The Experts below are selected from a list of 3180 Experts worldwide ranked by ideXlab platform
Joana Paredes - One of the best experts on this subject based on the ideXlab platform.
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P-Cadherin ExPression in Canine Mammary Tissues
Journal of Comparative Pathology, 2020Co-Authors: Adelina Gama, Joana Paredes, André Albergaria, Fátima Gärtner, Fernando SchmittAbstract:P-Cadherin is a classical Cadherin exPressed by myoePithelial cells in mammary tissue. Its exPression in human breast cancer has been associated with aggressive tumour behaviour. To analyse the Possible role of P-Cadherin in canine mammary carcinogenesis, its exPression was examined immunohistochemically in 82 samPles of normal (n=2), hyPerPlastic (n=11) and neoPlastic (n=69) canine mammary tissues. In normal and hyPerPlastic canine mammary glands, P-Cadherin was restricted to myoePithelial cells, usually at sites of cell-to-cell contact. In tumour tissues, however, P-Cadherin exPression was observed in both ePithelial and myoePithelial cells, with a cytoPlasmic Pattern of cellular distribution. Aberrant ePithelial P-Cadherin immunolabelling was found in 19/44 (43%) benign tumours and in 16/25 (64%) malignant tumours (P
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Review P-Cadherin exPression in breast cancer: a review
2020Co-Authors: Joana Paredes, André Albergaria, Ana Luisa Correia, Ana Sofia Ribeiro, Fernanda Milanezi, Fernando C. SchmittAbstract:P-Cadherin is frequently over-exPressed in high-grade invasive breast carcinomas and has been rePorted to be an enhancer of migration and invasion of breast cancer cells, being correlated with tumour aggressiveness. In addition, exPression of P-Cadherin is well established as an indicator of Poor Prognosis in human breast cancer, which has stimulated our interest in studying its role in this setting. This review describes the most imPortant findings on P-Cadherin exPression and function in normal mammary tissue and breast cancer cells, emPhasizing that further research is required to elucidate the role Played by this Protein in human mammary tumours.
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Aberrant P-Cadherin exPression: Is it associated with estrogen-indePendent growth in breast cancer?
Pathology Research and Practice, 2020Co-Authors: Joana Paredes, Fernanda Milanezi, Jorge S. Reis-filho, Dina Leitão, Daniel Abensur Athanazio, Fernando SchmittAbstract:Summary Breast carcinomas rePresent a heterogeneous grouP of tumors, with a diverse biologic behavior, outcome, and resPonse to theraPy. Recent studies have demonstrated that alterations in the exPression of adhesion molecules in cancer cells are related to aggressiveness and Poor Prognosis. The aim of our study was to investigate the exPression of P-Cadherin in breast carcinomas and correlate it with estrogen recePtor (ER) status. We selected 73 ductal carcinomas in situ (DCIS) and 149 invasive carcinomas of the breast, and assessed the exPression of P-Cadherin as well as other biologic markers. P-Cadherin exPression showed a strong inverse correlation with ER exPression in both tyPes of breast carcinoma ( in situ and invasive). P-Cadherin-Positive and ER-negative tumors were related to a higher histologic grade, a high Proliferation rate, and exPression of c-erbB-2. We demonstrated that P-Cadherin identifies a subgrouP of breast carcinomas that lacks ER exPression, and correlates with higher Proliferation rates and other Predictors of aggressive behavior. We believe that these tumors rePresent an advanced steP in cancer Progression, and our data suPPort the hyPothesis that an estrogen-indePendent Pathway regulates P-Cadherin exPression.
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P Cadherin and the journey to cancer metastasis
Molecular Cancer, 2015Co-Authors: Andre Filipe Vieira, Joana ParedesAbstract:P-Cadherin is a classical cell-to-cell adhesion molecule with a homeostatic function in several normal tissues. However, its behaviour in the malignant setting is notably dePendent on the cellular context. In some tumour models, such as melanoma and oral squamous cell carcinoma, P-Cadherin acts as a tumour suPPressor, since its absence is associated with a more aggressive cancer cell PhenotyPe; nevertheless, the overexPression of this molecule is linked to significant tumour Promoting effects in the breast, ovarian, Prostate, endometrial, skin, gastric, Pancreas and colon neoPlasms. Herein, we review the role of P-Cadherin in cancer cell invasion, as well as in loco-regional and distant metastatic dissemination. We focus in P-Cadherin signalling Pathways that are activated to induce invasion and metastasis, as well as cancer stem cell ProPerties. The signalling network downstream of P-Cadherin is notably dePendent on the cellular and tissue context and includes the activation of integrin molecules, recePtor tyrosine kinases, small molecule GTPases, EMT transcriPtion factors, and crosstalk with other Cadherin family members. As new oncogenic molecular Pathways mediated by P-Cadherin are uncovered, Putative theraPeutic oPtions can be tested, which will allow for the targeting of invasion or metastatic disease, dePending on the tumour model.
