation of the expression levels of antiapoptotic Bcl-2 family members, strongly sensitizing to chemotherapy-induced cell death. Moreover, Aurora-A silencing compromised the ability to form tumor xenografts in immunocompromised mice and reduced the migratory capacity of CR-CSC. Altogether, these results indicate that Aurora-A is essential for CR-CSC regeneration and resistance to cytotoxic stimuli and suggest that therapies directed against Aurora-A may effectively target the stem cell population in colorectal cancer. Cancer Res; 70(11); 4655–65. ©2010 AACR.
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- 2010
48. Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer
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Guido Gambara, Marta Baiocchi, Gabriella Minchiotti, M L De Angelis, Federica Francescangeli, Kiichi Watanabe, Matilde Todaro, Alfredo Pagliuca, R De Maria, Ann Zeuner, Nadia P. Castro, Alessandro Fiorenzano, David S. Salomon, Paola Contavalli, Alessandra Boe, Giorgio Stassi, Carolina Prezioso, Francescangeli, F., Contavalli, P., De Angelis, M., Baiocchi, M., Gambara, G., Pagliuca, A., Fiorenzano, A., Prezioso, C., Boe, A., Todaro, M., Stassi, G., Castro, N., Watanabe, K., Salomon, D., De Maria, R., Minchiotti, G., and Zeuner, A.
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Colorectal cancer ,Colorectal Neoplasm ,Cripto ,Mice ,Intercellular Signaling Peptides and Protein ,Tumor Cells, Cultured ,Regulation of gene expression ,Cultured ,stem cell ,CRIPTO 1 ,GPI-Linked Protein ,Cell biology ,Neoplasm Proteins ,Tumor Cells ,Gene Expression Regulation, Neoplastic ,Genes, src ,Neoplastic Stem Cells ,Intercellular Signaling Peptides and Proteins ,Female ,Stem cell ,Colorectal Neoplasms ,Human ,Signal Transduction ,colorectal cancer ,Biology ,GPI-Linked Proteins ,Animals ,Humans ,Proto-Oncogene Proteins c-akt ,Spheroids, Cellular ,Cell Biology ,Molecular Biology ,Neoplasm Protein ,Cancer stem cell ,Settore MED/04 - PATOLOGIA GENERALE ,medicine ,Gene silencing ,Clonogenic assay ,Protein kinase B ,src ,Original Paper ,Neoplastic ,Animal ,medicine.disease ,Gene Expression Regulation ,Genes ,Neoplastic Stem Cell ,Cellular ,Spheroids ,animals ,colorectal neoplasms ,female ,GPI-linked proteins ,gene expression regulation ,neoplastic ,genes, src ,humans ,intercellular signaling peptides and proteins ,mice ,neoplasm proteins ,neoplastic stem cells ,proto-oncogene proteins c-akt ,signal transduction ,spheroids ,cellular ,tumor cells ,cultured - Abstract
Stemness was recently depicted as a dynamic condition in normal and tumor cells. We found that the embryonic protein Cripto-1 (CR1) was expressed by normal stem cells at the bottom of colonic crypts and by cancer stem cells (CSCs) in colorectal tumor tissues. CR1-positive populations isolated from patient-derived tumor spheroids exhibited increased clonogenic capacity and expression of stem-cell-related genes. CR1 expression in tumor spheroids was variable over time, being subject to a complex regulation of the intracellular, surface and secreted protein, which was related to changes of the clonogenic capacity at the population level. CR1 silencing induced CSC growth arrest in vitro with a concomitant decrease of Src/Akt signaling, while in vivo it inhibited the growth of CSC-derived tumor xenografts and reduced CSC numbers. Importantly, CR1 silencing in established xenografts through an inducible expression system decreased CSC growth in both primary and metastatic tumors, indicating an essential role of CR1 in the regulation the CSC compartment. These results point to CR1 as a novel and dynamically regulated effector of stem cell functions in colorectal cancer.
