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  • 1
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    Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-11-06
    Description: The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-alpha (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-gamma and tumor necrosis factor-alpha. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kraman, Matthew -- Bambrough, Paul J -- Arnold, James N -- Roberts, Edward W -- Magiera, Lukasz -- Jones, James O -- Gopinathan, Aarthi -- Tuveson, David A -- Fearon, Douglas T -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2010 Nov 5;330(6005):827-30. doi: 10.1126/science.1195300.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21051638" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Neoplasm/immunology ; Cancer Vaccines/administration & dosage/immunology ; Carcinoma, Lewis Lung/*immunology/pathology/therapy ; Carcinoma, Pancreatic Ductal/*immunology/pathology ; Cell Hypoxia ; Cell Line, Tumor ; Cell Survival ; Gelatinases/*metabolism ; *Immune Tolerance ; Interferon-gamma/immunology/metabolism ; Membrane Proteins/*metabolism ; Mice ; Mice, Transgenic ; Necrosis ; Neoplasm Transplantation ; Serine Endopeptidases/*metabolism ; Stromal Cells/*immunology/metabolism ; Tumor Microenvironment/*immunology ; Tumor Necrosis Factor-alpha/immunology/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-07-08
    Description: Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404470/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404470/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeNicola, Gina M -- Karreth, Florian A -- Humpton, Timothy J -- Gopinathan, Aarthi -- Wei, Cong -- Frese, Kristopher -- Mangal, Dipti -- Yu, Kenneth H -- Yeo, Charles J -- Calhoun, Eric S -- Scrimieri, Francesca -- Winter, Jordan M -- Hruban, Ralph H -- Iacobuzio-Donahue, Christine -- Kern, Scott E -- Blair, Ian A -- Tuveson, David A -- CA084291/CA/NCI NIH HHS/ -- CA101973/CA/NCI NIH HHS/ -- CA105490/CA/NCI NIH HHS/ -- CA106610/CA/NCI NIH HHS/ -- CA111294/CA/NCI NIH HHS/ -- CA128920/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- R01 CA101973/CA/NCI NIH HHS/ -- R01 CA101973-05/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Jul 6;475(7354):106-9. doi: 10.1038/nature10189.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Li Ka Shing Centre, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21734707" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Alleles ; Animals ; Antioxidants/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics/*metabolism/*pathology ; Cells, Cultured ; Cytoskeletal Proteins/genetics/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibroblasts/metabolism ; Genes, myc/genetics ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; NF-E2-Related Factor 2/deficiency/genetics/*metabolism ; NIH 3T3 Cells ; Oncogenes/*genetics ; Oxidation-Reduction ; Pancreatic Neoplasms/genetics/*metabolism/*pathology ; Proto-Oncogene Proteins B-raf/genetics/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Reactive Oxygen Species/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-05-23
    Description: Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998180/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998180/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Olive, Kenneth P -- Jacobetz, Michael A -- Davidson, Christian J -- Gopinathan, Aarthi -- McIntyre, Dominick -- Honess, Davina -- Madhu, Basetti -- Goldgraben, Mae A -- Caldwell, Meredith E -- Allard, David -- Frese, Kristopher K -- Denicola, Gina -- Feig, Christine -- Combs, Chelsea -- Winter, Stephen P -- Ireland-Zecchini, Heather -- Reichelt, Stefanie -- Howat, William J -- Chang, Alex -- Dhara, Mousumi -- Wang, Lifu -- Ruckert, Felix -- Grutzmann, Robert -- Pilarsky, Christian -- Izeradjene, Kamel -- Hingorani, Sunil R -- Huang, Pearl -- Davies, Susan E -- Plunkett, William -- Egorin, Merrill -- Hruban, Ralph H -- Whitebread, Nigel -- McGovern, Karen -- Adams, Julian -- Iacobuzio-Donahue, Christine -- Griffiths, John -- Tuveson, David A -- CA084291/CA/NCI NIH HHS/ -- CA101973/CA/NCI NIH HHS/ -- CA105490/CA/NCI NIH HHS/ -- CA111292/CA/NCI NIH HHS/ -- CA114028/CA/NCI NIH HHS/ -- CA15704/CA/NCI NIH HHS/ -- F32 CA123939/CA/NCI NIH HHS/ -- F32 CA123939-03X1/CA/NCI NIH HHS/ -- F32CA123887-01/CA/NCI NIH HHS/ -- F32CA123939-02/CA/NCI NIH HHS/ -- K08 CA106610/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2009 Jun 12;324(5933):1457-61. doi: 10.1126/science.1171362. Epub 2009 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19460966" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*administration & dosage/metabolism/therapeutic use ; *Antineoplastic Combined Chemotherapy Protocols ; Apoptosis/drug effects ; Carcinoma, Pancreatic Ductal/blood supply/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Deoxycytidine/administration & dosage/*analogs & ; derivatives/metabolism/therapeutic use ; Disease Models, Animal ; Drug Resistance, Neoplasm ; Hedgehog Proteins/antagonists & inhibitors/*metabolism ; Humans ; Kruppel-Like Transcription Factors/metabolism ; Mice ; Neoplasm Transplantation ; Neovascularization, Pathologic ; Pancreatic Neoplasms/blood supply/*drug therapy/metabolism/pathology ; Receptors, G-Protein-Coupled/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Stromal Cells/drug effects/pathology ; Veratrum Alkaloids/*administration & dosage/pharmacokinetics/therapeutic use
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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