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P Cadherin role in normal breast develoPment and cancer
The International Journal of Developmental Biology, 2011Co-Authors: André Albergaria, Fernando Schmitt, Andre Filipe Vieira, Ana Sofia Ribeiro, Barbara Sousa, Anarita Nobre, Raquel Seruca, Joana ParedesAbstract:P-Cadherin is a cell-cell adhesion molecule, whose exPression is highly associated with undifferentiated cells in normal adult ePithelial tissues, as well as with Poorly differentiated carcinomas. Its exPression has been already rePorted in human embryonic stem cells and it is Presumed to be a marker of stem or Progenitor cells of some ePithelial tissues. In normal breast, P-Cadherin has an essential role during ductal mammary branching, being exPressed by the monolayer of ePithelial caP cells at the end buds. In mature mammary tissue, its exPression is restricted to the myoePithelium; it has been Postulated that it may also be Present in early luminal Progenitor cells. In breast cancer, P-Cadherin is frequently overexPressed in high-grade tumours, being a well-established indicator of Poor Patient Prognosis. It has been rePorted as an imPortant inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloProteases to the extracellular media, and the cleavage of a P-Cadherin soluble form with Pro-invasive activity. Intracellularly, this Protein interferes with the endogenous Cadherin/catenin comPlex, inducing P120-catenin delocalization to the cytoPlasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton. Considering P-Cadherin's role in cancer cell invasion and metastasis formation, a humanized monoclonal antibody was recently Produced to antagonize P-Cadherin-associated signalling Pathways, which is currently under Phase I clinical trials. In this review, the most imPortant findings about the role of P-Cadherin in normal breast develoPment and cancer will be illustrated and discussed, with emPhasis on the most recent data.
Fernando Schmitt - One of the best experts on this subject based on the ideXlab platform.
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P-Cadherin ExPression in Canine Mammary Tissues
Journal of Comparative Pathology, 2020Co-Authors: Adelina Gama, Joana Paredes, André Albergaria, Fátima Gärtner, Fernando SchmittAbstract:P-Cadherin is a classical Cadherin exPressed by myoePithelial cells in mammary tissue. Its exPression in human breast cancer has been associated with aggressive tumour behaviour. To analyse the Possible role of P-Cadherin in canine mammary carcinogenesis, its exPression was examined immunohistochemically in 82 samPles of normal (n=2), hyPerPlastic (n=11) and neoPlastic (n=69) canine mammary tissues. In normal and hyPerPlastic canine mammary glands, P-Cadherin was restricted to myoePithelial cells, usually at sites of cell-to-cell contact. In tumour tissues, however, P-Cadherin exPression was observed in both ePithelial and myoePithelial cells, with a cytoPlasmic Pattern of cellular distribution. Aberrant ePithelial P-Cadherin immunolabelling was found in 19/44 (43%) benign tumours and in 16/25 (64%) malignant tumours (P
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Aberrant P-Cadherin exPression: Is it associated with estrogen-indePendent growth in breast cancer?
Pathology Research and Practice, 2020Co-Authors: Joana Paredes, Fernanda Milanezi, Jorge S. Reis-filho, Dina Leitão, Daniel Abensur Athanazio, Fernando SchmittAbstract:Summary Breast carcinomas rePresent a heterogeneous grouP of tumors, with a diverse biologic behavior, outcome, and resPonse to theraPy. Recent studies have demonstrated that alterations in the exPression of adhesion molecules in cancer cells are related to aggressiveness and Poor Prognosis. The aim of our study was to investigate the exPression of P-Cadherin in breast carcinomas and correlate it with estrogen recePtor (ER) status. We selected 73 ductal carcinomas in situ (DCIS) and 149 invasive carcinomas of the breast, and assessed the exPression of P-Cadherin as well as other biologic markers. P-Cadherin exPression showed a strong inverse correlation with ER exPression in both tyPes of breast carcinoma ( in situ and invasive). P-Cadherin-Positive and ER-negative tumors were related to a higher histologic grade, a high Proliferation rate, and exPression of c-erbB-2. We demonstrated that P-Cadherin identifies a subgrouP of breast carcinomas that lacks ER exPression, and correlates with higher Proliferation rates and other Predictors of aggressive behavior. We believe that these tumors rePresent an advanced steP in cancer Progression, and our data suPPort the hyPothesis that an estrogen-indePendent Pathway regulates P-Cadherin exPression.
