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  1. Article: Tailoring DNA Vaccines: Designing Strategies Against HER2-Positive Cancers.

    Marchini, Cristina / Kalogris, Cristina / Garulli, Chiara / Pietrella, Lucia / Gabrielli, Federico / Curcio, Claudia / Quaglino, Elena / Cavallo, Federica / Amici, Augusto

    Frontiers in oncology

    2013  Volume 3, Page(s) 122

    Abstract: The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns ... ...

    Abstract The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs, and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has been widely demonstrated in transgenic cancer-prone mice, which recapitulate several features of human breast cancers. Nonetheless, the rational design of a cancer vaccine able to trigger a long-lasting immunity, and thus prevent tumor recurrence in patients, would require the understanding of how tolerance and immunosuppression regulate antitumor immune responses and, at the same time, the identification of the most immunogenic portions of the target protein. We herein retrace the findings that led to our most promising DNA vaccines that, by encoding human/rat chimeric forms of HER2, are able to circumvent peripheral tolerance. Preclinical data obtained with these chimeric DNA vaccines have provided the rationale for their use in an ongoing Phase I clinical trial (EudraCT 2011-001104-34).
    Language English
    Publishing date 2013-05-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2013.00122
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Dorsomorphin reverses the mesenchymal phenotype of breast cancer initiating cells by inhibition of bone morphogenetic protein signaling.

    Garulli, Chiara / Kalogris, Cristina / Pietrella, Lucia / Bartolacci, Caterina / Andreani, Cristina / Falconi, Maurizio / Marchini, Cristina / Amici, Augusto

    Cellular signalling

    2013  Volume 26, Issue 2, Page(s) 352–362

    Abstract: Increasing evidence supports the theory that tumor growth, homeostasis, and recurrence are dependent on a small subset of cells with stem cell properties, redefined cancer initiating cells (CICs) or cancer stem cells. Bone morphogenetic proteins (BMPs) ... ...

    Abstract Increasing evidence supports the theory that tumor growth, homeostasis, and recurrence are dependent on a small subset of cells with stem cell properties, redefined cancer initiating cells (CICs) or cancer stem cells. Bone morphogenetic proteins (BMPs) are involved in cell-fate specification during embryogenesis, in the maintenance of developmental potency in adult stem cells and may contribute to sustain CIC populations in breast carcinoma. Using the mouse A17 cell model previously related to mesenchymal cancer stem cells and displaying properties of CICs, we investigated the role of BMPs in the control of breast cancer cell plasticity. We showed that an autocrine activation of BMP signaling is crucial for the maintenance of mesenchymal stem cell phenotype and tumorigenic potential of A17 cells. Pharmacological inhibition of BMP signaling cascade by Dorsomorphin resulted in the acquisition of epithelial-like traits by A17 cells, including expression of Citokeratin-18 and E-cadherin, through downregulation of Snail and Slug transcriptional factors and Cyclooxygenase-2 (COX2) expression, and in the loss of their stem-features and self-renewal ability. This phenotypic switch compromised A17 cell motility, invasiveness and in vitro tumor growth. These results reveal that BMPs are key molecules at the crossroad between stemness and cancer.
    MeSH term(s) Animals ; Bone Morphogenetic Protein 4/pharmacology ; Bone Morphogenetic Protein Receptors, Type I/metabolism ; Bone Morphogenetic Protein Receptors, Type II/metabolism ; Bone Morphogenetic Proteins/metabolism ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Cyclooxygenase 2/genetics ; Cyclooxygenase 2/metabolism ; Epithelial-Mesenchymal Transition/drug effects ; Female ; Gene Expression Regulation/drug effects ; Humans ; Inhibitor of Differentiation Protein 1/metabolism ; Mice ; Neoplastic Stem Cells/cytology ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Phenotype ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Signal Transduction/drug effects
    Chemical Substances Bmp4 protein, mouse ; Bone Morphogenetic Protein 4 ; Bone Morphogenetic Proteins ; Idb1 protein, mouse ; Inhibitor of Differentiation Protein 1 ; Pyrazoles ; Pyrimidines ; dorsomorphin (10K52CIC1Z) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Bmpr1a protein, mouse (EC 2.7.11.30) ; Bmpr2 protein, mouse (EC 2.7.11.30) ; Bone Morphogenetic Protein Receptors, Type I (EC 2.7.11.30) ; Bone Morphogenetic Protein Receptors, Type II (EC 2.7.11.30)
    Language English
    Publishing date 2013-11-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1002702-6
    ISSN 1873-3913 ; 0898-6568
    ISSN (online) 1873-3913
    ISSN 0898-6568
    DOI 10.1016/j.cellsig.2013.11.022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2579: Show issues Location:
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  3. Article ; Online: Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2-positive breast carcinomas resistant to Lapatinib.