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- 2015
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49. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer
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Matilde Todaro, Federica Francescangeli, M L De Angelis, Giovanni Sette, R De Maria, Giorgio Stassi, Tiziana Apuzzo, G Zapparelli, Paola Contavalli, Adriana Eramo, Ann Zeuner, Mauro Biffoni, Marta Baiocchi, Zeuner, A., Francescangeli, F., Contavalli, P., Zapparelli, G., Apuzzo, T., Eramo, A., Baiocchi, M., De Angelis, M., Biffoni, M., Sette, G., Todaro, M., Stassi, G., and De Maria, R.
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Lung Neoplasms ,Mice, SCID ,Pharmacology ,Piperazines ,Antineoplastic Agent ,Nitrophenols ,Mice ,Mice, Inbred NOD ,Carcinoma, Non-Small-Cell Lung ,Cytotoxic T cell ,Non-Small-Cell Lung ,education.field_of_study ,Sulfonamides ,Tumor ,Animals ,Antineoplastic Agents ,Biphenyl Compounds ,Cell Line, Tumor ,Cell Proliferation ,Cell Survival ,Female ,Humans ,Neoplastic Stem Cells ,Tumor Burden ,Xenograft Model Antitumor Assays ,bcl-X Protein ,Molecular Biology ,Cell Biology ,Stem cell ,Human ,medicine.drug ,Xenograft Model Antitumor Assay ,Population ,Biology ,SCID ,Sulfonamide ,Cell Line ,Cancer stem cell ,medicine ,education ,Lung cancer ,Piperazine ,Settore MED/04 - Patologia Generale ,Original Paper ,Nitrophenol ,Animal ,Cell growth ,Carcinoma ,medicine.disease ,Gemcitabine ,Lung Neoplasm ,Cell culture ,Biphenyl Compound ,Cancer research ,Inbred NOD ,Neoplastic Stem Cell - Abstract
Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC.
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- 2014
50. Proliferation state and polo-like kinase1 dependence of tumorigenic colon cancer cells
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Mauro Biffoni, Lucia Ricci Vitiani, Ruggero De Maria, Federica Francescangeli, Matilde Todaro, Ann Zeuner, M Patrizii, Alfredo Pagliuca, Simone Di Franco, Marta Baiocchi, Michele Signore, Giulia Federici, Francescangeli, F, Patrizii, M, Signore, M, Federici, G, Di Franco, S, Pagliuca, A, Baiocchi, M, Biffoni, M, Ricci Vitiani, L, Todaro, M, De Maria, R, and Zeuner, A.
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Colorectal cancer ,Cancer stem cells,colorectal cancer,cell proliferation,cell cycle ,Cell Cycle Proteins ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,AC133 Antigen ,RNA, Small Interfering ,0303 health sciences ,education.field_of_study ,Pteridines ,Cell Cycle ,Cell cycle ,Immunohistochemistry ,3. Good health ,Mitochondria ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Molecular Medicine ,Female ,Stem cell ,Population ,Transplantation, Heterologous ,Cell Growth Processes ,Biology ,Protein Serine-Threonine Kinases ,PLK1 ,03 medical and health sciences ,Cancer stem cell ,Antigens, CD ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,education ,Protein Kinase Inhibitors ,030304 developmental biology ,Glycoproteins ,Settore MED/04 - Patologia Generale ,Cell growth ,Cell Biology ,medicine.disease ,Tumor progression ,Immunology ,Cancer research ,Peptides ,Developmental Biology - Abstract
Tumor-initiating cells are responsible for tumor maintenance and relapse in solid and hematologic cancers. Although tumor-initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the proliferative activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo-like kinase1 (Plk1), a mitotic kinase essential for cell proliferation, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer-initiating cells in vitro. In vivo, Plk1 inhibitors killed CD133+ colon cancer cells leading to complete growth arrest of colon cancer stem cell-derived xenografts, whereas chemotherapeutic agents only slowed tumor progression. While chemotherapy treatment increased CD133+ cell proliferation, treatment with Plk1 inhibitors eliminated all proliferating tumor-initiating cells. Quiescent CD133+ cells that survived the treatment with Plk1 inhibitors could be killed by subsequent Plk1 inhibition when they exited from quiescence. Altogether, these results provide a new insight into the proliferative status of colon tumor-initiating cells both in basal conditions and in response to therapy and indicate Plk1 inhibitors as potentially useful in the treatment of colorectal cancer.
- Published
- 2012
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