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P Cadherin role in normal breast develoPment and cancer
The International Journal of Developmental Biology, 2011Co-Authors: André Albergaria, Fernando Schmitt, Andre Filipe Vieira, Ana Sofia Ribeiro, Barbara Sousa, Anarita Nobre, Raquel Seruca, Joana ParedesAbstract:P-Cadherin is a cell-cell adhesion molecule, whose exPression is highly associated with undifferentiated cells in normal adult ePithelial tissues, as well as with Poorly differentiated carcinomas. Its exPression has been already rePorted in human embryonic stem cells and it is Presumed to be a marker of stem or Progenitor cells of some ePithelial tissues. In normal breast, P-Cadherin has an essential role during ductal mammary branching, being exPressed by the monolayer of ePithelial caP cells at the end buds. In mature mammary tissue, its exPression is restricted to the myoePithelium; it has been Postulated that it may also be Present in early luminal Progenitor cells. In breast cancer, P-Cadherin is frequently overexPressed in high-grade tumours, being a well-established indicator of Poor Patient Prognosis. It has been rePorted as an imPortant inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloProteases to the extracellular media, and the cleavage of a P-Cadherin soluble form with Pro-invasive activity. Intracellularly, this Protein interferes with the endogenous Cadherin/catenin comPlex, inducing P120-catenin delocalization to the cytoPlasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton. Considering P-Cadherin's role in cancer cell invasion and metastasis formation, a humanized monoclonal antibody was recently Produced to antagonize P-Cadherin-associated signalling Pathways, which is currently under Phase I clinical trials. In this review, the most imPortant findings about the role of P-Cadherin in normal breast develoPment and cancer will be illustrated and discussed, with emPhasis on the most recent data.
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extracellular cleavage and shedding of P Cadherin a mechanism underlying the invasive behaviour of breast cancer cells
Oncogene, 2010Co-Authors: Ana Sofia Ribeiro, André Albergaria, Fernando Schmitt, Ana Luisa Correia, Marc Bracke, Barbara Sousa, Raquel Seruca, Joana ParedesAbstract:Cell-cell adhesion is an elementary Process in normal ePithelial cellular architecture. Several studies have shown the role mediated by Cadherins in this Process, besides their role in the maintenance of cell Polarity, differentiation and cell growth. However, during tumour Progression, these molecules are frequently altered. In breast cancer, tumours that overexPress P-Cadherin usually Present a high histological grade, show decreased cell Polarity and are associated with worse Patient survival. However, little is known about how this Protein dictates the very aggressive behaviour of these tumours. To achieve this goal, we set uP two breast cancer cell models, where P-Cadherin exPression was differently modulated and analysed in terms of cell invasion, motility and migration. We show that P-Cadherin overexPression, in breast cancer cells with wild-tyPe E-Cadherin, Promotes cell invasion, motility and migration. Moreover, we found that the overexPression of P-Cadherin induces the secretion of matrix metalloProteases, sPecifically MMP-1 and MMP-2, which then lead to P-Cadherin ectodomain cleavage. Further, we showed that soluble P-Cadherin fragment is able to induce in vitro invasion of breast cancer cells. Overall, our results contribute to elucidate the mechanism underlying the invasive behaviour of P-Cadherin exPressing breast tumours. Oncogene (2010) 29, 392-402; doi:10.1038/onc.2009.338; Published online 9 November 2009
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P Cadherin exPression in breast cancer a review
Breast Cancer Research, 2007Co-Authors: Joana Paredes, André Albergaria, Fernando Schmitt, Ana Luisa Correia, Ana Sofia Ribeiro, Fernanda MilaneziAbstract:P-Cadherin is frequently over-exPressed in high-grade invasive breast carcinomas and has been rePorted to be an enhancer of migration and invasion of breast cancer cells, being correlated with tumour aggressiveness. In addition, exPression of P-Cadherin is well established as an indicator of Poor Prognosis in human breast cancer, which has stimulated our interest in studying its role in this setting. This review describes the most imPortant findings on P-Cadherin exPression and function in normal mammary tissue and breast cancer cells, emPhasizing that further research is required to elucidate the role Played by this Protein in human mammary tumours.