    Tilio, Martina / Gambini, Valentina / Wang, Junbiao / Garulli, Chiara / Kalogris, Cristina / Andreani, Cristina / Bartolacci, Caterina / Elexpuru Zabaleta, Maria / Pietrella, Lucia / Hysi, Albana / Iezzi, Manuela / Belletti, Barbara / Orlando, Fiorenza / Provinciali, Mauro / Galeazzi, Roberta / Marchini, Cristina / Amici, Augusto

    Cancer letters

    2016  Volume 381, Issue 1, Page(s) 76–84

    Abstract: HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration ... ...

    Abstract HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Δ16HER2 isoform (Δ16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Δ16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer. Of note, Dacomitinib, an irreversible small molecule pan-HER inhibitor, was able to completely suppress Δ16HER2-driven breast carcinogenesis. Thus, only Dacomitinib may offer benefit in this molecularly defined patient subset by irreversibly inhibiting Δ16HER2 activation.
    MeSH term(s) Alternative Splicing ; Animals ; Benzodioxoles/pharmacology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/enzymology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; Female ; Genetic Predisposition to Disease ; Humans ; Inhibitory Concentration 50 ; Mammary Neoplasms, Experimental/drug therapy ; Mammary Neoplasms, Experimental/enzymology ; Mammary Neoplasms, Experimental/genetics ; Mammary Neoplasms, Experimental/pathology ; Mice, Transgenic ; Phenotype ; Protein Isoforms ; Protein Kinase Inhibitors/pharmacology ; Quinazolines/pharmacology ; Quinazolinones/pharmacology ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism ; Signal Transduction/drug effects ; Time Factors
    Chemical Substances Benzodioxoles ; PF 00299804 ; Protein Isoforms ; Protein Kinase Inhibitors ; Quinazolines ; Quinazolinones ; lapatinib (0VUA21238F) ; saracatinib (9KD24QGH76) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
    Language English
    Publishing date 2016--10
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2016.07.028
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1177: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Sanguinarine suppresses basal-like breast cancer growth through dihydrofolate reductase inhibition.

    Kalogris, Cristina / Garulli, Chiara / Pietrella, Lucia / Gambini, Valentina / Pucciarelli, Stefania / Lucci, Cristiano / Tilio, Martina / Zabaleta, Maria Elexpuru / Bartolacci, Caterina / Andreani, Cristina / Giangrossi, Mara / Iezzi, Manuela / Belletti, Barbara / Marchini, Cristina / Amici, Augusto

    Biochemical pharmacology

    2014  Volume 90, Issue 3, Page(s) 226–234

    Abstract: Basal-like breast cancer (BLBC) remains a great challenge because of its clinically aggressive nature and lack of effective targeted therapy. We analyzed the potential anti-neoplastic effects of sanguinarine, a natural benzophenanthridine alkaloid, ... ...

