The Experts below are selected from a list of 12987 Experts worldwide ranked by ideXlab platform
David Malkin - One of the best experts on this subject based on the ideXlab platform.
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cisplatin treatment increases survival and expansion of a highly tumorigenic side population fraction by upregulating vegf flt1 Autocrine Signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-tumorigenic osteosarcoma SP fraction to a highly tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 Signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 Autocrine Signaling leads to the survival and expansion of a highly tumorigenic SP fraction.
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Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 Autocrine Signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-tumorigenic osteosarcoma SP fraction to a highly tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 Signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 Autocrine Signaling leads to the survival and expansion of a highly tumorigenic SP fraction.
Mahitosh Mandal - One of the best experts on this subject based on the ideXlab platform.
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Abstract P6-01-02: Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 Autocrine Signaling
Poster Session Abstracts, 2013Co-Authors: Mahitosh Mandal, Bn Prasanth KumarAbstract:Background Tamoxifen (TAM) is widely used in the chemotherapy of breast cancer and as a preventive agent against recurrence after surgery. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. Celecoxib (CXB), a selective COX-2 inhibitor, suppresses VEGF gene expression by targeting the VEGF promoter responsible for its inhibitory effect. For this study, we had selected CXB as non-steroidal anti-inflammatory drug in combination with TAM for suppressing VEGF expression and simultaneously reducing doses of both the drugs. Methods The effects of CXB combined with TAM were examined in two human breast cancer cell lines in culture, MCF7 and MDA-MB-231. Assays of proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, and receptor Signaling were performed. Results Here, we elucidated how the combination of TAM and the selective COX-2 inhibitor, celecoxib (CXB) at nontoxic doses exerts anti-angiogenic effects by specifically targeting VEGF/VEGFR2 Autocrine Signaling through ROS generation. At the molecular level, TAM-CXB suppresses VHL-mediated HIF-1a activation, responsible for expression of COX-2, MMP-2 and VEGF. Besides low VEGF levels, TAM-CXB also suppresses VEGFR2 expression, confirmed through quantifying secreted VEGF levels, luciferase and RT-PCR studies. Interestingly, we observed that TAM-CXB was effective in blocking VEGFR2 promoter induced expression and further 2 fold decrease in VEGF levels was observed in combination than TAM alone in both cell lines. Secondly, TAM-CXB regulated VEGFR2 inhibits Src expression, responsible for tumor progression and metastasis. FACS and in vivo enzymatic studies showed significant increase in the reactive oxygen species upon TAM-CXB treatment. Conclusions Taken together, our experimental results indicate that this additive combination shows promising outcome in anti-metastatic and apoptotic studies. In a line, our preclinical studies evidenced that this additive combination of TAM and CXB is a potential drug candidate treatment for breast tumors expressing high levels of VEGF and VEGFR2. This ingenious combination might be a better tailored clinical regimen than TAM alone for breast cancer treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-01-02.
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celecoxib alleviates tamoxifen instigated angiogenic effects by ros dependent vegf vegfr2 Autocrine Signaling
BMC Cancer, 2013Co-Authors: B Prashanth N Kumar, Shashi Rajput, Kaushik Kumar Dey, Aditya Parekh, Subhasis Das, Abhijit Mazumdar, Mahitosh MandalAbstract:Background Tamoxifen (TAM) is widely used in the chemotherapy of breast cancer and as a preventive agent against recurrence after surgery. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. Celecoxib (CXB), a selective COX-2 inhibitor, suppresses VEGF gene expression by targeting the VEGF promoter responsible for its inhibitory effect. For this study, we had selected CXB as non-steroidal anti-inflammatory drug in combination with TAM for suppressing VEGF expression and simultaneously reducing doses of both the drugs.
Rika Tsuchida - One of the best experts on this subject based on the ideXlab platform.
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cisplatin treatment increases survival and expansion of a highly tumorigenic side population fraction by upregulating vegf flt1 Autocrine Signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-tumorigenic osteosarcoma SP fraction to a highly tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 Signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 Autocrine Signaling leads to the survival and expansion of a highly tumorigenic SP fraction.
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Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 Autocrine Signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-tumorigenic osteosarcoma SP fraction to a highly tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 Signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 Autocrine Signaling leads to the survival and expansion of a highly tumorigenic SP fraction.
Andrea L. Richardson - One of the best experts on this subject based on the ideXlab platform.
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Paracrine and Autocrine signals induce and maintain mesenchymal and stem cell states in the breast.