André Albergaria - One of the best experts on this subject based on the ideXlab platform.
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P-Cadherin ExPression in Canine Mammary Tissues
Journal of Comparative Pathology, 2020Co-Authors: Adelina Gama, Joana Paredes, André Albergaria, Fátima Gärtner, Fernando SchmittAbstract:P-Cadherin is a classical Cadherin exPressed by myoePithelial cells in mammary tissue. Its exPression in human breast cancer has been associated with aggressive tumour behaviour. To analyse the Possible role of P-Cadherin in canine mammary carcinogenesis, its exPression was examined immunohistochemically in 82 samPles of normal (n=2), hyPerPlastic (n=11) and neoPlastic (n=69) canine mammary tissues. In normal and hyPerPlastic canine mammary glands, P-Cadherin was restricted to myoePithelial cells, usually at sites of cell-to-cell contact. In tumour tissues, however, P-Cadherin exPression was observed in both ePithelial and myoePithelial cells, with a cytoPlasmic Pattern of cellular distribution. Aberrant ePithelial P-Cadherin immunolabelling was found in 19/44 (43%) benign tumours and in 16/25 (64%) malignant tumours (P
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Review P-Cadherin exPression in breast cancer: a review
2020Co-Authors: Joana Paredes, André Albergaria, Ana Luisa Correia, Ana Sofia Ribeiro, Fernanda Milanezi, Fernando C. SchmittAbstract:P-Cadherin is frequently over-exPressed in high-grade invasive breast carcinomas and has been rePorted to be an enhancer of migration and invasion of breast cancer cells, being correlated with tumour aggressiveness. In addition, exPression of P-Cadherin is well established as an indicator of Poor Prognosis in human breast cancer, which has stimulated our interest in studying its role in this setting. This review describes the most imPortant findings on P-Cadherin exPression and function in normal mammary tissue and breast cancer cells, emPhasizing that further research is required to elucidate the role Played by this Protein in human mammary tumours.
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the basal ePithelial marker P Cadherin associates with breast cancer cell PoPulations harboring a glycolytic and acid resistant PhenotyPe
BMC Cancer, 2014Co-Authors: André Albergaria, Andre Filipe Vieira, Ana Sofia Ribeiro, Barbara Sousa, Anarita Nobre, Diana Martins, Nair Lopes, Celine PinheiroAbstract:Background: Cancer stem cells are hyPoxia-resistant and Present a PrePonderant glycolytic metabolism. These characteristics are also found in basal-like breast carcinomas (BLBC), which show increased exPression of cancer stem cell markers. Recently, we demonstrated that P-Cadherin, a biomarker of BLBC and a Poor Prognostic factor in this disease, mediates stem-like ProPerties and resistance to radiation theraPy. Thus, the aim of the Present study was to evaluate if P-Cadherin exPression was associated to breast cancer cell PoPulations with an adaPted PhenotyPe to hyPoxia. Methods: Immunohistochemistry was Performed to address the exPression of P-Cadherin, hyPoxic, glycolytic and acid-resistance biomarkers in Primary human breast carcinomas. In vitro studies were Performed using basal-like breast cancer cell lines. qRT-PCR, FACS analysis, western blotting and confocal microscoPy were used to assess the exPression of P-Cadherin after HIF-1α stabilization, achieved by CoCl2 treatment. siRNA-mediated knockdown was used to silence the exPression of several targets and qRT-PCR was emPloyed to evaluate the effects of P-Cadherin on HIF-1α signaling. P-Cadherin high and low breast cancer cell PoPulations were sorted by FACS and levels of GLUT1 and CAIX were assessed by FACS and western blotting. MammosPhere forming efficiency was used to determine the stem cell activity after sPecific siRNA-mediated knockdown, further confirmed by western blotting. Results: We demonstrated that P-Cadherin overexPression was significantly associated with the exPression of HIF-1α, GLUT1, CAIX, MCT1 and CD147 in human breast carcinomas. In vitro, we showed that HIF-1α stabilization was accomPanied by increased membrane exPression of P-Cadherin and that P-Cadherin silencing led to a decrease of the mRNA levels of GLUT1 and CAIX. We also found that the cell fractions harboring high levels of P-Cadherin were the same exhibiting more GLUT1 and CAIX exPression. Finally, we showed that P-Cadherin silencing significantly decreases the mammosPhere forming efficiency in the same range as the silencing of HIF-1α, CAIX or GLUT1, validating that all these markers are being exPressed by the same breast cancer stem cell PoPulation.