    Abstract Basal-like breast cancer (BLBC) remains a great challenge because of its clinically aggressive nature and lack of effective targeted therapy. We analyzed the potential anti-neoplastic effects of sanguinarine, a natural benzophenanthridine alkaloid, against BLBC cells. Sanguinarine treatment resulted in a reduction of cell migration, in a dose-dependent inhibition of cell viability and in the induction of cell death by apoptosis in both human (MDA-MB-231 cells) and mouse (A17 cells) in vitro models of BLBC. In vivo experiments demonstrated that oral administration of sanguinarine reduced the development and growth of A17 transplantable tumors in FVB syngeneic mice. Western blotting analysis revealed that suppression of BLBC growth by sanguinarine was correlated with a concurrent upregulation of p27 and downregulation of cyclin D1 and with the inhibition of STAT3 activation. In addition, we identified sanguinarine as a potent inhibitor of dihydrofolate reductase (DHFR), able to impair enzyme activity even in methotrexate resistant MDA-MB-231 cells. These results provide evidence that sanguinarine is a promising anticancer drug for the treatment of BLBC.
    MeSH term(s) Animals ; Antineoplastic Agents, Phytogenic/adverse effects ; Antineoplastic Agents, Phytogenic/pharmacology ; Antineoplastic Agents, Phytogenic/therapeutic use ; Apoptosis/drug effects ; Benzophenanthridines/adverse effects ; Benzophenanthridines/pharmacology ; Benzophenanthridines/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/enzymology ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Drug Resistance, Neoplasm ; Female ; Folic Acid Antagonists/adverse effects ; Folic Acid Antagonists/pharmacology ; Folic Acid Antagonists/therapeutic use ; Humans ; Isoquinolines/adverse effects ; Isoquinolines/pharmacology ; Isoquinolines/therapeutic use ; Methotrexate/pharmacology ; Mice ; Mice, Inbred Strains ; Necrosis ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/metabolism ; Neoplasm Transplantation ; Neoplasms, Basal Cell/drug therapy ; Neoplasms, Basal Cell/enzymology ; Neoplasms, Basal Cell/pathology ; Random Allocation ; Tetrahydrofolate Dehydrogenase/chemistry ; Tetrahydrofolate Dehydrogenase/metabolism ; Tumor Burden/drug effects
    Chemical Substances Antineoplastic Agents, Phytogenic ; Benzophenanthridines ; Folic Acid Antagonists ; Isoquinolines ; Neoplasm Proteins ; sanguinarine (AV9VK043SS) ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Methotrexate (YL5FZ2Y5U1)
    Language English
    Publishing date 2014-08-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2014.05.014
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 19: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  5. Article ; Online: p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells.

    Bisaro, Brigitte / Montani, Maura / Konstantinidou, Georgia / Marchini, Cristina / Pietrella, Lucia / Iezzi, Manuela / Galiè, Mirco / Orso, Francesca / Camporeale, Annalisa / Colombo, Shana M / Di Stefano, Paola / Tornillo, Giusy / Camacho-Leal, Maria P / Turco, Emilia / Taverna, Daniela / Cabodi, Sara / Amici, Augusto / Defilippi, Paola

    Breast cancer research : BCR

    2012  Volume 14, Issue 5, Page(s) R137

    Abstract: Introduction: Intrinsic plasticity of breast carcinoma cells allows them to undergo a transient and reversible conversion into mesenchymal cells to disseminate into distant organs, where they can re-differentiate to an epithelial-like status to form a ... ...

    Abstract Introduction: Intrinsic plasticity of breast carcinoma cells allows them to undergo a transient and reversible conversion into mesenchymal cells to disseminate into distant organs, where they can re-differentiate to an epithelial-like status to form a cohesive secondary mass. The p130Cas scaffold protein is overexpressed in human ER+ and HER2+ breast cancer where it contributes to cancer progression, invasion and resistance to therapy. However, its role in regulating mesenchymal aggressive breast cancer cells remains to be determined. The aim of this study was to investigate the molecular and functional involvement of this adaptor protein in breast cancer cell plasticity.
    Methods: We used silencing strategies and rescue experiments to evaluate phenotypic and biochemical changes from mesenchymal to epithelial traits in breast tumor cell lines. In the mouse A17 cell model previously related to mesenchymal cancer stem cells and basal-like breast cancer, we biochemically dissected the signaling pathways involved and performed functional in vivo tumor growth ability assays. The significance of the signaling platform was assessed in a human setting through the use of specific inhibitors in aggressive MDA-MB-231 subpopulation LM2-4175 cells. To evaluate the clinical relevance of the results, we analyzed publicly available microarray data from the Netherlands Cancer Institute and from the Koo Foundation Sun Yat-Sen Cancer Center.
    Results: We show that p130Cas silencing induces loss of mesenchymal features, by downregulating Vimentin, Snail, Slug and Twist transcriptional factors, resulting in the acquirement of epithelial-like traits. Mechanistically, p130Cas controls Cyclooxygenase-2 transcriptional expression, which in turn contributes to p130Cas-dependent maintenance of mesenchymal phenotype. This cascade of events also compromises in vivo tumor growth through inhibition of cell signaling controlling cell cycle progression. c-Src and JNK kinases are sequential players in p130Cas/ Cyclooxygenase-2 axis and their pharmacological inhibition is sufficient to downregulate Cyclooxygenase-2 leading to an epithelial phenotype. Finally, in silico microarray data analysis indicates that p130Cas and Cyclooxygenase-2 concomitant overexpression predicts poor survival and high probability of breast tumor recurrence.
    Conclusions: Overall, these data identify a new p130Cas/Cyclooxygenase-2 axis as a crucial element in the control of breast tumor plasticity, opening new therapeutic strategies leading to inhibition of these pathways in aggressive breast carcinoma.
    MeSH term(s) Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; CSK Tyrosine-Protein Kinase ; Cell Line, Tumor ; Crk-Associated Substrate Protein/genetics ; Crk-Associated Substrate Protein/metabolism ; Cyclooxygenase 2/genetics ; Cyclooxygenase 2/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mice ; Models, Biological ; Phenotype ; Quantitative Trait, Heritable ; src-Family Kinases/metabolism
    Chemical Substances Crk-Associated Substrate Protein ; Cyclooxygenase 2 (EC 1.14.99.1) ; CSK Tyrosine-Protein Kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; CSK protein, human (EC 2.7.10.23) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2012-10-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2015059-3
    ISSN 1465-542X ; 1465-5411
    ISSN (online) 1465-542X
    ISSN 1465-5411
    DOI 10.1186/bcr3342
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5494: Show issues Location:
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  6. Article ; Online: The human splice variant Δ16HER2 induces rapid tumor onset in a reporter transgenic mouse.