Cell, 2011Co-Authors: Christina Scheel, Elinor Ng Eaton, Ferenc Reinhardt, Christine L. Chaffer, Kong-jie Kah, George W. Bell, Wenjun Guo, Jeffrey S. Rubin, Andrea L. RichardsonAbstract:The epithelial-mesenchymal transition (EMT) has been associated with the acquisition of motility, invasiveness, and self-renewal traits. During both normal development and tumor pathogenesis, this change in cell phenotype is induced by contextual signals that epithelial cells receive from their microenvironment. The signals that are responsible for inducing an EMT and maintaining the resulting cellular state have been unclear. We describe three Signaling pathways, involving transforming growth factor (TGF)-β and canonical and noncanonical Wnt Signaling, that collaborate to induce activation of the EMT program and thereafter function in an Autocrine fashion to maintain the resulting mesenchymal state. Downregulation of endogenously synthesized inhibitors of Autocrine signals in epithelial cells enables the induction of the EMT program. Conversely, disruption of Autocrine Signaling by added inhibitors of these pathways inhibits migration and self-renewal in primary mammary epithelial cells and reduces tumorigenicity and metastasis by their transformed derivatives.
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Abstract LB-108: Formation and maintenance of mesenchymal and stem-cell states in the breast by paracrine and Autocrine signals
Tumor Biology, 2011Co-Authors: Christina Scheel, Ferenc Reinhardt, Elinor Ng-eaton, Christine L. Chaffer, Kong-jie Kah, George W. Bell, Wenjun Guo, Jeffrey S. Rubin, Andrea L. RichardsonAbstract:Passage through an epithelial-mesenchymal transition (EMT) is associated with the acquisition of migratory and self-renewal abilities in human mammary epithelial cells (MECs). The Signaling mechanisms that induce and then maintain these properties have remained unclear. We describe three Signaling pathways, involving Transforming Growth Factor (TGF)-beta as well as canonical and non-canonical Wnt Signaling, that collaborate to induce epithelial MECs to enter into a mesenchymal and SC-like state. Acting as Autocrine Signaling loops, these pathways then maintain migratory and self-renewal abilities in normal MECs and control tumorigenicity and metastasis in their transformed derivatives. Autocrine Signaling is enabled, at least in part, through downregulation of secreted Wnt antagonists and Bone Morphogenetic Proteins. Like immortalized and transformed MECs, the maintenance of migratory and self-renewal abilities in primary human MECs is dependent on these Autocrine loops, suggesting that similar mechanisms regulate biological properties of normal tissue stem cells and tumor-initiating cells in the breast Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-108. doi:10.1158/1538-7445.AM2011-LB-108
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Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) Signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Yasushi Kojima, Christina Scheel, Elinor Ng Eaton, Ahmet Acar, Kieran T. Mellody, Ittai Ben-porath, Tamer T. Onder, Zhigang C. Wang, Andrea L. Richardson, Robert A. WeinbergAbstract:Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two Autocrine Signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These Autocrine-Signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 Autocrine Signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This Autocrine-Signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs.
Beat M. Jucker - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of FGF/FGFR Autocrine Signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230
Oncotarget, 2016Co-Authors: Christina Blackwell, Christian S. Sherk, Maggie Fricko, Gopinath Ganji, Mary S. Barnette, Bao Hoang, James Tunstead, Tina Skedzielewski, Hasan Alsaid, Beat M. JuckerAbstract:// Christina Blackwell 1, * , Christian Sherk 1, * , Maggie Fricko 1, * , Gopinath Ganji 1 , Mary Barnette 1 , Bao Hoang 2 , James Tunstead 2 , Tina Skedzielewski 2 , Hasan Alsaid 2 , Beat M. Jucker 2 , Elisabeth Minthorn 1 , Rakesh Kumar 1 , M. Phillip DeYoung 1 1 Oncology R&D, GlaxoSmithKline Research and Development, Collegeville, PA 19426, USA 2 Platform Technology and Science, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA * These authors have contributed equally to this work Correspondence to: M. Phillip DeYoung, email: maurice.p.deyoung@gsk.com Keywords: fibroblast growth factor, ligand trap, mesothelioma, Signaling, angiogenesis Received: December 15, 2015 Accepted: May 01, 2016 Published: May 20, 2016 ABSTRACT Fibroblast growth factor (FGF) ligand-dependent Signaling has a fundamental role in cancer development and tumor maintenance. GSK3052230 (also known as FP-1039) is a soluble decoy receptor that sequesters FGFs and inhibits FGFR Signaling. Herein, the efficacy of this molecule was tested in models of mesothelioma, a tumor type shown to express high levels of FGF2 and FGFR1. GSK3052230 demonstrated antiproliferative activity across a panel of mesothelioma cell lines and inhibited growth of tumor xenografts in mice. High expression of FGF2 and FGFR1 correlated well with response to FGF pathway inhibition. GSK3052230 inhibited MAPK Signaling as evidenced by decreased phospho-ERK and phospho-S6 levels in vitro and in vivo . Additionally, dose-dependent and statistically-significant reductions in tumor vessel density were observed in GSK3052230-treated tumors compared to vehicle-treated tumors. These data support the role of GSK3052230 in effectively targeting FGF-FGFR Autocrine Signaling in mesothelioma, demonstrate its impact on tumor growth and angiogenesis, and provide a rationale for the current clinical evaluation of this molecule in mesothelioma patients.