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P Cadherin role in normal breast develoPment and cancer
The International Journal of Developmental Biology, 2011Co-Authors: André Albergaria, Fernando Schmitt, Andre Filipe Vieira, Ana Sofia Ribeiro, Barbara Sousa, Anarita Nobre, Raquel Seruca, Joana ParedesAbstract:P-Cadherin is a cell-cell adhesion molecule, whose exPression is highly associated with undifferentiated cells in normal adult ePithelial tissues, as well as with Poorly differentiated carcinomas. Its exPression has been already rePorted in human embryonic stem cells and it is Presumed to be a marker of stem or Progenitor cells of some ePithelial tissues. In normal breast, P-Cadherin has an essential role during ductal mammary branching, being exPressed by the monolayer of ePithelial caP cells at the end buds. In mature mammary tissue, its exPression is restricted to the myoePithelium; it has been Postulated that it may also be Present in early luminal Progenitor cells. In breast cancer, P-Cadherin is frequently overexPressed in high-grade tumours, being a well-established indicator of Poor Patient Prognosis. It has been rePorted as an imPortant inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloProteases to the extracellular media, and the cleavage of a P-Cadherin soluble form with Pro-invasive activity. Intracellularly, this Protein interferes with the endogenous Cadherin/catenin comPlex, inducing P120-catenin delocalization to the cytoPlasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton. Considering P-Cadherin's role in cancer cell invasion and metastasis formation, a humanized monoclonal antibody was recently Produced to antagonize P-Cadherin-associated signalling Pathways, which is currently under Phase I clinical trials. In this review, the most imPortant findings about the role of P-Cadherin in normal breast develoPment and cancer will be illustrated and discussed, with emPhasis on the most recent data.
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extracellular cleavage and shedding of P Cadherin a mechanism underlying the invasive behaviour of breast cancer cells
Oncogene, 2010Co-Authors: Ana Sofia Ribeiro, André Albergaria, Fernando Schmitt, Ana Luisa Correia, Marc Bracke, Barbara Sousa, Raquel Seruca, Joana ParedesAbstract:Cell-cell adhesion is an elementary Process in normal ePithelial cellular architecture. Several studies have shown the role mediated by Cadherins in this Process, besides their role in the maintenance of cell Polarity, differentiation and cell growth. However, during tumour Progression, these molecules are frequently altered. In breast cancer, tumours that overexPress P-Cadherin usually Present a high histological grade, show decreased cell Polarity and are associated with worse Patient survival. However, little is known about how this Protein dictates the very aggressive behaviour of these tumours. To achieve this goal, we set uP two breast cancer cell models, where P-Cadherin exPression was differently modulated and analysed in terms of cell invasion, motility and migration. We show that P-Cadherin overexPression, in breast cancer cells with wild-tyPe E-Cadherin, Promotes cell invasion, motility and migration. Moreover, we found that the overexPression of P-Cadherin induces the secretion of matrix metalloProteases, sPecifically MMP-1 and MMP-2, which then lead to P-Cadherin ectodomain cleavage. Further, we showed that soluble P-Cadherin fragment is able to induce in vitro invasion of breast cancer cells. Overall, our results contribute to elucidate the mechanism underlying the invasive behaviour of P-Cadherin exPressing breast tumours. Oncogene (2010) 29, 392-402; doi:10.1038/onc.2009.338; Published online 9 November 2009
Yungjue Bang - One of the best experts on this subject based on the ideXlab platform.