    Marchini, Cristina / Gabrielli, Federico / Iezzi, Manuela / Zenobi, Santa / Montani, Maura / Pietrella, Lucia / Kalogris, Cristina / Rossini, Anna / Ciravolo, Valentina / Castagnoli, Lorenzo / Tagliabue, Elda / Pupa, Serenella M / Musiani, Piero / Monaci, Paolo / Menard, Sylvie / Amici, Augusto

    PloS one

    2011  Volume 6, Issue 4, Page(s) e18727

    Abstract: Several transgenic mice models solidly support the hypothesis that HER2 (ERBB2) overexpression or mutation promotes tumorigenesis. Recently, a HER2 splice variant lacking exon-16 (Δ16HER2) has been detected in human breast carcinomas. This alternative ... ...

    Abstract Several transgenic mice models solidly support the hypothesis that HER2 (ERBB2) overexpression or mutation promotes tumorigenesis. Recently, a HER2 splice variant lacking exon-16 (Δ16HER2) has been detected in human breast carcinomas. This alternative protein, a normal byproduct of HER2, has an increased transforming potency compared to wild-type (wt) HER2 receptors. To examine the ability of Δ16HER2 to transform mammary epithelium in vivo and to monitor Δ16HER2-driven tumorigenesis in live mice, we generated and characterized a mouse line that transgenically expresses both human Δ16HER2 and firefly luciferase under the transcriptional control of the MMTV promoter. All the transgenic females developed multifocal mammary tumors with a rapid onset and an average latency of 15.11 weeks. Immunohistochemical analysis revealed the concurrent expression of luciferase and the human Δ16HER2 oncogene only in the mammary gland and in strict correlation with tumor development. Transgenic Δ16HER2 expressed on the tumor cell plasma membrane from spontaneous mammary adenocarcinomas formed constitutively active homodimers able to activate the oncogenic signal transduction pathway mediated through Src kinase. These new transgenic animals demonstrate the ability of the human Δ16HER2 isoform to transform "per se" mammary epithelium in vivo. The high tumor incidence as well as the short latency strongly suggests that the Δ16HER2 splice variant represents the transforming form of the HER2 oncoprotein.
    MeSH term(s) Alternative Splicing ; Animals ; Cell Line, Tumor ; Dimerization ; Disulfides ; Female ; Genes, Reporter ; Humans ; Mammary Neoplasms, Animal ; Mice ; Mice, Transgenic ; Mutation ; Oncogenes ; Promoter Regions, Genetic ; Protein Isoforms ; Receptor, ErbB-2/genetics
    Chemical Substances Disulfides ; Protein Isoforms ; ERBB2 protein, human (EC 2.7.10.1) ; Erbb2 protein, mouse (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
    Language English
    Publishing date 2011-04-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0018727
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