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down regulation of P Cadherin with Pf 03732010 inhibits cell migration and tumor growth in gastric cancer
Investigational New Drugs, 2012Co-Authors: Jinah Park, Doyoun Oh, Yungjue Bang, Eunju Park, Seockah ImAbstract:P-Cadherin is frequently uP-regulated in solid tumors such as gastric, colon, lung, Pancreatic and breast cancers. Although P-Cadherin Promotes Cadherin-mediated cell adhesion, the gastric cancer-linked regulation of P-Cadherin has not been extensively investigated. In this study, we found ePigenetic regulation of P-Cadherin in human gastric cancer cells that was induced by treatment with DNA demethylating drug and histone deacetylase inhibitor. Silencing P-Cadherin by using siRNA induces aPoPtosis in gastric cells and blocks exPression of Tie-2, an angiogenic recePtor tyrosine kinase. In contrast, ectoPically exPressed P-Cadherin by generating P-Cadherin stable cell line enhances Tie-2 exPression and cell mobility. We also demonstrated that inhibition of P-Cadherin by PF-03732010, a fully humanized anti-P-Cadherin IgG1 monoclonal antibody, suPPressed cell migration in vitro and tumor growth in BALB/c nude mice bearing SNU620 gastric cancer xenograft. The data rePorted here are the first to reveal that the inhibition of P-Cadherin decreases tumor cell migration and blocks a tumorigenesis by down-regulation of Tie-2 in gastric cancer. This demonstrates the Potential for P-Cadherin to be used as a target for treatment of gastric cancer.
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P Cadherin exPression in gastric carcinoma its regulation mechanism and Prognostic significance
Human Pathology, 2010Co-Authors: Eun Ji Jung, Hankwang Yang, Doyoun Oh, Yungjue BangAbstract:Summary P-Cadherin is a member of the Cadherin family and is exPressed in several solid tumors. This molecule was recently highlighted with the develoPment of a new targeted comPound being studied in a clinical trial on solid tumors. In the Present study, we examined the Protein and messenger RNA (mRNA) exPression status of P-Cadherin and its Promoter methylation in gastric carcinoma cell lines and tissues. Of the 10 cell lines, 4 were found to exPress P-Cadherin Protein and mRNA, and the P-Cadherin gene was found to be hyPomethylated in its Promoter region in these cell lines. NonneoPlastic gastric mucosal tissues from gastric carcinoma Patients were negative for P-Cadherin Protein evaluated by immunohistochemistry and Western blotting and had a methylated P-Cadherin Promoter region. In carcinoma tissues, 70.8% (749/1058) of cases showed P-Cadherin Protein exPression, and P-Cadherin Positive cases had a well or moderately differentiated histology according to the World Health Organization classification, intestinal-tyPe histology by Lauren classification, and an earlier PT class. Furthermore, Patients with P-Cadherin exPressing tumors had a favorable Prognosis by univariate and multivariate survival analyses. In addition, P-Cadherin Protein exPression was found to be significantly correlated with Promoter hyPomethylation. In summary, P-Cadherin is silenced in nonneoPlastic gastric mucosa, and P-Cadherin exPressing tumors constitute a subset of gastric carcinoma with intestinal-tyPe histology and a favorable Prognosis. In addition, our findings suggest that P-Cadherin Promoter methylation underlies the regulation of its exPression. These findings may aid Patient selection and the interPretation of P-Cadherin targeted theraPy and clinical trial results.
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P-Cadherin exPression in gastric carcinoma: its regulation mechanism and Prognostic significance ☆
Human Pathology, 2010Co-Authors: Eun Ji Jung, Hankwang Yang, Doyoun Oh, Yungjue BangAbstract:Summary P-Cadherin is a member of the Cadherin family and is exPressed in several solid tumors. This molecule was recently highlighted with the develoPment of a new targeted comPound being studied in a clinical trial on solid tumors. In the Present study, we examined the Protein and messenger RNA (mRNA) exPression status of P-Cadherin and its Promoter methylation in gastric carcinoma cell lines and tissues. Of the 10 cell lines, 4 were found to exPress P-Cadherin Protein and mRNA, and the P-Cadherin gene was found to be hyPomethylated in its Promoter region in these cell lines. NonneoPlastic gastric mucosal tissues from gastric carcinoma Patients were negative for P-Cadherin Protein evaluated by immunohistochemistry and Western blotting and had a methylated P-Cadherin Promoter region. In carcinoma tissues, 70.8% (749/1058) of cases showed P-Cadherin Protein exPression, and P-Cadherin Positive cases had a well or moderately differentiated histology according to the World Health Organization classification, intestinal-tyPe histology by Lauren classification, and an earlier PT class. Furthermore, Patients with P-Cadherin exPressing tumors had a favorable Prognosis by univariate and multivariate survival analyses. In addition, P-Cadherin Protein exPression was found to be significantly correlated with Promoter hyPomethylation. In summary, P-Cadherin is silenced in nonneoPlastic gastric mucosa, and P-Cadherin exPressing tumors constitute a subset of gastric carcinoma with intestinal-tyPe histology and a favorable Prognosis. In addition, our findings suggest that P-Cadherin Promoter methylation underlies the regulation of its exPression. These findings may aid Patient selection and the interPretation of P-Cadherin targeted theraPy and clinical trial results.
Richard Bauer - One of the best experts on this subject based on the ideXlab platform.
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downregulation of P Cadherin exPression in hePatocellular carcinoma induces tumorigenicity
International Journal of Clinical and Experimental Pathology, 2014Co-Authors: Richard Bauer, D Valletta, Karin Bauer, Wolfgang E Thasler, Arndt Hartmann, Martina Muller, Torsten E Reichert, C HellerbrandAbstract:P-Cadherin is a major contributor to cell-cell adhesion in ePithelial tissues, Playing Pivotal roles in imPortant morPhogenetic and differentiation Processes and in maintaining tissue integrity and homeostasis. Alterations of P-Cadherin exPression have been observed during the Progression of several carcinomas where it aPPears to act as tumor suPPressive or oncogenic in a context-dePendent manner. Here, we found a significant downregulation of P-Cadherin in hePatocellular carcinoma (HCC) cell lines and tissues comPared to Primary human hePatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched Pairs of HCC tissue and corresPonding non-tumorous liver tissue of 69 Patients confirmed reduced P-Cadherin exPression in more than half of the cases. In 35 human HCC tissues, the P-Cadherin immunosignal was comPletely lost which correlated with tumor staging and Proliferation. Also in vitro, P-Cadherin suPPression in HCC cells via siRNA induced Proliferation comPared to cells transfected with control-siRNA. In summary, downregulation of P-Cadherin exPression aPPears to induce tumorigenicity in HCC. Therefore, P-Cadherin exPression may serve as a Prognostic marker and theraPeutic target of this highly aggressive tumor.
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P Cadherin induces an ePithelial like PhenotyPe in oral squamous cell carcinoma by gsk 3beta mediated snail PhosPhorylation
Carcinogenesis, 2009Co-Authors: Karin Bauer, Anjakatrin Bosserhoff, Albert Dowejko, T E Reichert, Richard BauerAbstract:: Cadherins belong to a family of Ca(2+)-dePendent homoPhilic cell-cell adhesion Proteins that are imPortant for correct cellular localization and tissue integrity. They Play a major role in the develoPment and homeostasis of ePithelial architecture. Recently, it has become more and more evident that P-Cadherin contributes to the oncogenesis of many tumors. To analyze the role of P-Cadherin in oral squamous cell carcinoma (OSCC), we used a cell line that was deficient of the classical Cadherins, P-Cadherin, E-Cadherin and N-Cadherin. This cell line was transfected with full-length P-Cadherin (PCI52_PC). After overexPression of P-Cadherin, PCI52_PC gained an ePithelial-like brickstone morPhology in contrast to the mock-transfected cells with a sPindle-shaPed mesenchymal morPhology. Immunohistochemical analysis revealed a strong nuclear Snail staining in mock-transfected cells comPared with a significantly reduced nuclear staining and translocation to the cytoPlasm in P-Cadherin-overexPressing cells. Interestingly, the effects triggered by P-Cadherin overexPression could be reversed by transfecting the cells with an antisense P-Cadherin Plasmid construct. Additional investigations showed a reexPression of E-Cadherin in all P-Cadherin-transfected cell clones in contrast to the mock controls. Analyzing the signaling mechanism behind it, we found glycogen-synthase-kinase-3beta (GSK-3beta) bound to Snail in all cell clones. Furthermore, P-Cadherin-overexPressing cell lines showed activated GSK-3beta that PhosPhorylated Snail leading to its cytoPlasmic translocation. In summary, our results reveal P-Cadherin as one major comPonent in reconfiguring mesenchymal cells with ePithelial features by triggering GSK-3beta-mediated inactivation and cytoPlasmatic translocation of Snail in OSCC.
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Truncated P‐Cadherin is Produced in oral squamous cell carcinoma
FEBS Journal, 2008Co-Authors: Richard Bauer, Anjakatrin Bosserhoff, Albert Dowejko, Oliver Driemel, Torsten E ReichertAbstract:Cadherins belong to a family of homoPhilic cell–cell adhesion Proteins that are resPonsible for the establishment of a Precise cell architecture and tissue integrity. Moreover, exPerimental data suggest that loss of intercellular adhesion is inversely correlated with cellular differentiation. Furthermore, dedifferentiation is closely linked to tumor Progression. Recently, we have shown that a secreted 50 kDa N-terminal fragment of P-Cadherin Plays a role in the Progression of malignant melanoma. In this study, we have detected both the full-length and the truncated versions of P-Cadherin in cell lysates of differentiated head and neck oral squamous cell carcinoma cell lines, whereas in cell lysates of dedifferentiated cell lines, we detected only the truncated 50 kDa version of P-Cadherin. Treatment of the cell lines with a recombinantly exPressed biotinylated, soluble 50 kDa form of the N-terminal Part of P-Cadherin revealed a major effect on cell aggregation and migration of oral squamous cell carcinoma cells. However, the 50 kDa N-terminal fragment of P-Cadherin did not show any influence on cell Proliferation in 2D and 3D cell culture. These results suggest that generation of truncated P-Cadherin during the Progression of oral squamous carcinoma attenuates tissue integrity, facilitates cellular seParation, and leads to the acquisition of a more migratory PhenotyPe.
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functional imPlication of truncated P Cadherin exPression in malignant melanoma
Experimental and Molecular Pathology, 2006Co-Authors: Richard Bauer, Anjakatrin BosserhoffAbstract:Abstract Cadherins comPrise Ca 2+ -dePendent homoPhilic cell–cell adhesion molecules which are resPonsible for correct location of cells and for tissue integrity. They are crucial factors for the develoPment and maintenance of ePithelial architecture. Aberrantly exPressed Cadherins are known to be involved in malignant transformation of different tyPes of tissues. In a Previous study, we determined the exPression of a short truncated 50 kDa form of P-Cadherin only consisting of the N-terminal Part in malignant melanoma. Further analysis revealed that this short 50 kDa form of P-Cadherin rePresenting the N-terminal, extracellular region, is secreted by melanoma cells in contrast to the membrane bound form in melanocytes. In order to define the functional relevance of exPression of the 50 kDa P-Cadherin variant in malignant melanoma, antisense P-Cadherin cell clones were generated. The clones in which P-Cadherin exPression is reduced show no changes in Proliferation or in attachment-indePendent growth when comPared to controls. However, a strong reduction of migratory and invasive ProPerties was observed in these cells, suggesting that truncated P-Cadherin Promotes melanoma cell invasion and migration and therefore has an imPortant role in the Progression of malignant melanoma. Functionally, the secreted form of P-Cadherin could Play a role as regulator of the homoPhilic interaction between P-Cadherin molecules by antagonizing their biological role acting as a dominant negative form to interruPt cell–cell attachment.
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Prognostic relevance of P-Cadherin exPression in melanocytic skin tumours analysed by high-throughPut tissue microarrays.
Journal of Clinical Pathology, 2006Co-Authors: Richard Bauer, Peter J. Wild, Stefanie Meyer, Frauke Bataille, Armin Pauer, Monika Klinkhammer-schalke, Ferdinand Hofstaedter, Anjakatrin BosserhoffAbstract:Aim: To investigate whether Protein exPression or cellular localisation of P-Cadherin is associated with clinicoPathological characteristics in benign and malignant melanocytic skin tumours. ExPerimental design: P-Cadherin exPression and the Ki-67 labelling index were analysed immunohistochemically by using tissue microarrays (TMAs). Membranous and cytoPlasmic exPression was scored semiquantitatively (0 to 2+). Results: P-Cadherin Protein exPression of any intensity (1+ to 2+) was detected in the membrane in 41.5% (132/318) and in the cytoPlasm in 64.2% (204/318) of Patients. In general, P-Cadherin exPression was significantly reduced in malignant melanomas (P Conclusions: Loss of cytoPlasmic P-Cadherin exPression is common in advanced melanomas and can be a Prognostic marker of Progression in Patients with melanoma, most useful in Patients with Primary tumours
